Q4 2022 Exelixis Inc Earnings Call

February 17, 2022

Okay.

Yeah.

Good day, ladies and gentlemen, and welcome to the <unk> fourth.

Good day, ladies and gentlemen, and welcome to the Exelixis fourth quarter and four year 2021 financial results conference call.

Fourth quarter and full year 2021 financial results conference call My.

My name is Tawanda and I will be your operator for today.

Thank you for your participation.

My name is to Wanda and I will be your operator for today.

As a reminder, this call is being recorded for replay.

As a reminder, this call is being recorded for replay purposes, I would now like to turn the call over to your host for today Ms. Susan Hubbard Executive Vice President of Public Affairs, and Investor Relations you may begin.

I would now like to turn the call over to your host for today, Ms. Susan Hubbard, Executive Vice President of Public Affairs and Investor Relations.

Good day, ladies and gentlemen, and welcome to the Exelixis fourth quarter and four year 2021 Financial Results Conference call.

You may begin.

Thank you to Rhonda and thank you all for joining us for the <unk> fourth quarter 2021, and full year 2021 financial results Conference call.

Thank you Tawanda and thank you all for joining us for the Exelixis fourth quarter 2021 and full year 2021 financial results conference call.

My name is Tawanda and I will be your operator for today.

Joining me on today's call are Mike Morrissey, our president and CEO, Chris Senner, our chief financial officer, PJ Haley, our executive vice president of commercial, Vicki Goodman, our chief medical officer, and Peter Lamb, our chief scientific officer, who will together review our progress for the fourth quarter 2021 and December 31, 2021.

As a reminder, this call is being recorded for replay.

With me on today's call are Mike Morrissey, our president and CEO , Chris Senner, Our Chief Financial Officer P. J Haley, our executive Vice President of commercial banking Goodman, our Chief Medical Officer, and Peter Lamb, Our Chief Scientific Officer, who will together review our progress for the fourth quarter 2021 ended December 31 two.

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During the call today, we will refer to financial measures not calculated according to generally accepted accounting principles. Please refer to today's press release, which is posted on our website, for an explanation of our reasons for using such non-GAAP measures, as well as tables deriving these measures from our GAAP results.

During the call today, we will refer to financial measures not calculated according to general generally accepted accounting principles. Please refer to today's press release, which is posted on our website for an explanation of our reasons for using such non-GAAP measures as well as tables deriving these measures from our GAAP results.

During the course of this presentation, we will be making forward-looking statements regarding future events and the future performance of the company. This includes statements about possible developments regarding discovery, product development, regulatory, commercial, financial, and strategic matters. Actual events or results could, of course, differ materially. We refer you to the documents we file from time to time with the FTC, which under the heading risk factors, identify important factors that could cause actual results to differ materially from those expressed by the company verbally and in writing today, including without limitation, risks and uncertainties related to product commercial success, market competition, regulatory review and approval processes, conducting clinical trials, compliance with applicable regulatory requirements, our dependence on collaboration partners, and the level of cost associated with discovery, product development, business development, and commercialization.

I would now like to turn the call over to your host for today, Ms. Susan Hubbard, Executive Vice President of Public Affairs and Investor Relations.

During the course of this presentation and we will be making forward looking statements regarding future events and the future performance of the company. This includes statements about possible developments regarding discovery product development regulatory commercial financial and strategic matters actual events or results could of course differ materially we refer you to the documents we file from time to.

You may begin.

Time, with the SEC, which under the heading risk factors identify important factors that could cause actual results to differ materially from those expressed by the company verbally and in writing today, including without limitation risks and uncertainties related to product commercial success market competition regulatory review and approval processes conducting clinical.

Trials compliance with applicable regulatory requirements, our dependence on collaboration partners and the level of costs associated with discovery product development business development and commercialization activities and with that I will turn the call over to Mike Alright. Thank you Susan and thanks to everyone for joining us on the call today <unk> had a strong fourth.

And with that, I will turn the call over to Mike.

All right, thank you, Susan.

And thanks to everyone for joining us on the call today.

Thank you, Tawanda, and thank you all for joining us for the Exelixis fourth quarter 2021 and full year 2021 financial results conference call.

Exelixis had a strong fourth quarter and full year 2021 across all components of our enterprise as we continue to grow the Cobbless Antidote business and advance a diversified and growing pipeline of clinical and discovery programs.

Joining me on today's call are Mike Morrissey, our President and CEO, Chris Senner, our Chief Financial Officer, PJ Haley, our Executive Vice President of Commercial, Vicki Goodman, our Chief Medical Officer, and Peter Lamb, our Chief Scientific Officer, who will together review our progress for the fourth quarter 2021 ended December 31, 2021.

<unk> full year 2021 across all components of our enterprise as we continue to grow as accomplished entity business and advance a diversified and growing pipeline of clinical and discovery programs.

We'll keep our prepared remarks short today as we recently gave a detailed update to start 2022 at the J.P. Morgan Health Care Conference in January.

We'll keep our prepared remarks short today as we recently gave a detailed update to start the 2000 to start 2022 at the Jpmorgan Healthcare conference in January .

Key topics we'll focus on today include, first, the Chabot Medics business continues to grow and fuel the investment in advancing our portfolio of next generation therapies for oncology. Chabot Medics maintained its status as the leading TKI for RCC and surpassed the billion-dollar net product revenue threshold in the U.S. in 2021 with a 45% year-over-year growth compared to 2020.

Key topics, we will focus on to include first the carbon X business continues to grow and fuel the investments in advancing our portfolio of next generation therapies for oncology.

<unk> maintained its status as the leading PKI for RCC and surpassed the $1 billion net product revenue thresholds in the U S. In 2021, with a 45% year over year growth compared to 2020.

Second, we expect our development team, now led by Vicki Goodman, to grow in size, scope, and stature in 2022 and beyond with the build out of Exelixis East, complementing our extensive development breadth and depth in Alameda.

Second we expect our development team now led by Vicky Goodman to grow in size scope and stature in 2022 and beyond with the build out of <unk> East complementing our extensive development breadth and depth in Alameda.

2022 could be a year of significant portfolio growth with a focus on expanding potential indications for Cabo with numerous expected top-line results and advancing our important pipeline molecules XL092, XB002, and XL102.

2022 could be a year of significant portfolio growth with a focus on expanding potential indications for cabo with numerous expected topline results and advancing our important pipeline molecules XL <unk>, XP, <unk> and <unk>, including the initiation of the pivotal trial program for <unk>.

Including the initiation of the Pivotal Trial Program for Excel 09.

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Third and finally, our drug discovery network of internal and collaborative efforts across both small molecule and biologic platforms continues to advance at a rapid pace with the selection of up to five new development candidates expected in 2020.

Business development activities remain a core component of this strategy.

Business development activities remain a core component of this strategy, we expect to bring additional collaborations forward, including the potential preclinical assets, where we have increased conviction for both a clinical and commercial perspective.

We expect to bring additional collaborations forward, including the potential for clinical assets, where we have increased conviction from both a clinical and commercial perspective.

With that, please see our press release issued an hour ago for our fourth quarter financial results and an extensive list of key corporate milestones achieved in the quarter.

With that please see our press release issued an hour ago for our fourth quarter financial results and an extensive list of key corporate milestones achieved in the quarter.

I'll now turn the call over to Chris, who will review our fourth quarter and full year 2021 financial results.

And with that, I will turn the call over to Mike.

Now I'll turn the call over to Chris who will review, our fourth quarter and full year 2021 financial results, Chris Thanks, Mike for the fourth quarter of 2021. The company reported total revenues of $451 1 billion.

Chris?

All right, thank you, Susan.

Which included Cabozantinib franchise, net product revenues of $302 $7 million.

<unk> net product revenues were $295 1 million, which included approximately $8 million in clinical trial sales.

Our trade inventory weeks on hand remained relatively flat when compared to the third quarter of 2021.

Total revenues also include $148 5 million in collaboration revenues, primarily from Ipsen, Takeda and Genentech.

In the fourth quarter of 2021, <unk> recorded a $100 million milestone payment due from ipsen in connection with the achievement of $400 million in net sales and its related license territory over four consecutive quarters.

Our total operating expenses for the fourth quarter, 2021 were $334 $5 million compared to $276 $8 million in the third quarter of 2021.

R&D expense was the primary driver of the increase in total operating expenses, which was primarily related to higher license fee expenses.

Provision for income taxes for the fourth quarter of 2021 was.

It was $22 9 million compared to $15 1 million for the third quarter of 2021.

The company reported GAAP net income of $95 2 million or <unk> 29 per share on a fully diluted basis for the fourth quarter of 2021.

Company also reported non-GAAP net income of $113 3 million or <unk> 35 per share on a fully diluted basis non-GAAP net income excludes the impact of approximately $18 2 million of stock based compensation expense net of the related income tax effect.

Cash and investments for the quarter ended December 31, 2021 was approximately $1 9 billion.

Turning to our full year 2022 financial guidance.

Which was previewed at the JP Morgan Conference in January we are now, including total revenues guidance, which is expected to be in the range of 1525 and $1 65 billion.

The remaining full year 'twenty to 2022 financial guidance items can be found on slide 12.

And thanks to everyone for joining us on the call today.

With that I'll turn the call over to P. J. Thank you, Chris 2021 was a transformative year for the Cabozantinib franchise, primarily driven by the approval of <unk> in combination with <unk> in first line RCC in January of 2021.

We'll keep our prepared remarks short today as we recently gave a detailed update to start 2022 at the J.P. Morgan Health Care Conference in January.

Thanks, Mike.

Key topics we'll focus on today include, first, the chiropractic medicine business continues to grow and fuel the investment in advancing our portfolio of next-generation therapies for oncology.

For the fourth quarter 2021, the company reported total revenues of $451.1 million, which included comprehensive franchise net product revenues of $302.7 million. Problematics net product revenues were $295.1 million, which included approximately $8 million in clinical trials.

Chiropractic medicine maintained its status as the leading TKI for RCC and surpassed the billion-dollar net product revenue threshold in the U.S. in 2021 with a 45% year-over-year growth compared to 2020.

<unk> reached a significant milestone in 2021, surpassing $1 billion of U S net product revenue.

Our trade inventory, weeks on hand, remained relatively flat when compared to the third quarter of 2020.

Total revenues also included $148.5 million in collaboration revenues, primarily from Ipsen, Takeda, and Genentech. In the fourth quarter of 2021, Exelixis recorded a $100 million milestone payment due from Ipsen in connection with the achievement of $400 million in net sales in its related licensed territory over four consecutive quarters.

Team continues to execute at a high level and this has resulted in <unk>, becoming the number one prescribed <unk> in RCC.

Furthermore, <unk> total prescriptions or <unk> has now grown for five consecutive quarters.

Additionally, the launch of <unk> and differentiated thyroid cancer, DTC, which received FDA approval in September is off to a strong start.

Taken together the strength of the business and the momentum of 2021 positions <unk> well for growth in 2022.

Prescription trends remain strong in Q4, both for <unk> and Trs <unk>.

Year over year growth in Q4 was 40% for <unk> and 50% for Trs.

As the launch progresses the success of <unk> in combination with Diebold Mab is changing the mix of patients on <unk> in RCC.

Given the clinical data from the Checkmate <unk> study we anticipate.

These first line combination patients to receive therapy for approximately one and a half years or more.

Thus driving a significantly longer treatment duration for Cabo medics.

We are encouraged by the fact that in our data we see a doubling of the amount of new patient starts at the 40 milligram dose in 2021 relative to 2020.

This is further indication that the combination uptake in the first line setting is robust.

Turning to the <unk> market basket of Cabo medics, and lighter Sutent votary BMO.

Cabo medics Trs market share increased every quarter in 2021.

With market share in the fourth quarter, reaching 35%.

This growth is driven by combination usage in the first line RCC setting.

As we have discussed previously the first line RCC market is very competitive and we're pleased with the performance of <unk> in combination with <unk> in this setting.

Furthermore, we haven't seen significant competitive impact on our market share.

Uptake in the first line is broad across clinical risk groups and practice settings and prescriber experience to date has been positive.

We believe all of this taken together with the momentum in the business positions <unk> for continued growth in 2022.

Turning to other settings, we're pleased that the Cabo second line RCC business remained strong and was stable in Q4.

In HCC, our market share was stable in Q4, and <unk> continues to be the most prescribed <unk> in the second line setting for patients treated with immunotherapy in the first line.

With regards to second line DTC.

We are pleased with the launch and in Q4, we saw a strong trend of new patient starts in this indication which exceeded our expectations.

They were previously no therapies approved for this patient population with significant unmet medical need and we believe we are quickly becoming a standard of care in this setting.

We are proud that this fifth indication for <unk> adds to the body of data in the label and enables <unk> to help more patients with severe cancer.

Looking beyond the five current U S indications for Cabozantinib, we're planning for the numerous lifecycle expansion opportunities as they begin to have top line data readouts in 2022.

We look forward to having the opportunity pending data and approval to bring <unk> to more patients in need of therapies.

Our team remains highly focused and motivated to compete every day to bring the benefit of <unk> to all eligible patients as we continue to build the franchise and maximize potential and with that I'll turn the call over to Vicki.

Thanks P J.

Our total operating expenses for the fourth quarter 2021 were $334.5 million compared to $276.8 million in the third quarter. R&D expense was the primary driver of the increase in total operating expenses, which was primarily related to higher licensing expenses.

Good afternoon, it's great to be here today, now a month and a half after I joined <unk> as Chief Medical Officer.

Provision for income taxes for the fourth quarter 2021, with $22.9 million compared to $15.1 million for the third quarter of 2020.

I'd like to take a moment to introduce myself.

In the medical oncologists and Hematologists with nearly 18 years of experience in oncology drug development, both in government at the food and drug administration and subsequently in industry.

Prior to joining <unk> in early January I spent 15 years in roles with increasing responsibility at.

The company reported a gap in net income of $95.2 million, or 29 cents per share, on a fully diluted basis for the fourth quarter of 2021. Company also reported non gap net income of $113.3 million or 35 cents per share on a fully diluted, Non-GAAP net income excludes the impact of approximately $18.2 million of stock-based compensation expense net of the related income tax effect.

Cash and investments for the quarter ended December 31, 2021 was approximately $1.9 billion.

Turning to our full year 2022 financial guidance. Which was previewed at the J.P. Morgan Conference in January, we are now including total revenues guidance, which is expected to be in the range of $1.525 and $1.625 billion.

Three global pharma companies, most recently at Merck, where I was therapeutic area head for late stage oncology.

During my industry career, I have developed both small molecule drugs, including kinase inhibitors.

And biologics, including immuno oncology agents and anti body drug conjugates across all phases of drug development.

IND filings and phase one to designing and implementing Registrational studies, leading to successful first approvals as well as additional major indications.

Today, I will cover our progress towards our organizational expansion to the east coast extra Linksys East.

The remaining full year 2022 financial guidance items can be found on slide 12.

As well as progress on our pipeline and upcoming milestones for 2022.

As we announced in early January we intend to develop a presence on the east coast specifically in the Philadelphia area as we seek to access talent on both coasts to support our expanding development organization.

I'm happy to report that we have now identified short term move in ready office space in King of Prussia, Pennsylvania in the western suburbs of Philadelphia, and a convenient and accessible location for much of the greater Philadelphia and Central New Jersey, Biopharma talent base.

We have also added the king of Prussia location as an option for the majority of open roles within the development and medical Affairs organization and intend to initiate recruitment efforts immediately.

Turning now to an update on our pipeline beginning with our Cabozantinib Registrational trials.

With that, I'll turn the call over to Peter.

2022 could be a year of significant portfolio growth with a focus on expanding potential indications for CABO with numerous expected top-line results and advancing our important pipeline molecules XL092, XB002, and XL102.

Thank you, Chris.

Including the initiation of the Pivotal Trial Program for Excel 09.

We are on track for three phase III Readouts this year.

2021 was a transformative year for the Cabo Zantanab franchise, primarily driven by the approval of Cabo Medics in combination with Novolumab in first line RCC in January of 2021.

Tableau Medics reached a significant milestone in 2021, surpassing $1 billion of US net product revenue.

The team continues to execute at a high level, and this has resulted in Cabo Medics becoming the number one prescribed TKI in RCC. Furthermore, TaboMedx Total Prescriptions, or TRX, have now grown for five consecutive quarters.

Cosmic 313, evaluating cabozantinib in combination with Novo <unk> and at the whim of Nab in intermediate and poor risk renal cell carcinoma is expected in the first half of the year.

An interim primary endpoint readout for contact Juan and readout of the progression free survival primary endpoint for contactless three.

In combination with the cursor lithium mab in PD, one experienced non small cell lung cancer and renal cell carcinoma, respectively are expected in second half of 2022.

Additionally, the final readout for overall survival in cosmic 312, and have hydro cellular carcinoma will it.

Occur later this quarter and we anticipate regulatory filing shortly thereafter if appropriate.

Contact owe to our phase III study in combination with the Tesla lithium mab in metastatic castrate resistant prostate cancer is expected to complete enrollment this year.

We continue to make progress on our pipeline molecules XL <unk> two our next generation met Axel Merck and Veg F. R. Tyrosine kinase inhibitor is being explored in combination with several checkpoint inhibitors and I O combinations.

Additionally, the launch of CaboMedx in Differentiated Thyroid Cancer, or DTC, which received FDA approval in September, is off to a strong start.

And it's progressing towards Registrational studies.

We recently initiated dosing on an Ebola Mab based immuno oncology combination study and genitourinary malignancies.

And continue to explore additional potential combination opportunities with novel agents.

Our first planned phase III in third line microsatellite stable colorectal cancer will be initiated in the second quarter of this year.

Data supporting this study comes from two studies of Cabozantinib in colorectal cancer, which were presented at ESMO Gi in January and demonstrated promising activity in comparison to historical controls <unk>. The current standard of care.

<unk>, our first antibody drug conjugate, which targets tissue factor without interfering with the coagulation pathway in preclinical models is in dose escalation.

Thus far it has been well tolerated with no bleeding events observed.

Our phase one study of XL, one O two our oral CDK <unk> inhibitor is expected to move into both single agent and combination expansion cohorts after completion of ongoing dose escalation and determination of the phase III <unk>.

Finally, XL 114 has an approved IND.

And is currently in study initiation with first site activation expected this quarter.

We expect to present phase one clinical updates for <unk>, two <unk>, two and <unk> 102 at medical conferences in the second half of this year.

I'm excited to be working with the very talented <unk> team as we continue to progress our pipeline. Our current early clinical pipeline as well as ongoing small molecule and biotherapeutic discovery efforts targeting novel mechanisms.

<unk> us well to continue to address areas of unmet need to improve the lives of patients with cancer with that I'll turn it over to Peter for a discovery update.

Thank you Vicky I am pleased to provide a quick overview of the <unk> preclinical pipeline.

Business development activities remain a core component of this strategy.

We expect to bring additional collaborations forward, including the potential for clinical assets, where we have increased conviction from both a clinical and commercial perspective.

With that, please see our press release issued an hour ago for our fourth quarter financial results and an extensive list of key corporate milestones achieved in the quarter.

We have multiple programs ongoing both internally and with our collaborators with over 10 programs in process with the aim of advancing up to five compounds into preclinical development in 2022.

As youll see in the pipeline slide the preclinical pipeline has a balanced mix of small molecules and biotherapeutics, which is reflective of how we see the clinical pipeline evolving in the future.

As we could just commented <unk> 002 is advancing through phase one and we encourage equivalents of preclinical and clinical profile, we've seen to date.

Tissue factor is broadly over expressed in a wide variety of solid tumors and frequently we observe compelling efficacy in multiple pdx models.

The PK data we've obtained so far from the phase one trial will associate with high levels of intact ADC with low levels of free payload, indicating that it is a stable molecule.

Hence, we believe that the underlying antibody as an excellent starting point for ADC development.

The recent deal that we did with iconic allows us to develop additional adcs based on the same antibody and we've started work to link it to additional payloads, particularly DNA damaging payload, which is T counts.

Totally this will allow us to match different tissue factor targeting adcs to different tumor types, depending upon the sensitivity of each tumor type to different MLR is of the payload.

A quick comment about X P. Zero zero. This is almost recent development compound and is our first internally generated ADC because it has been funded through our network of collaborators.

<unk> 010 target to yonker fecal antigen <unk> full which is over expressed in multiple solid tumors, including non small cell lung breast head and neck gastric carcinomas and utilizes Kevalin smart tag site specific conjugation technology and proprietary linker coupled for MMA.

This gives us a homogeneous ADC with a controlled drug antibody ratio and a highly stable linker, which reduces free circulating payload.

Our approach with XP 010 is consistent with the philosophy behind Expedia, referring to which is to advance next generation Adcs, incorporating contemporary ADC technologies directed against well documented targets.

<unk> 010 has now moved into preclinical development and could yield an IMD in 2023.

We are anticipating publishing preclinical data later this year at a major meeting or in a suitable journal and.

And with that I'll turn the call back over to Mike Alright. Thanks, Peter as you heard on the call today, our team continued to execute across all facets of our business in the fourth quarter and full year 2021 with significant progress across our pipeline clinical development and commercial activities as we enter 2022, we're excited about the potential.

Taken together, the strength of the business and the momentum of 2021 positioned Cabo well for growth in 2022.

I'll now turn the call over to Chris, who will review our fourth quarter and full year 2021 financial results.

Prescription trends remain strong in Q4 both for NRX and TRX. Year-over-year growth in Q4 was 40% for NRX and 50% for TRX.

As the launch progresses, the success of CaboMedix in combination with Novolumab is changing the mix of patients on CaboMedix in RCC.

Given the clinical data from the CheckMate 90R study, we anticipate these first-line combination patients to receive therapy for approximately one and a half years or more, thus driving a significantly longer treatment duration for carbometics.

Chris?

For the multiple growth drivers ahead of us to move the business forward and most importantly put <unk> in a position to help many more cancer patients.

We are encouraged by the fact that in our data, we see a doubling of the amount of new patient starts at the 40 milligram dose in 2021 relative to 2020. This is further indication that the combination uptake in the first line setting is robust.

Turning to the TKI market basket of Cabo Medix and Lida, Sutin, Votrient, and Levima.

Thanks, Mike.

Search as I highlighted during my recent J P. M presentation, we have the vision drive growing resources to become a multi product enterprise and to begin to expand our operations to serve cancer patients on a global scale with our planned <unk> East coast presence as the first step in that journey.

We look forward to updating you on our progress in the future. Thank you for your continued support and interest in <unk>, We're happy to now open the call for questions.

Cabo Medics TRX market share increased every quarter in 2021, with market share in the fourth quarter reaching 35%. This growth is driven by combination usage in the first line RCC setting.

For the fourth quarter 2021, the company reported total revenues of $451.1 million, which included comprehensive franchise net product revenues of $302.7 million.

As we have discussed previously, the first line RCC market is very competitive and we are pleased with the performance of Cabo Medix in combination with the Volumath in this setting.

Thank you.

Kalametics net product revenues were $295.1 million, which included approximately $8 million in clinical trials.

Furthermore, we haven't seen significant competitive impact on our market share.

Ladies and gentlemen, as a reminder to ask the question you will need to press Star then one on your telephone.

Uptake in the first line is broad across clinical risk groups and practice settings. The prescriber experience to date has been positive.

We believe all of this taken together with the momentum in the business positions Cabo Medix for continued growth in 2022.

Turning to other settings, we are pleased that the Cabo 2nd line RCC business remains strong and was stable in Q4.

In HCC, our market share was stable in Q4, and Cabo Medix continues to be the most prescribed TKI in the second line setting for patients treated with immunotherapy in the first line.

With regards to second line DTC. We are pleased with the launch, and in Q4, we saw a strong trend of new patient starts in this indication, which exceeded our expectations. There were previously no therapies approved for this patient population with significant unmet medical need.

To withdraw your question press the pound key.

And we believe we are quickly becoming a standard of care in this setting.

We are proud that this fifth indication for Cobomedics adds to the body of data and the label and enables Exelixis to help more patients with severe cancer.

Again, Thats star one to ask a question. Please standby, while we compile the Q&A roster.

Our first question comes from the line of Jason Goldberg with Bank of America. Your line is open.

Looking beyond the five current U.S. indications for Cabozantinib, we're planning for the numerous lifecycle expansion opportunities as they begin to have top-line data readouts in 2022.

Our trade inventory weeks on hand remain relatively flat when compared to the third quarter of 2020.

Hi, Good evening, everyone. This is chi on for Jason Thanks for taking our questions.

We look forward to having the opportunity, pending data and approval, to bring Cabo Medix to more patients in need of therapy.

Our team remains highly focused and motivated to compete every day to bring the benefit of CaboMedx to all eligible patients as we continue to build the franchise and maximize potential.

And with that, I'll turn the call over to, Thanks, PJ.

First question is on cost like you're one of the three.

On the data I expect that first half how should investors think about the level of details from the top line reached out.

Thank God I E. Our topic, we felt pretty good indicator for the level of initial disclosure, except wood pole fight in 313, and then a couple of follow up after that thanks.

Yeah.

Hey, Vic do you want to take that one.

Good afternoon.

Today I will cover our progress towards our organizational expansion to the East Coast, Exelixis East, as well as progress on our pipeline and upcoming milestones for 2022. As we announced in early January, we intend to develop a presence on the East Coast. Specifically in the Philadelphia area, as we seek to access talent on both coasts to support our expanding development organization. I'm happy to report that we have now identified short-term, move-in-ready office space in King of Prussia, Pennsylvania, in the western suburbs of Philadelphia, and a convenient and accessible location for much of the greater Philadelphia and central New Jersey biopharma talent. We have also added the King of Prussia location as an option for the majority of open roles within the development and medical affairs organization, and intend to initiate recruitment efforts immediately.

It's great to be here today, now a month and a half after I joined Exelixis as chief medical officer.

I'd like to take a moment to introduce myself.

Turning now to an update on our pipeline, beginning with our Cabozantinib Registrational Trial.

Sure happy to.

I am a medical oncologist and hematologist with nearly 18 years of experience in oncology drug development, both in government at the Food and Drug Administration and subsequently in industry. Prior to joining Exelixis in early January, I spent 15 years in roles with increasing responsibility at three global pharma companies, most recently at Merck, where I was therapeutic area head for late stage oncology. During my industry career, I have developed both small molecule drugs, including kinase inhibitors, and biologics including immuno-oncology agents and antibody drug conjugates across all phases of drug development. From IND filings in Phase 1 to designing and implementing registrational studies, leading to successful first approvals, as well as additional major indicators.

We are on track for three phase three readouts this year. Cosmic 313, evaluating hebozantinib in combination with nivolumab and ipilimumab in intermediate and poor risk renal cell carcinoma is expected in the first half of the year.

An interim primary endpoint readout for Contact 01 and readout of the progression-free survival primary endpoint for Contact 03, In combination with the tezolizumab in PD-1 experienced non-small cell lung cancer and renal cell carcinoma, respectively, are expected in second half of 2022.

So.

Additionally, the final readout for overall survival in COSMIC-312 in hepatocellular carcinoma will occur later this quarter, and we anticipate regulatory filing shortly thereafter, if appropriate.

I would anticipate that in terms of the top line results in our press release, it will be consistent with our prior practice and then we will hold the full top line report for a medical meeting later this year.

Contact O2, our phase three study, in combination with the tezolizumab in metastatic castrate-resistant prostate cancer, is expected to complete enrollment this year.

We continue to make progress on our pipeline molecule.

Got it.

<unk> on X deal or whats your initial data in second half this year.

No.

The company is highlight safety and bleeding.

Josh a differentiating feature for this drug.

So I'm curious do you believe that data is in the second half.

The initial disclosure will offer sufficient exposure or duration of treatment.

Fully characterized the that that aspect of <unk> profile.

Yes, so we're excited about the opportunity with <unk> in particular.

XL092, our next generation MET, AXL, MER, and VEGFR tyrosine kinase inhibitor, is being explored in combination with several checkpoint inhibitors and IO combinations, and is progressing towards registrational study.

We recently initiated dosing on a nivolumab-based immuno-oncology combination study in genitourinary malignancies, and continue to explore additional potential combination opportunities with novel agents.

<unk> because.

From a preclinical perspective, we've seen that it doesn't get your fear of the binding of tissue factor too.

The coagulation pathway and so we don't believe it will interfere with the with the X transit.

Collect coagulation pathway. We are we remain in dose escalation at this point as I mentioned in my remarks, we have not yet seen any bleeding events and we will plan of course.

Can you disclose the safety profile that we've seen when we presented at a medical meeting later this year.

Got it and just a last one from me.

Curious on the patent litigation with from maybe what's the status on the Catholic case, given the recent litigation stay.

It's a situation where parties are looking to consolidate a new patents and look at what's going on with the MSA in case any color you can put by Dan to the extent you can't that would be helpful.

Yeah, Hey, it's Mike Thanks for the question.

Thank you.

Jason and I'm sure you're in volunteer Kev.

<unk> been tracking.

Court docket pretty closely.

Written on that others have so that's been fun.

To read you guys have covered I think the facts per the dock it pretty well.

Really wanted to avoid opining on what's happening beyond what's in the docket the facts that are.

There for all to see.

We will continue to speak when appropriate.

As more and more information emerges from the court.

Thanks, so much.

Thank you T.

Thank you.

Our first planned phase three and third line microsatellite stable colorectal cancer will be initiated in the second quarter of this year. Data supporting this study comes from two studies of cabozantinib in colorectal cancer, which were presented at ASCO GI in January and demonstrated promising activity in comparison to historical controls of regorafenib, the current standard of care.

Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Hey, guys. Thanks for taking my questions.

One four P chaired wonderful Peter the first one.

Nice to see the <unk> market share among PKI grow could you can you break out at this point what your share is in first line and in second line RCC, respectively.

Yes. This is P J Michael Thanks for the question.

So with regards to that what I'll do is just kind of reiterate what we said previously.

In terms of the second line share starting there we have a.

The majority of share certainly in the post Io setting.

I think we said previously it's around two thirds or so of the patients who received Io therapy in the first line.

Previously and then four.

For our first line market share we haven't disclosed.

Specific numbers recently and Theres certainly some out there that you could you could look at what I would say is we've had significant momentum and as I can.

Kind of mentioned in the prepared remarks, that's really what's been driving our growth.

As the rest of the business has been stable. So as you look at our <unk> market share increasing.

Over the year of 2021 from 30% to 35%.

Essentially almost all being driven by first line uptake. So we're very pleased with that as the.

The messaging and the data are resonating extremely well with oncologists.

<unk> of data.

Data in terms of our overall survival or toxicity profile.

As well as the quality of life data are resonating well with physicians and we're actually really excited.

This weekend here in San Francisco, We've got the <unk> meeting and it is going to be live so.

Really looking forward to.

Our presence, there which will be significant.

Meeting with many many of the Kols in person.

Fantastic.

Honestly haven't had as much opportunity to do that in the pandemic. So we're we're very pleased with our position as I mentioned I think we have really great momentum heading into 2022.

And then yes. Thank you and then I had a question perhaps for Peter.

This one is really around some of the early stage activities specifically around.

The storm Therapeutics collaboration and I was just wondering if you could just comment.

What.

Makes that particular company's technology exciting and.

Any additional insights on.

The first target I would be curious to hear about that thank you.

Yes, absolutely be happy to speak to that.

Generally speaking this doing collaborations fits in with.

Overall approach and philosophy.

With respect to small molecule discovery.

So we have a very significant and growing into it.

Molecule discovery effort.

But we're having to kind of complement that with.

I am sorry partnerships and collaborations as makes sense in terms of providing complementary expertise or insights and still very much fits into that.

The leading target, which took us install is adenosine via M&A.

One.

Let's say if you look at a lot of the publicly available Chris.

CRISPR based tool FH based target discovery, that's been done in oncology over the last couple of years.

One is a target that has come out with a very strong case.

In a number of those screens so.

<unk> included a very hot targets in oncology right now.

That's probably up to about 30% of tumors with so that will probably dependent upon.

Ongoing and $8 one activity.

Help restrained would essentially becomes a interferon mediated cell death.

Some of the basic biology.

Behind this.

It has been on our radar screen for a while is an interesting target.

We're not experts in metal transferred raises per site soon.

<unk> platform is a mental medical trends raise and kind of RNA epigenetics platform.

And they've done a fair amount of work both on their platform generally but also on the 801 specifically.

In terms of putting together the assays necessary to prosecute and effective lead optimization scheme, which business side I will just say a non trivial to put together they.

It also made good progress on kind of enabling and structural biology approach. The target. So you know all of you was it would very much jumpstart program in the area to work with them rather than us trying to rebuild all of that internally.

It's early days for the collaboration we're certainly excited to be to be at Mason I would often running through the <unk>.

Be able to update on progress at some point in the future.

Okay Super interesting. Thank you appreciate it.

Thank you. Thank you next question.

XB002, our first antibody drug conjugate, which targets tissue factor without interfering with the coagulation pathway in preclinical models, is in dose escalation, Thus far it has been well tolerated with no bleeding events observed.

Provision for Income Taxes for the fourth quarter of 2021 with $22.9 million compared to $15.1 million for the third quarter of 2021.

Our next question comes from the line of Andy <unk> with William Blair. Your line is open.

The company reported a gap in net income of $95.2 million or $0.29 per share on a fully diluted basis for the fourth quarter of 2020, company also reported non gap net income of $113.3 million or 35 cents per share on a fully diluted, Non-GAAP net income excludes the impact of approximately $18.2 million of stock-based compensation expense net of the related income tax effect.

Cash and investments for the quarter ended December 31, 2021 was approximately $1.9 billion.

Oh, great. Thanks for taking my question.

So I have three.

Two really quick ones. So one is.

Maybe for <unk>.

Chris just from a modeling standpoint, how should we think about.

DTC contribution.

In the Grand scheme of things.

Second one maybe P. J I think sometimes you talked about with these waves of TICC contraction is.

The normalization of the RCC market I'm just wondering.

What the current status that you seen during the quarter and also maybe.

Europe is maybe a little bit in that.

In Q1.

And.

Lastly, maybe for for Vicki in terms of just thinking about XL overnight to and I think Mike had said this previously about.

Potentially positioning that in HCC.

And given the learnings from.

Cosmic 312, I'm just wondering if there is a way to.

Set a minimum for hepatitis B, driven HCC and also <unk> or a maximum for hepatitis C trip in patients and the potential.

Potentially future trial just to really.

Maximize the probability of success.

Thank you.

Great Andy Thanks for the question. This is P J I'll actually.

The remaining full year 2022 financial guidance items can be found on slide 12.

The first two so.

So starting with DTC and kind of how we're thinking about.

With that, I'll turn the call over to Peter.

That opportunity as I mentioned in my prepared remarks, we're really pleased with the with the launch and certainly.

Thank you, Chris.

2021 was a transformative year for the Cabo Zantanen franchise, primarily driven by the approval of Cabo Medics in combination with Novolumab in first line RCC in January of 2021. Cabo Medics reached a significant milestone in 2021, surpassing $1 billion of U.S. net product revenue. The team continues to execute at a high level, and this has resulted in Cabo Medics becoming the number one prescribed TKI in RCC.

In Q4, we saw more patients.

Starting therapy really than we anticipated.

Hmm.

Which is gratifying.

Area of significant unmet need and we believe we're off to a fast start.

Towards becoming a standard of care in that setting.

The duration if you look at the PFS in the 311 trial, it's around 11 months so.

We believe there is a nice duration of therapy. There is we're kind of thinking about that opportunity at a high level, we're thinking it's about $100 million.

Give or take at peak, so that's kind of how we're thinking about DTC.

Furthermore, KaboMedx Total Prescriptions, or TRX, have now grown for five consecutive quarters.

So with regards to your second question.

In terms of kind of how we're seeing the market.

One way to view that as just looking at the prescription data from <unk>.

Time, obviously in the pandemic, we saw some some ebbs and flows.

There, but I think we've really stabilized.

Over the second half of last year.

We did see the market expand in terms of <unk>.

I'd say the last few quarters of.

Of last year.

And I would expect as Iot kpis.

Become more and more of us.

Staple in frontline therapy, which they are becoming in combinations in general are really continue to grow in in the first line setting up to maybe close to 80% of patients receiving a combination therapy, but as more of those.

As those combinations of Iot can become more prevalent I would just expect to see.

Longer duration of therapy, there that continues to drive overall growth of the <unk> market.

That kind of.

That kind of goes in parallel to what we're talking about when we see.

The duration of therapy for 90 are continuing to provide.

Growth in 2022 or potentially beyond.

For Cabo medics.

I'll turn it over to Vicki for the third question.

Yes. Thank you.

So we're excited about the opportunity for <unk> <unk> two in many different tumor types, including HTC and other tumors, where cabozantinib has demonstrated activity.

To the point that you made we have seen that different etiology.

Of liver disease in HCC may respond differently to different therapies, including checkpoint inhibitors.

And did you have directed therapies and we'll be taking all of those learnings into account as we build the development program for <unk> two antibodies cellular carcinoma.

Got it.

That's very helpful. Thank you so much.

Yes, Thanks, Andy.

Thank you. Our next question comes from the line of Jay Olson with Oppenheimer. Your line is open.

Oh, Hey, congrats on the results and thank you for taking the questions.

Can you talk about how much runway you see for Cabo plus <unk> growth in the first line RCC setting and any feedback youre getting from clinicians.

How cabo plus <unk> compares to lend that nib, plus <unk> in a real world setting and then maybe just a follow up on <unk>.

With the initiation of a pivotal study in CRC are you planning to initiate additional pivotal studies this year for <unk> and how would you prioritize the various opportunities for O&M to in your clinical development plans. Thank you.

Okay. Yes. Thanks for the question. This is P. J I'll I'll take the first part there. So I think in terms of I wont quantify growth other than to say if you look at our guidance.

We're anticipating a robust growth.

For for demand underlying that in prescriptions in 2022 for Cabo medicine.

Additionally, the launch of Cobomedics in Differentiated Thyroid Cancer, or DTC, which received FDA approval in September, is off to a strong start.

The reason I say that is really the majority of our growth I mentioned DTC earlier, that's obviously some growth but outside of that the majority of that growth is due to first line combination usage as we think about it.

Taken together, the strength of the business and the momentum of 2021 position Cabo well for growth in 2022.

Prescription trends remain strong in Q4 both for NRX and TRX. Year-over-year growth in Q4 was 40% for NRX and 50% for TRX.

As the launch progresses, the success of CaboMedix in combination with Nivolumab is changing the mix of patients on CaboMedix in RCC.

Given the clinical data from the CheckMate 90R study, we anticipate these first-line combination patients to receive therapy for approximately 1 1⁄2 years or more, thus driving a significantly longer treatment duration for carbomedics.

<unk> with noble will map.

As I mentioned earlier, the duration of therapy will continue.

Just a year on the market now so that's going to continue to drive growth going forward and we believe we have the opportunity to continue to.

Turning to the TKI market basket of Cabo Medix and Lida, Sutin, Botrient, and Levima.

Cabo Medics TRX market share increased every quarter in 2021, with market share in the fourth quarter reaching 35%. This growth is driven by combination usage in the first line RCC setting.

Get more and more new patients on therapy.

As we have discussed previously, the first line RCC market is very competitive and we are pleased with the performance of Cabo Medix in combination with the Volumath in this setting.

Given our data and the story and kind of the strength of that resonating with physicians.

Strong execution of our team.

I will say that.

I think the experience of prescribers with the combination of the feedback we get either through market research advisory boards is very positive.

Furthermore, we haven't seen significant competitive impact on our market share.

Uptake in the first line is broad across clinical risk groups and practice settings. Prescriber experience to date has been positive.

They view the balance of efficacy and safety in their hands as a positive.

Positive impression so I think that will also continue to augment our utilization going forward.

Turn it over to Vicki for the second question.

Thanks P J.

We believe all of this taken together with the momentum in the business positions Cabo Medix for continued growth in 2022.

Turning to other settings, we're pleased that the Cabo second line RCC business remains strong and was stable in Q4.

Looking beyond the five current U.S. indications for Cabozantinib, we're planning for the numerous lifecycle expansion opportunities as they begin to have top-line data readouts in 2022.

So we're looking to build a robust pivotal trial program for <unk>.

In HCC, our market share was stable in Q4, and Cabo Medix continues to be the most prescribed TKI in the second line setting for patients treated with immunotherapy in the first line.

We look forward to having the opportunity, pending data and approval, to bring CalgoMedics to more patients in need of therapy.

Our team remains highly focused and motivated to compete every day to bring the benefit of CaboMedx to all eligible patients as we continue to build the franchise and maximize potential.

And we believe we are quickly becoming a standard of care in this setting.

We are proud that this fifth indication for carbometics adds to the body of data and the label and enables Exelixis to help more patients with severe cancer.

Looking at various combination regimens, including novel mechanisms of action beyond the first SKU that we're evaluating currently and stellar or wanted to.

Cosmic <unk> 21, a signal finding study.

That will help inform our plans for <unk> as I mentioned earlier, they have a very similar kinase profile. So we believe that there's an opportunity to develop <unk> in places, where we've seen activity with cabozantinib, including from various cohorts of cosmic <unk> 21, and so.

Cohorts as they readout will help inform our plans for moving into pivotal trials with <unk> beyond the CRC trial that we've already announced.

Okay, great. Thank you very much.

Thanks Jay.

And with that, I'll turn the call over to, Thanks, PJ.

Thank you.

Good afternoon.

It's great to be here today, now a month and a half after I joined Exelixis as chief medical officer.

Our next question comes from the line of Mike King with H C. Wainwright. Your line is open.

I'd like to take a moment to introduce myself.

I am a medical oncologist and hematologist with nearly 18 years of experience in oncology drug development, both in government at the Food and Drug Administration and subsequently in industry. Prior to joining Exelixis in early January, I spent 15 years in roles with increasing responsibility at three global pharma companies, most recently at Merck, where I was therapeutic area head for late-stage oncology. During my industry career, I have developed both small-molecule drugs, including kinase, and Biologics including immuno-oncology agents and antibody drug conjugates across all phases of drug development from IND filings in Phase 1 to designing and implementing registrational studies leading to successful first approvals as well as additional major indications.

Today, I will cover our progress towards our organizational expansion to the East Coast, Exelixis East, as well as progress on our pipeline and upcoming milestones for 2022. As we announced in early January, we intend to develop a presence on the East Coast. Specifically in the Philadelphia area, as we seek to access talent on both coasts to support our expanding development organization. I'm happy to report that we have now identified short-term, move-in-ready office space in King of Prussia, Pennsylvania, in the western suburbs of Philadelphia, and a convenient and accessible location for much of the greater Philadelphia and central New Jersey biopharma talent.

Hey, guys. Thanks for taking the question I just wanted to maybe to follow up on Jamie's question about.

We have also added the King of Prussia location as an option for the majority of open roles within the Development and Medical Affairs Organization, and intend to initiate recruitment efforts immediately.

Use in first line RCC do you have more color on the proportion of probably use that as in conjunction with <unk>.

Turning now to an update on our pipeline, beginning with our Cabo Zantimib Registrational Trial.

A checkpoint and I'm just curious if those are what I'd say add on therapy.

Regimen, starting whereas as a triple.

Yes, Mike. This is this is P J so.

I guess, what I would say is that in the first line setting. We previously we've had the Cabo some sort of data in our label, which was mono therapy. When we got approved for.

Combination usage, a little over a year ago with <unk> in combination with <unk>.

In the first line.

We really have seen the majority of utilization of <unk> in the first line shift to that doublet.

Given the given the strength of the data.

And oncologists have been highly receptive of that.

So really that's what we're seeing primarily in the first line setting with regards to <unk> as utilization of the doublet I think as we think forward.

Two.

<unk> III should that be a positive study.

In terms of Cabo NEVA and it would be I think that just will potentially expand the market opportunity for <unk> in the first line setting there's certainly a lot of patients that do receive.

The combination of <unk> <unk> in the first line so I think if there.

There is an opportunity to add <unk> with.

And appropriate risk benefit profile to that to those patients we can get more and more patients should that study be positive. So hopefully that helps.

Frame frame that for you.

An interim primary endpoint readout for Contact 01 and readout of the progression-free survival primary endpoint for Contact 03, In combination with the tezolizumab and PD-1 experience, non-small cell lung cancer and renal cell carcinoma, respectively, are expected in the second half of 2022.

Great I appreciate that and maybe one for Rob.

Additionally, the final readout for overall survival in COSMIC-312 in hepatocellular carcinoma will occur later this quarter, and we anticipate regulatory filing shortly thereafter, if appropriate.

Just wondering how we ought to think about.

The.

A combo of Cabo and <unk>.

No.

Yes, there hasnt been a development of our anthrax.

Non small cell in a while just thinking about how that.

That Mike.

Provide some upside that really hasnt been widely discussed here.

Yes. Thank you for the question. So so bright contact a one is a combination of cabozantinib with a Tesla lithium mab.

Contact O2, our phase three study, in combination with the tezolizumab in metastatic castrate-resistant prostate cancer, is expected to complete enrollment this year.

Versus Docetaxel, which remains a standard of care in non small cell lung cancer after treatment.

With a checkpoint inhibitor plus or minus chemotherapy, it's really an underserved area with a lot of unmet need.

The primary endpoint here is overall survival and we're expecting a readout of an interim analysis on overall survival.

Sometime later this year again.

Docetaxel is an old therapy.

With not particularly good outcomes and so we really believe this is an area of high unmet need and.

And an opportunity.

To demonstrate further benefit for these patients. So we're looking forward to that readout later this year.

Thanks, so much appreciate it.

Thank you.

Our next question comes from the line of Jaap Van Weber with Cowen Your line is open.

Thanks very much this is gabe on for your own.

A Phase I study of Excel 102, our oral CDK7 inhibitor, is expected to move into both single-agent and combination-expansion cohorts after completion of ongoing dose escalation and determination of a Phase II dose.

We continue to make progress on our pipeline molecules. XL092, our next generation MET, AXL, MER, and VEGFR tyrosine kinase inhibitor, is being explored in combination with several checkpoint inhibitors and IO combinations, and is progressing towards registrational study.

My questions are on the pipeline first what kind of data can we expect for the CDK <unk> program X out one or two in the second half specifically will it be data from multiple cohorts in multiple dose cohorts do you expect to see monotherapy activity with objective responses.

Finally, XL114 has an approved IND and is currently in study initiation with first site activation expected this quarter.

Our first planned Phase 3 and 3rd line microsatellite stable colorectal cancer will be initiated in the second quarter of this year. Data supporting this study comes from two studies of cabozantinib in colorectal cancer, which were presented at ASCO GI in January and demonstrated promising activity in comparison to historical controls of regorafenib, the current standard of care.

And then for <unk> two in CRC, Vicki touched on a little bit but could you. Please discuss a little more detail maybe some of the early data that gives you confidence to go into the third line pivotal study versus regular half. Thank you.

Sure.

We expect to present Phase 1 clinical updates for XL092, XB002, and XL102 at medical conferences in the second half of this year.

I'm excited to be working with the very talented Exelixis team as we continue to progress our pipeline, our current early clinical pipeline, as well as ongoing small molecule and biotherapeutic discovery efforts targeting novel mechanisms, positions us well to continue to address areas of unmet need to improve the lives of patients with cancer.

With that, I'll turn it over to Peter for a discovery update.

A phase 1 study of XL102, our oral CDK7 inhibitor, is expected to move into both single agent and combination expansion cohorts after completion of ongoing dose escalation and determination of a phase 2 dose.

Thanks for the question, so I'll take the one or two first.

Thank you, Vicky.

Finally, Excel 114 has an approved IND and is currently in study initiation with first site activation expected this quarter.

Right now we're in dose escalation with one or two and that's what we anticipate we anticipate the dose escalation cohorts will be presented at a medical conference. Sometime later this year. So these will still be fairly early data and we will also look forward to additional clinical updates on that molecule in 2002.

I am pleased to provide a quick overview of the Exelixis preclinical pipeline. We have multiple programs ongoing, both internally and with our collaborators, with over 10 programs in process with the aim of advancing up to five compounds into preclinical development in 2020.

We expect to present Phase 1 clinical updates for XL092, XB002, and XL102 at medical conferences in the second half of this year.

As you'll see in the pipeline slide, the preclinical pipeline is a balanced mix of small molecules and biotherapeutics, which is reflective of how we see the clinical pipeline evolving in the future.

With that, I'll turn it over to Peter for a discovery update.

As Vicky just commented, XB002 is advancing through Phase I, and we're encouraged by both the preclinical and clinical profile we've seen to date.

Tissue factor is broadly overexpressed in a wide variety of solid tumors, and preclinically we observe compelling efficacy in multiple PDX models.

The PK data we've obtained so far from the Phase 1 trial also show high levels of intact ADC with low levels of free payload, indicating that it is a stable molybdenum. Hence, we believe that the underlying antibody is an excellent starting point for ADC development.

The recent deal that we did with ICONIC allows us to develop additional ADCs based on this same antibody, and we've started work to link it to additional payloads, particularly DNA-damaging payloads such as PKP.

Ultimately, this will allow us to match different tissue-factor-targeting ADCs to different tumor types, depending upon the sensitivity of each tumor type to different MOAs of the payload.

'twenty three.

Thank you, Vicky.

Regarding your question on.

I'm pleased to provide a quick overview of the Exelixis preclinical pipeline. We have multiple programs ongoing, both internally and with our collaborators, with over 10 programs in process with the aim of advancing up to five compounds into preclinical development in 2020.

The phase III plan phase III in colorectal cancer for 192.

As you'll see in the pipeline slide, the preclinical pipeline is a balanced mix of small molecules and biotherapeutics, which is reflective of how we see the clinical pipeline evolving in the future.

This is a.

This is a study in patients with third line.

As Vicky just commented, XB002 is advancing through Phase I, and we're encouraged by both the preclinical and clinical profile we've seen to date.

<unk> stable metastatic colorectal cancer, so they failed other therapies.

Tissue factor is broadly overexpressed in a wide variety of solid tumors, and preclinically we observe compelling efficacy in multiple PDX models.

A quick comment about XB010, this is our most recent development compound and is our first internally generated ADC that has advanced through our network of collaborators. XB010 targets the oncofetal antigen 5T4, which is overexpressed in multiple solid tumors, including non-small cell lung, breast, head and neck, and gastric carcinoma, and utilizes Catalan smart tag site-specific conjugation technology and proprietary linker coupled to MMAE. This gives a homogeneous ADC with a controlled drug-antibody ratio and a highly stable linker which reduces free-circulating payload.

The PK data we've obtained so far from the Phase 1 trial also show high levels of intact ADC with low levels of free payload, indicating that it is a stable molecule. Hence, we believe that the underlying antibody is an excellent starting point for ADC development.

Requiring documented Ras mutation status.

Our approach with XB010 is consistent with the philosophy behind XB002, which is to advance next-generation ADCs incorporating contemporary ADC technologies directed against well-documented targets. XB010 has now moved into preclinical development and could yield an IND in 2020. We anticipate publishing preclinical data later this year at a major meeting or in a suitable journal.

Ultimately, this will allow us to match different tissue factor targeting ADCs to different tumor types, depending upon the sensitivity of each tumor type to different MOAs of the payload.

And basically randomize them to either <unk> or <unk> with the lithium nab.

And with that, I'll turn the call back over to Mike.

<unk>.

All right, thanks, Peter.

The data that are supporting this study come from two studies that were presented at <unk> Gi as I mentioned earlier in my remarks, one was a cohort.

Cosmic <unk> 21, and the other was.

An investigator sponsored trial called the <unk> study.

So I can quickly run through some of those results for you.

Cosmic <unk> 'twenty, one colorectal cancer cohort.

Sponsor rate overall was 10%, but what we saw was a 25% response rate in patients two of Ras Wild type.

That was in combination with the Tesla lithium mab in patients who had no known MSI high or DMR. So.

Miller population to what we plan to study in 303, Likewise and Camille.

The overall response rate in the overall population was 28%, but again in Ras Wild type patients did better with a 50% response rate and this was a <unk> combo also in microsatellite stable patients. So as a result of these findings we believe that the place where most likely to see benefits.

The wild type.

Patient population and so the primary overall survival endpoint.

We will be focused on Ras wild type. However, we will also look at the population overall.

And thanks, very much maybe I'll add just for point of reference the typical <unk> response rate is about 2%.

Great. Thank you.

Thank you.

Our next question comes from a cost to worry with Jefferies.

Line is open.

This is Amy <unk>. Thanks, so much for taking our question.

Just wanted to contextualize your 2022, Cabo revenue guidance of $1 375 billion at midpoint with your prior expectations are probably hitting a $1 5 billion run rate.

As you heard on the call today, our team continued to execute across all facets of our business in the fourth quarter and full year 2021 with significant progress across our pipeline, clinical development, and commercial activity.

As we enter 2022, we're excited about the potential for the multiple growth drivers ahead of us to move the business forward and, most importantly, put Exelixis in a position to help many more candidates.

As we enter 2022, we're excited about the potential for the multiple growth drivers ahead of us to move the business forward, and most importantly, put Exelixis in a position to help many more cancer patients.

With our employees now back in the office working together side by side, I want to thank the Exelixis team for their individual and collective efforts in navigating the many significant challenges during the pandemic, including the recent Omicron surge.

Are you still comfortable with this run rate. Additionally, have you seen any seasonality and raw copper demand and channel inventory and is there any color you can provide on the overall median duration of treatment for Cabo in RCC. Thanks, so much.

As I highlighted during my recent JPM presentation, we have the vision, drive, and growing resources to become a multi-product enterprise and to begin to expand our operation to serve cancer patients on a global scale with our planned Exelixis East Coast presence as the first step in that.

As I highlighted during my recent JPM presentation, we have the vision, drive, and growing resources to become a multiproduct enterprise and to begin to expand our operation to serve cancer patients on a global scale with our planned Exelixis East Coast presence as the first step in that.

We look forward to updating you on our progress in the future.

Thank you for your continued support and interest in Exelixis.

We're happy to now open the call.

We're happy to now open the call for questions.

Yes, thanks for the question Amy.

Thank you.

Ladies and gentlemen, as a reminder to ask a question, you need to press star then one on your telephone.

From a from an inventory perspective, I'll start with that one.

On it during the.

In my prepared remarks.

Inventory stayed relatively flat Q3 versus Q4, it actually was flat all year.

But from a weeks on hand perspective, but it has been growing in line with demand throughout the year as demand increased.

To withdraw your question, press the pound.

Ladies and gentlemen, as a reminder to ask a question, you will need to press star then one on your telephone. To withdraw your question, press the pound.

The first question is.

This seasonality, but thats part of the inventory.

So the west coast I am sorry.

On the $1 $5 billion run rate, yes, I mean, if you think about where we're.

We guided it does it does gets you into that.

That range of getting to a run rate of $1 as we exit the year.

Okay, Great just Oh, sorry. This is P. J just to kind of take the question.

With regards of duration of therapy that.

Our thoughts about the Cabo <unk> combination in first line setting.

We've been on the market for a year or so.

And the trial, we see year and a half give or take.

Or more of <unk>.

So it's really early to be able to have a look back to see.

The significant duration, we're expecting from 90 are but as I mentioned.

We believe that's a driver of significant growth for us and I would just say that we are.

We're certainly pleased with what we're seeing thus far.

Great. Thank you so much.

Yeah. Thank you Amy.

Thank you. Our next question comes from the line of do Kim with Piper Sandler Your line is open.

Again, it's stall one to ask the question.

Again, it's all one to ask the question.

Please stand by while we compile the Q&A roster.

Hi, Thanks for taking my questions.

First on contact zero one.

I was hoping you could frame for us the.

The expected median survival for the control arm.

And.

Maybe provide what your expectation or the hazard ratio that the study is powered to show.

Yes so.

Our first question comes from the line of Jason Gerberry with Bank of America.

Your line is open.

There really arent great data in this setting of second line so.

Hi, good evening, everyone.

Standard of care has changed.

The.

This is Chi for Jason.

Thanks for taking our questions.

You know there isn't great data Docetaxel is used because it was the second line therapy.

Maybe just the first question is on COSMIC-313.

Following platinum therapy in the past it has continued to be a second line therapy in patients who received generally speaking.

Nio and and platinum combination so.

On the data expected first half, how should investors think about the level of details from the top-line results?

Do you think 9ER top-line results are a pretty good indicator for the level of initial disclosure, except we pulled slide in 313?

And then a couple of follow-ups on that.

I can speak to the fact that you know for patients who had.

Do you think 9ER top-line results is a pretty good indicator for the level of initial disclosure except we'll provide in 313?

Lung cancer in the past.

Metastatic lung cancer, the median survivals, where we're less than a year in the first line.

Obviously substantially shorter than that in the second line.

And.

We're shooting really for a substantial clinical effect here with respect to the.

And then a couple of follow-ups on that.

Cabo combination and so again, we will see the first data from an interim analysis of overall survival.

Later this year.

Okay. Thanks.

I have another question on <unk>.

Seasonality for Cabo sales.

As we look to 2022.

Should we start seeing your typical first quarter seasonality due to reimbursement factors.

Looking back at the.

The sales for Cabo you see too both through any potential impact.

Is this something we should start considering now or do you manage the gross to net to offset those factors.

Hey, Joe its Mike.

Probably not wise for us to be giving.

Q1 guidance in the middle of Q1 so.

Stay tuned in the numbers when we have the Q1 call in May we feel really good about how the brand is doing.

Again timing with <unk> on the call are somewhat fortuitous, but we have a lot of support out there both.

The academic and community setting and we feel like based on the data and based on the strong team that we have we're going to continue to be able to educate physicians to the benefits of that combination so but Q1 statement.

Understood.

And then last question.

For <unk> one for <unk>.

How are you thinking about the opportunity for a <unk> inhibitor.

Is it primarily overcoming.

T cell lymphomas.

That have PTK inhibitor resistance or are you expecting to see.

The drug.

Performed better than PTK inhibitor in aggressive NHL.

Yes. This is Peter let me, let me take that one.

Correct me identify <unk> resistance is a significant setting.

For one one for the.

The mechanism of action is clearly downstream of PTK in terms of inhibiting activation of the car.

Bcl multiple and complex.

So that's certainly an area of interest.

There are also subtypes of lymphoma is b cell lymphoma, specifically PTK inhibitors are not active.

There are other mutations in the California, including in <unk> itself.

The way, we believe will move four could have activity, where PTK inhibitors wouldn't so those are two kind of early stage initial stage opportunities that.

It could be it could be limited.

Great. Thank you and thanks for taking my question and congrats on the quarter.

Hey, Vicky, you want to take that one?

Yeah.

Thank you. Our next question comes from the line of Peter Lawson with Barclays. Your line is open great. Thank you. Thanks for taking the questions.

Sure, happy to.

XO, one or two CDK inhibitor.

So I would anticipate that in terms of the top-line results in a press release, it will be consistent with our prior practice, and then we will hold the full top-line report for our medical meeting later this year.

Should we think about as success.

And what should we be looking for in that data.

Thanks for this year.

Yes, Peter it's Mike.

Got it.

And on SD-002 initial data second half this year, the company has highlighted safety and bleeding as a potential differentiating feature for this drug.

It's probably premature to give you that level of guidance.

It's early in the year.

We'll have a pretty fulsome update when we do present that later in the year.

Peter if you would like to go through the basic biology, there and give you a sense on how we think went on too is different but again, it's probably early to start opining upon what we might see in our presentation months and months from now.

So I'm curious, do you believe that data is in the second half?

Peter So, let's say a few words.

The initial disclosure will offer sufficient exposure or duration of treatment to fully characterize that aspect of the 002 profile.

Yeah.

Yes, so we're excited about the opportunity with XB002 in particular because from a preclinical perspective, we've seen that it doesn't interfere of the binding of tissue factor to the coagulation pathway, and so we don't believe it will interfere with the extrinsic coagulation pathway.

Oh sure yeah. So.

We remain in dose escalation at this point.

As I mentioned in my remarks, we have not yet seen any bleeding events, and we will plan, of course, to disclose the safety profile that we've seen when we presented at a medical meeting later this year.

Got it, and just last one from me, curious on the patent litigation front, maybe what's the status on the Teva case given the recent litigation state?

I think if you look at this so it gets to be a CDK inhibitor development, we're at a pretty pretty interesting stage right now one way or another people have been trying to advance CDK inhibitors.

Is this a situation where parties are looking to consolidate a new patent similar to what's going on with the MSM?

No probably 20 years.

Any color you can provide there to the extent you can, that would be helpful.

If you look at the CDK family, they really fall broadly speaking into two buckets. There were those CDK that are primarily involved in cell cycle regulation.

CDK is wanting to CDK.

CDK four six where obviously, we have given clinical proof of concept.

Mechanism of CDK seven also clearly falls into that group.

Upstream of CDK 4612, and very clearly has a role in controlling entry into various phases of both the sale cycle.

No.

There are a lot of interesting opportunities for a CDK <unk> inhibitor CDK four six inhibitor resistance being being just one of those.

The tumor types, such as triple negative breast or ovarian.

Possible opportunities, maybe I would just add in addition to its CDK regulatory role CDK seven will serve directly.

And houses transcription from both <unk> and <unk>. So then that leads to opportunities in combination in <unk> dependent tumors as well.

Hey, it's Mike.

Thanks for the question.

In terms of the profile of the CDK <unk> inhibitor.

I think Jason, and I'm sure you are involved here, have been tracking the court docket pretty closely.

Yes, we obviously have all of you, what's an ideal profile and excellent wanting to fix that we think some of the important characteristics of first needs to be highly selective in an extra one zero to it.

You've written on that.

Second I think this is a mechanism of action, where you're really going to want to have maximal dosing flexibility to give you the best chance of optimizing therapeutic index.

Others have.

So that's been fun to read.

You guys have covered, I think, the facts per the docket pretty well.

I really want to avoid opining on what's happening beyond what's in the docket, the facts that are there for all to see.

Thanks so much.

And we'll continue to speak when appropriate as more information emerges from the court.

Thank you, Chi.

Except one or two is a covalent inhibitor, but at least in preclinical models cleared out all of the plasma out of the circulation very rapidly.

You don't have a little bit hanging around in the circulation, but you do have a prolonged pharmacodynamic duration of action based on the covalent covalent mechanism.

So maybe I'll just finish by kind of segway segway into afforded related program.

The second bucket of kind of CDK is not that much involved in cell cycle regulation, but they are involved in regulating transcription and various subsets of genes that would include CDK nine, but also CDK 12 and 13.

<unk> also seen as we have a program ongoing pre clinically with origin.

Nothing in the clinic to get for a CDK <unk> inhibitor I think it's fair.

Interesting based on a lot of biology, but wont part of which is the CDK 12 is very much involved in regulating the transcription of DNA damage response genes.

Things like around 51 breakout and the like so there is also potential directions to which and which could take the CDK <unk> inhibitor.

You can go well, we will be advancing wanting to preclinical development in the not too distant future.

Thank you.

And the CDK <unk> inhibitor that you think could have.

Single agent activity or really requires combination.

Well I can tell you is certainly pre clinically what we've seen is we've seen robust single agent activity.

And a number of different models.

As Vicki commented would it takes a willing to we're fairly early in the dose escalation of this at this point in time. So suddenly there is a rationale both both of the single agent and in combination, but time will tell with respect to the development of clinical data.

Thank you.

Just a final question around first line HCC.

The filing for mm 302 is that the.

Appendant upon OS been significant.

<unk> way of doing too.

Luke.

Yes, so for 312, we'll be seeing the final OS analysis later this quarter.

And we will be evaluating the totality of the data.

As we do in other tumor types, where cabozantinib has demonstrated activity and we'll be thinking about.

<unk> plans for <unk> in that tumor as well.

Perfect. Thank you so much.

Thank you Peter.

Our next question comes from the line of Michael Schmidt with Guggenheim.

Thank you. Our next question comes from the line of Kennan Mackay with RBC capital market. Your line is open.

Your line is open.

Hey, Vicki, you want to pick that one?

Hey, Thanks for taking the question for Mike or maybe.

How quickly do you think the cosmic 313 data can be turned around into a <unk>.

Hey guys, thanks for taking my questions.

Successful if that data is.

In the first half.

That was something that could happen later this year and then maybe for P. J.

With three category one in CCM recommendations for frontline treatment of favorable risk for.

Poor and intermediate risk what have been the drivers of physician preference for one regimen over another that's going on that is there anything in the longitudinal checkmate 90 yards out there. That's good for you because we've done that you think could impact physician choice here. Thanks.

Thank you.

I just had one for Piche and one for Peter.

I'll take that one.

The 313.

Sure, happy to.

Yes, sure happy to write so.

So I would anticipate that in terms of the top line results in a press release, it will be consistent with our prior practice, and then we will hold the full top line report for our medical meeting later this, Got it.

So we are expecting to see the cosmic 313 <unk>.

Progression free survival primary endpoint readout in.

In the first half of this year.

We're obviously working with a partner on this study Bristol Myers Squibb, and we'd be very motivated to work very closely with them and get that filing and as soon as possible data dependent.

Great.

P J Kevin.

With regards to your question.

In terms of physician preference and kind of what we're seeing in first line.

Utilization as I've mentioned is as broad and.

Thats really cuts across the the clinical risk groups of favorable intermediate and poor.

Chorus disease.

We're also seeing broad uptake whether its community.

Or academic settings, and I think that's really it's really driven by the balance of.

Kind of efficacy tolerability and quality of life data that we that we.

We see a 90 or and I think that's resonating really well with prescribers.

And they're seeing good results in their patients. So I think that we're on.

Only a year into this so I think.

The experience, they're getting it gives us further opportunities.

To continue to kind of grow in that perspective, what I will say with regards to the data. This weekend is we're certainly pleased with it.

In terms of the longer follow up.

I think the.

It shows the durability of the data data set overall the complete response rate.

Increasing to about 12% certainly is a plus.

Importantly.

Nothing that really changed the perception of the Tolerability profile. So I think just.

More follow up gives it gives our story.

A little more.

A little more power behind it so we're very pleased with that and.

As I mentioned, we're very optimistic towards the.

The momentum of the business this year.

Yeah.

Hey, Thanks, Kevin.

Thank you.

Our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open.

Thank you for taking the question most of my questions have been asked so maybe one on partnerships. Since you mentioned that you expect to bring additional clinical partnerships.

Ford can you talk about your strategy going forward in terms of collaborations for additional technologies is it more to be more opportunistic with new platforms and technologies or are there certain capabilities and technologies that you want to remain more focused on.

Thanks Peter.

Yes.

I kind of alluded to earlier.

Discovery preclinical side, we've been we continue to look broadly both on the biotherapeutics in small molecule sites. Both for platforms that we think will be complementary to what we have access to now that may kind of broaden our ability to.

Tracon will tackle various targets would target classes.

So we're.

We're happy to do those as as they makes sense for us.

Kind of all continents.

Well of course, we continue to look at assets as well individual emphasis particularly ones that are either late late preclinical early clinical but because we've got a number of times before on that front.

To be an asset that we have conviction behind in terms of being able to.

Mountain effective click.

Clinical development campaign, so basically it's the right molecule right time, right price kind of mantra that we're still thinking through that.

Okay.

Thank you.

Thank you Jeff.

Thank you. Our next question comes from the line of Chris Schott with tiny.

Your line is open.

Great. Thank you for the questions.

Describe the first line RCC marketplace as being a very competitive dynamic.

Two questions and it certainly has been where the regimens that have.

Taken primacy have shifted.

Use of the Io doublet Nemo.

In combination with <unk>.

What would you say is the outlook for what the share of use could be in the first line setting over the coming years I think you've previously said it's about 2025%.

To be stable.

<unk> to be greater or less.

Yeah, Hey, Chris It's P J.

It certainly is a competitive market and that's what we've seen in the data with regards to <unk>.

As far as predicting it given as you pointed out.

Competitive nature of the market I wouldn't endeavor to do that.

As I think about that.

Though in terms of potential positive 313 study I think it just really gives us a lot of opportunity.

<unk> to add Teekay, I, which is the mainstay of RCC treatment for.

15 years now to a potential.

I O doublet, which obviously has a solid place in the treatment regimen. So I think.

Yes, I think from more of a dynamic perspective, that's how I think about things going forward.

Got it and then a question for Vicki, perhaps Vicki I know you come from.

A lot of experience working at some of the leading players in oncology Mark Bristow as well as at the FDA, we've been observing more broadly across the industry. Some interesting decisions by the FDA, perhaps even over the last couple of weeks.

Where we're seeing this question of timelines for acceleration of approval.

Be factored in with this question of unmet need and I'm asking this question in the context of how youre thinking about.

The development strategy for <unk> two.

As it follows an.

Is that factoring into your thinking at all as you decide how to prioritize the next steps for <unk>, two I know that you've.

Talk about advancing into CRC, but theres other realms as well.

Yes, so as we're thinking about development plan. We're obviously looking at multiple factors I think clinical unmet need is a big focus.

Areas, where we believe we have the opportunity to transform the care of patients with cancer and of course at the same time as we're thinking about this we are watching the regulatory landscape and thinking about how that may impact our development plans.

So we're closely watching the FDA trends.

Of course, taking that into account.

As we're developing our plans realizing of course that we intend to develop our therapies.

Globally right. So we have to look at the regulatory climate around the world, but really we're focused on areas, where we believe.

That our experimental medicine may demonstrate a benefit for patients with cancer.

Got it and then lastly, just one housekeeping in terms of the combo revenue in line.

Just thinking back to over the past summer, where the clinical trial sales and you also did I break out within the $2, 95% that you had that $8 million or for clinical trial sales can you give us a sense for what that.

Your visibility into clinical trial sales in 2022.

Is there anything in particular about quarters that can hit or miss or make things maybe.

Maybe unique one off events.

Yes, Chris it's Chris.

I'd say, we don't have.

Very good visibility, obviously up to those that are running the trial to place the purchase order with us so generally.

Those timings will find out few weeks few months in advance and so we don't have good visibility throughout the year, but it's not included in our guidance number.

Got it and then lastly, if I could squeeze one more in Mike. Congratulations you had a new add to the board at the end of the year I was intrigued to see it with someone from outside of healthcare in the tech sector tell us about how you were thinking about the overall composition of the board you've had some folks who've been around for a very long time Lance in stereo and whatnot and you made an addition here how should we be in <unk>.

We're putting that thinking at the board level.

Sure. So we're very pleased to have Jackie Wright joined the board from from Microsoft She is a.

It's just amazing resource to us from a broad.

And digital technology perspective, and as I'm sure we've talked about at a high level previously part of our part of our corporate growth and part of our really expansion into digital.

As a key component of how we want to go not only by constantly but also globally going forward. So to have her engaged is just a tremendous resource for us we're going to learn a lot from her and look forward to engaging with her on all aspects of both her view of how to really digitize health care, but also been helping our business.

How much more efficient digitally as well.

Great. Thank you for all the questions.

Thank you Chris.

Thank you as a reminder, ladies and gentlemen that star one to ask a question.

Our next question comes from the line of Stephen Willey with Stifel. Your line is open.

Yes, Thanks for squeezing me in.

Just a question on <unk> and then actually I just have a quick follow up.

With respect to <unk>. So I know the stellar 303 study was obviously predicated on the notion that you had this very good data with Cabo.

But I guess when we look at the GE <unk> development strategy with Bristol.

We have nebo Cabo plus I think <unk> combo data in both RCC and bladder, we advertise a combo data in prostate.

Obviously, no IL two data yet but.

Just trying to better understand how the <unk> strategy is I guess going a bit deeper on the expansion cohort side as opposed to go into a phase III like you did with stellar.

Vicki you want us to take a shot at that maybe I can provide some color commentary afterwards.

Yes, sure happy to.

Right. So we're looking at multiple potential combinations for <unk> I think as I said earlier.

We may in order to advance the program quickly look also at.

Data coming out of the cosmic <unk> 'twenty, one trial, which is cabozantinib right to move forward in a limited number of steadying, the colorectal cancer being one of them.

And again, you may see additional phase III launch from there down the road, but we believe that Io checkpoint inhibitors in I O combos are important for the combination of <unk> and that study stellar or two which recently initiated enrollment will be important to evaluating the potential of <unk>.

<unk> in combination with those agents.

Yes, maybe I can just add Steve that we are in the business of raising the bar.

In terms of standard of care for patients everything we do is focused on that so less about generating <unk> data, but it's more about go into the next level and I think things like <unk>.

A good example of that first first company first trial is going against.

<unk> as the as.

The control arm.

Certainly with <unk>, two we have the opportunity to do that.

Cros.

Rod indications across across narrow indications as we develop that program. So so I wouldn't look at the stellar <unk> as the first first wave really of that of that signal searching signal validating type efforts, while we're launching a pivotal trial program. We have a variety of other discussions ongoing with other combination partner.

There's other other combination.

I Wonder if you will people with different different Io and other types of molecules that we and they want to combine with <unk>. So the program is advancing really.

In a multi dimensional way and I think what you're seeing here is just the beginning.

Okay. That's helpful. And then just one quick follow up on.

On stellar so I know.

Camilo was a investigator sponsored trial.

But I know that study used a modified resist criteria.

And I've seen it used before in.

Liver cancer, but I guess I haven't seen it used before in colorectal and so just wondering if you guys know why a modified resist response was used in this instance, the patients all have liver Mets or something I'm, just trying to figure that out.

Yes, I don't know Steve do you have anything you can say there.

Not really I don't know specifically, but what I would say is that having the two data sets, including our own internal data set from cosmic <unk> 'twenty one.

Both trending in the same direction in terms of better overall response rate then we would expect with historic controls and although they are both single arm the PFS and OS medians were also encouraging.

Relative to what has been seen historically for <unk>.

Okay. Thanks for taking the questions.

Yes, Thanks, Steve.

Thank you.

At this time there are no further questions.

Q, So I would now like to turn the call back over to today's host Susan Hubbard Ms. Hubbard, great. Yeah, great. Thank you and thank you all for joining US today, we certainly welcome your follow up calls with any additional questions you may have.

Ladies and gentlemen that concludes today's conference call. Thank you for your participation you may now disconnect.

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Good day, ladies and gentlemen, and welcome to the <unk> fourth quarter and full year 2021 financial results Conference call My.

The first one is, you know, nice to see the Kabomatics market share among TKIs grow.

And on XT002 initial data, second half this year, note the company has highlighted safety and bleeding as a potential differentiating feature for this drug.

Did you or can you break out at this point what your share is in first line and in second line RCC respectively?

So I'm curious, do you believe that data is in the second half?

My name is to Wanda and I will be your operator for today.

Yeah, this is PJ.

The initial disclosure will offer sufficient exposure or duration of treatment to fully characterize that aspect of the 002 profile.

Michael, thanks for the question.

So with regard to that, what I'll do is just kind of reiterate what we said previously, in terms of the second line share starting there, we have a, The majority of share, certainly in the post-IO setting, I think we said previously that's around, you know, two-thirds or so of the patients who received IO therapy in the first line previously.

We remain in dose escalation at this point.

Thank you Wanda and thank you all for joining us for the <unk> fourth quarter 2021, and full year 2021 financial results Conference call. Joining me on today's call are Mike Morrissey, our president and CEO , Chris Senner, Our Chief Financial Officer P. J Haley, our executive Vice President of commercial banking Goodman.

And then for, you know, for our first-line market share, we haven't disclosed specific numbers recently, and there's certainly some out there that you could look at.

What I would say is we've had significant momentum, and as I kind of mentioned in the prepared remarks, that's really what's been driving our growth, as the rest of the business has been stable.

Got it.

So, as you look at our TKI market share increasing over the year 2021 from 30 to 35 percent, that's essentially almost all being driven by first-line uptake, so we're very pleased with that as the, The messaging and the data are resonating extremely well with oncologists.

And just a last one from me.

You know, the balance of data in terms of our overall survival, our toxicity profile.

Our Chief Medical Officer, and Peter Lamb, Our Chief Scientific Officer, who will together review our progress for the fourth quarter 2021 ended December 31 2021.

Actual events or results could of course differ materially we refer you to the documents we file from time to time with the SEC, which under the heading risk factors identify important factors that could cause actual results to differ materially from those expressed by the company verbally and in writing today, including without limitation risks and uncertainties related to product <unk>.

<unk> success market competition regulatory review and approval processes conducting clinical trials compliance with applicable regulatory requirements, our dependence on collaboration partners and the level of costs associated with discovery product development business development and commercialization activities and with that I will turn the call over to Mike Alright. Thank you.

As well as the quality of life data resonating well with physicians and we're actually really excited this weekend here in San Francisco we've got the ASCO-GU meeting and it's going to be live so really looking forward to our presence there which will be significant and you know meeting with many many of the KOLs in person which will really be fantastic as we've obviously hadn't had as much opportunity to do that in the pandemic so we're we're very pleased with our position as I mentioned I think we have really great momentum heading into 2020.

Yeah, and then, yeah, thank you.

Curious on the patent litigation front.

Susan and thanks to everyone for joining us on the call today.

And then I had a question perhaps for Peter.

Maybe what's the status on the TAVA case given the recent litigation state?

This one is really around some of the early stage activities, specifically around the Storm Therapeutics collaboration.

Is this a situation where parties are looking to consolidate a new patent similar to what's going on with the MFA?

<unk> had a strong fourth quarter and full year 2021 across all components of our enterprise.

Any color you can provide there to the extent you can, that would be helpful.

We continue to grow the cabozantinib business and advance a diversified and growing pipeline of clinical and discovery programs.

Hey, it's Mike.

We'll keep our prepared remarks short today as the recently gave a detailed update to start the 2000 to start 2022 at the Jpmorgan Healthcare conference in January .

And I was just wondering if you could just comment, you know, what makes that particular company's technology exciting and, you know, any additional insights on the first target.

Thanks for the question.

Key topics, we will focus on today include first the carbon X business continues to grow and fuel the investments in advancing our portfolio of next generation therapies for oncology <unk> maintained its status as the leading PKI for RCC and surpassed the $1 billion net product revenue threshold in the U S. In 2021.

With a 45% year over year growth compared to 2020.

Second we expect our development team now led by Vicky Goodman to grow in size scope and stature in 2022 and beyond with the Buildout of Excellences East complementing our extensive development breadth and depth in Alameda.

I'd be curious to hear about that.

2022 could be a year of significant portfolio growth with a focus on expanding the potential indications for cabo with numerous expected topline results and advancing our important pipeline molecules XL <unk>, XP, <unk> and <unk>, including the initiation of the pivotal trial program for <unk> hundred 90.

Thank you.

Yeah, absolutely.

I'd be happy to speak to that.

You know, generally speaking, the STORM collaboration fits in with our overall approach and philosophy with respect to small molecule discovery.

Obviously, we have a very significant and growing internal small molecule discovery effort.

Two.

Third and finally, our Greg Discovery network of internal and collaborative efforts across both small molecule and biologic platforms continues to advance at a rapid pace with the selection of up to five new development candidates expected in 2022.

Development activities remain a core component of this strategy.

We expect to bring additional collaborations forward, including the potential preclinical assets, where we have increased conviction for both a clinical and commercial perspective.

But we're happy to kind of complement that with.

With that please see our press release issued an hour ago for our fourth quarter financial results and an extensive list of key corporate milestones achieved in the quarter I'll now turn the call over to Chris who will review, our fourth quarter and full year 2021 financial results, Chris Thanks, Mike for the fourth quarter of 2021, the company reported total revenue.

Worldwide partnerships and collaborations as makes sense in terms of providing complementary expertise or insights.

The storm very much fits into that.

The leading target which took this storm is Adenosine Deaminase or ADAR1.

You know, I'd say if you look at a lot of the publicly available CRISPR-based or SH-based target discovery that's been done in oncology over the last couple of years, 801 is a target that's come out as a very strong hit.

<unk>, a $451 1 million, which included Cabozantinib franchise net product revenues of $302 7 million.

<unk> net product revenues were $295 1 million, which included approximately $8 million in clinical trial sales.

Our trade inventory weeks on hand remained relatively flat when compared to the third quarter of 2021.

Total revenues also include $148 $5 million in collaboration revenues, primarily from Ipsen, Takeda and Genentech.

In the fourth quarter of 2021, <unk> recorded a $100 million milestone payment due from <unk> in connection with the achievement of $400 million in net sales and its related license territory over four consecutive quarters.

Our total operating expenses for the fourth quarter 2021 were $334 5 million compared to $276 8 million in the third quarter of 2021.

R&D expense was the primary driver of the increase in total operating expenses, which was primarily related to higher license fee expenses.

Provision for income taxes for the fourth quarter of 2021.

It was $22 9 million compared to $15 1 million for the third quarter of 2021.

The company reported GAAP net income of $95 2 million or <unk> 29 per share on a fully diluted basis for the fourth quarter of 2021.

Cash and investments for the quarter ended December 31, 2021 was approximately $1 9 billion.

Turning to our full year 2022 financial guidance.

Which was previewed at the JP Morgan Conference in January we are now, including total revenues guidance, which is expected to be in the range of 152, 5% at $1 65 billion.

The remaining full year 'twenty to 2022 financial guidance items can be found on slide 12 with that I'll turn the call over to P. J. Thank you Chris 2021 was a transformative year for the Cabozantinib franchise, primarily driven by the approval of Cabo medics in combination with <unk> in first line RCC.

In a number of those screens, so to be colloquial, I would call it a very hot target in oncology right now.

I think Jason, and I'm sure you're involved here, have been tracking the court docket pretty closely.

Probably up to about 30% of tumors or so that are probably dependent upon ongoing ADAR-1 activity to help restrain what essentially becomes an interferon-mediated cell death.

In January of 2021.

You've written on that.

<unk> reached a significant milestone in 2021, surpassing $1 billion of U S net product revenue.

Others have.

The team continues to execute at a high level and this has resulted in <unk>, becoming the number one prescribed <unk> in RCC.

Furthermore, <unk> total prescriptions or <unk> have now grown for five consecutive quarters.

So that's been fun to read.

You guys have covered, I think, the facts per the docket pretty well.

Additionally, the launch of <unk> and differentiated thyroid cancer, DTC, which received FDA approval in September is off to a strong start.

Taken together the strength of the business and the momentum of 2021 position <unk> well for growth in 2022.

Prescription trends remain strong in Q4, both for <unk> and <unk>.

Year over year growth in Q4 was 40% for <unk> and 50% for Trs.

As the launch progresses the success of <unk> in combination with <unk> is changing the mix of patients on <unk> in RCC.

Given the clinical data from the Checkmate <unk> study we anticipate.

<unk> first line combination patients to receive therapy for approximately one five years or more thus driving a significantly longer treatment duration for Cabo medics.

We are encouraged by the fact that in our data we see a doubling of the amount of new patient starts at the 40 milligram dose in 2021 relative to 2020.

This is further indication that the combination uptake in the first line setting is robust.

Turning to the <unk> market basket of Cabo medics, and lighter Sutent votary inland bema.

<unk> T Rx market share increased every quarter in 2021 with.

With market share in the fourth quarter, reaching 35%.

This growth is driven by combination usage in the first line RCC setting.

As we have discussed previously the first line RCC market is very competitive and we are pleased with the performance of <unk> in combination with <unk> in this setting.

Furthermore, we haven't seen significant competitive impact on our market share.

Uptake in the first line is broad across clinical risk groups and practice settings and prescriber experience to date has been positive.

We believe all of this taken together with the momentum in the business positions <unk> for continued growth in 2022.

Turning to other settings, we're pleased that the Cabo second line RCC business remained strong and was stable in Q4.

In HCC, our market share was stable in Q4, and <unk> continues to be the most prescribed teekay.

And the second line setting for patients treated with immunotherapy in the first line.

With regards to second line DTC.

We are pleased with the launch and in Q4, we saw a strong trend of new patient starts in this indication which exceeded our expectations.

They were previously no therapies approved for this patient population with significant unmet medical need and we believe we are quickly becoming a standard of care in this setting.

We are proud that this fifth indication for <unk> adds to the body of data in the label and enables <unk> to help more patients with severe cancer.

Looking beyond the five current U S indications for Cabozantinib.

We're planning for the numerous lifecycle expansion opportunities as they begin to have topline data readouts in 2022.

We look forward to having the opportunity pending data and approval to bring <unk> to more patients in need of therapies.

I really want to avoid opining on what's happening beyond what's in the docket, the facts that are there for all to see.

And we'll continue to speak when appropriate as more information emerges from the court.

Thanks P J.

Thanks so much.

So that's some of the basic biology behind it.

Good afternoon, it's great to be here today, now a month and a half after I joined <unk> as Chief Medical Officer.

So what has been on our radar screen for a while is an interesting target.

Thank you, Chi.

Like to take a moment to introduce myself.

Thank you.

On the medical oncologists and Hematologists with nearly 18 years of experience in oncology drug development, both in government at the food and drug administration and subsequently in industry.

Our next question comes from the line of Michael Schmidt with Guggenheim.

Prior to joining <unk> in early January I spent 15 years in roles with increasing responsibility at.

We're not experts in methyl transferases per se. Storm Soul Platform is a methyl transferase and kind of RNA epigenetics platform.

Your line is open.

And they've done a fair amount of work both on that platform generally, but also on ADAR-1 specifically in terms of putting together the assays necessary to prosecute an effective lead optimization scheme, which, as an aside, I will just say are non-trivial to put together.

Hey guys, thanks for taking my questions.

At three global pharma companies, most recently at Merck, where I was therapeutic area head for late stage oncology.

I just had one for Piche and one for Peter.

During my industry career, I have developed both small molecule drugs, including kinase inhibitors.

And biologics, including immuno oncology agents and anti body drug conjugates across all phases of drug development.

<unk> IND filings and phase one to designing and implementing Registrational studies, leading to successful first approvals as well as additional major indications.

Today, I will cover our progress towards our organizational expansion to the east Coast <unk> East.

They've also made good progress on kind of enabling a structural biology approach to the target.

The first one is, you know, nice to see the Kablematics market share among TKIs grow.

As well as progress on our pipeline and upcoming milestones for 2022.

So our view was it would very much jumpstart a program in the area to work with them rather than us trying to rebuild all that internally.

Can you break out, at this point, what your share is in first line and in second line RCC, respectively?

So it's early days for the collaboration.

Turning now to an update on our pipeline beginning with our Cabozantinib Registrational trials.

We are on track for three phase III Readouts this year.

Cosmic 313, evaluating cabozantinib in combination with <unk> and Epilemma Mab in intermediate and poor risk renal cell carcinoma is expected in the first half of the year.

An interim primary endpoint readout for contact our one and readout of the progression free survival primary endpoint for contactless III.

In combination with the cursor lithium mab in PD, one experienced non small cell lung cancer and renal cell carcinoma, respectively are expected in second half of 2022.

Additionally, the final readout for overall survival in cosmic 312, and have hydro cellular carcinoma will occur later this quarter and we anticipate regulatory filing shortly thereafter if appropriate.

Contact <unk>, our phase III study in combination with the Tesla lithium mab in metastatic castrate resistant prostate cancer is expected to complete enrollment this year.

We continue to make progress on our pipeline molecules XL into our next generation met Axel Merck and veg fr tyrosine kinase inhibitor is being explored in combination with several checkpoint inhibitor.

I O combinations.

And it's progressing towards Registrational studies.

We recently initiated dosing on <unk> based immuno oncology combination study and genitourinary malignancies.

And continue to explore additional potential combination opportunities with novel agents.

Our first planned phase III in third line microsatellite stable colorectal cancer will be initiated in the second quarter of this year.

Data supporting this study comes from two studies of Cabozantinib in colorectal cancer, which were presented at <unk> Gi in January and demonstrated promising activity in comparison to historical controls of <unk>. The current standard of care.

<unk>, our first antibody drug conjugate, which targets tissue factor without interfering with the coagulation pathway in preclinical models is in dose escalation.

Thus far it has been well tolerated with no bleeding events observed.

Finally, XL 114 has an approved IND.

And is currently in study initiation with first site activation expected this quarter.

We expect to present phase one clinical updates for <unk> two <unk>.

<unk> <unk>, two and <unk> 102 at medical conferences in the second half of this year.

<unk> us well to continue to address areas of unmet need to improve the lives of patients with cancer with that I'll turn it over to Peter for a discovery update.

Thank you Vicky.

I'm pleased to provide a quick overview of the <unk> preclinical pipeline.

We have multiple programs ongoing both internally and with our collaborators with over 10 programs in process with the aim of advancing up to five compounds into preclinical development in 2022.

As youll see in the pipeline slide the preclinical pipeline has a balanced mix of small molecules and bio therapeutics, which is reflective of how we see the clinical pipeline evolving in the future.

As we could just commented <unk> 002 is advancing through phase one and we encourage equivalents of preclinical and clinical profile, we've seen to date.

Tissue factor is broadly over expressed in a wide variety of solid tumors and pre clinically we observed compelling efficacy in multiple pdx models.

The PK data we've obtained so far from the phase one trial also show high levels of intact ADC with low levels of free payload, indicating that it is a stable molecule.

We believe that the underlying antibody as an excellent starting point for ADC development.

The recent deal that we did with iconic allows us to develop additional adcs based on this same antibody and we've started work to link it to additional payloads, particularly DNA damaging payload, which is T. <unk>.

Ultimately this will allow us to match different tissue factor targeting adcs to different tumor types, depending upon the sensitivity of each tumor type to different MLR is of the payload.

A quick comment about <unk> 010. This is all most recent development compound and is our first internally generated ADC found through our network of collaborators.

<unk> 010 target to yonker fecal antigen <unk>, four which is over expressed in multiple solid tumors, including non small cell lung breast head and neck and gastric carcinomas and utilizes kevalin smart pad site specific conjugation technology and proprietary linker coupled for MMA.

This gives us a homogeneous ADC with a controlled drug antibody ratio and a highly stable linker, which reduces free circulating payload.

Our approach with XP 010 is consistent with the philosophy behind <unk>, which is to advance next generation Adcs, incorporating contemporary ADC technologies directed against well documented targets.

<unk> zero zero has now moved into preclinical development and could yield an IMD in 2023.

We are anticipating publishing preclinical data later this year at a major meeting or in a suitable journal.

We're certainly excited to be in it and have it off and running.

Yeah, this is PJ.

Michael, thanks for the question.

So hopefully we'll be able to update on progress at some point in the, Hey, super interesting.

Thank you.

So with regard to that, what I'll do is just kind of reiterate what we said previously, in terms of the second line share starting there, we have a, A majority of share, certainly in the post-IO setting, I think we said previously that's around, you know, two-thirds or so of the patients who received IO therapy in the first line, previously and then for you know for our first line market share we haven't disclosed specific numbers recently and there's certainly some out there that you could you could look at what I would say is we've had significant momentum and as I kind of mentioned in the prepared remarks that's really what's been driving our growth as the rest of the business has been stable so as you look at our TKI market share increasing over the year 2021 from 30 to 35 percent that's essentially almost all being driven by first-line uptake so we're very pleased with that as the, The messaging and the data are resonating extremely well with oncologists, you know, the balance of data in terms of our overall survival, our toxicity profile, as well as the quality of life data resonating well with the physicians.

<unk> for the multiple growth drivers ahead of us to move the business forward and most importantly put <unk> in a position to help many more cancer patients.

With our employees not back in the office working together side by side I want to thank the <unk> team for their individual and collective efforts in navigating the many significant challenges during the pandemic, including the recent <unk> search as I highlighted during my recent J P. M presentation, we have the vision drive and growing <unk>.

Appreciate it.

Thank you.

And we're actually really excited this weekend here in San Francisco.

Thank you, Michael.

Resources to become a multi product enterprise and to begin to expand our operations to serve cancer patients on a global scale with our planned <unk> East coast presence as the first step in that journey.

Our next question comes from the line of Andy Hsieh with Wim Blair.

We look forward to updating you on our progress in the future. Thank you for your continued support and interest in <unk>, We're happy to now open the call for questions.

Thank you.

Ladies and gentlemen, as a reminder to ask a question you will need to press Star then one on your telephone to withdraw your question press the pound key again Thats star one to ask a question. Please standby, while we compile the Q&A roster.

Our first question comes from the line of Jason <unk> with Bank of America. Your line is open.

Your line is open.

Hi, Good evening, everyone. This is chi on for Jason Thanks for taking our questions.

Oh, great.

First question is on cost.

Of the three.

On the data I expect that first half how should investors think about the level of details from the top line results.

Thank <unk>.

Our top line results are pretty good indicators for the level of initial disclosure, except with five in 313, and then a couple of follow up after that thanks.

Hey, Thank you want to take that one.

Sure happy to.

So.

I would anticipate that in terms of the topline results in our press release, it will be consistent with our prior practice and then we will hold the full top line report for a medical meeting later this year.

Got it and on <unk> initial data second half of this year.

The company is highlight safety and bleeding as a professional differentiating feature for this drug.

I'm curious do you believe that data is in the second half.

The initial disclosure, where opex affection exposure or duration of treatment.

Fully characterize the that that aspect of <unk> profile.

Yes, so we're excited about the opportunity with <unk> in particular because.

From a preclinical perspective, we've seen that it doesn't get your fear of the binding of tissue factor too.

The coagulation pathway and so we don't believe it will interfere with the with the X transit.

Coagulation pathway. We are we remain in dose escalation at this point as I mentioned in my remarks, we have not yet seen any bleeding events and we will plan of course.

Should disclose the safety profile that we've seen when we presented at a medical meeting later this year.

Got it and just last one from me.

Curious on the patent litigation from maybe what's the status on the Cabot case, given the recent litigation stay.

With a situation where parties are looking to consolidate a new pattern similar to what's going on with the MSA in case any color you can provide there to the extent you can that would be helpful.

Yeah, Hey, it's Mike Thanks for the question.

Thank you.

Jason and I'm sure you are involved here.

<unk> been tracking.

The court docket pretty closely.

Written on that others have so that's been fun.

To read you guys have covered I think the facts per the dock it pretty well.

Really wanted to avoid opining on what's happening beyond what's in the docket the facts that are.

There for all to see.

We will continue to speak when appropriate.

As more and more information emerges from the court.

Thanks, so much.

Yes, Thank you team.

Thank you.

Thanks for taking my question.

Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Hey, guys. Thanks for taking my questions I just had one for PJ had wonderful Peter the first one.

So I have three, two really quick ones.

Nice to see the <unk> market share among <unk> grow could you can you break out at this point what your share is in first line and in second line RCC, respectively.

Yes. This is P J Michael Thanks for the question.

So with regards to that what I'll do is just kind of reiterate what we said previously.

In terms of the second line share starting there we have a.

The majority of share certainly in the post Io setting.

I think we've said previously it's around two thirds or so of the patients who received Io therapy in the first line.

Previously and then four.

For our first line market share we haven't disclosed.

Specific numbers recently and there is certainly some out there that you could you can look at what I would say is we've had significant momentum and as I kind of mentioned in the prepared remarks, that's really what's been driving our growth.

As the rest of the business has been stable. So as you look at our <unk> market share.

Creasing.

Over the year of 2021 from 30% to 35% that's essentially almost all being driven by first line uptake. So we're very pleased with that as the.

The messaging and the data are resonating extremely well with oncologists.

The balance of.

Data in terms of our overall survival or toxicity profile.

As well as the quality of life data are resonating well with physicians and we're actually really excited.

This weekend here in San Francisco, We've got the <unk> meeting and it's going to be live so really looking forward to.

We've got the ASCO-GU meeting and it's going to be live.

So really looking forward to our presence there, which will be significant and, you know, meeting with many of the KOLs in person, which will really be fantastic as we obviously haven't had as much opportunity to do that in the pandemic.

Our presence, there, which will be significant and meeting with many many of the kols in person to really be fantastic as.

As we obviously haven't had as much opportunity to do that in the pandemic. So we're we're very pleased with our position as I mentioned I think we have really great momentum heading into 2022.

So we're very pleased with our position, as I mentioned.

I think we have really great momentum heading into 2020.

Yeah, and then, yeah, thank you.

And then yes. Thank you and then I had a question perhaps for Peter.

And then I had a question perhaps for Peter.

This one is really around some of the early stage activities, specifically around the Storm Therapeutics collaboration.

One is really around some of the early stage activities specifically around.

The storm therapeutics.

Collaboration and I was just wondering if you could just comment.

And I was just wondering if you could just comment, you know, what makes that particular company's technology exciting and, you know, any additional insights on the first target, I'd be curious to hear about that.

What.

Makes that particular company's technology exciting and.

Any additional insights on that.

The first target of be curious to hear about that thank you.

Thank you.

Yeah, absolutely.

Yes, absolutely be happy to speak to that.

Generally speaking this doing collaborations fits in with.

Overall approach and philosophy, we certainly respect to small molecule discovery.

So we have a very significant and growing internal small molecule discovery effort.

I'd be happy to speak to that.

But we're having to kind of complement that with.

I am sorry partnerships and collaborations as makes sense in terms of providing complementary expertise or insight and still very much fits into that.

You know, generally speaking, the STORM collaboration fits in with our overall approach and philosophy with respect to small molecule discovery.

Obviously, we have a very significant and growing internal small molecule discovery effort.

But we're happy to kind of complement that with.

The leading target, which took us install is addressing the eliminated 801.

Sarah Farrar, talkin to side website partnerships and collaborations as make sense in terms of providing complimentary experience or insight.

The leading target which took this storm is Adenosine Deaminase, or ADAR1.

The storm very much fits into that.

You know, I'd say if you look at a lot of the publicly available CRISPR-based or FH-based target discovery that's been done in oncology over the last couple of years, 801 is a target that's come out as a very strong hit.

Let's say if you look at a lot of the publicly available Chris.

CRISPR based tool FH based target discovery, that's been done in oncology over the last couple of years.

One is a target that has come out of a very strong case.

In a number of those screens.

In a number of those screens, so to be colloquial, I would call it a very hot target in oncology right now, probably up to about 30% of tumors or so that are probably dependent upon ongoing ADAR-1 activity to help restrain what essentially becomes an interferon-mediated cell death.

We hope to be colloquial included very hot targets in oncology right now.

That's probably up to about 30% of tumors with so that will probably dependent upon.

Ongoing and $8 one activity.

To help restrained would essentially becomes a interferon mediated cell death.

So that's some of the basic biology behind it.

Some of the basic biology.

Behind this.

It's been on our radar screen for was an interesting target.

So what has been on our radar screen for a while is an interesting target.

We're not experts in metal transfer raises per site.

We're not experts in methyltransferases per se.

<unk> platform is a metal medical trends raise and kind of RNA epigenetics platform.

Storm's Hole Platform is a methyltransferase and kind of RNA epigenetics platform.

And they've done a fair amount of work both on that platform generally, but also on ADAR-1 specifically in terms of putting together the assays necessary to prosecute an effective lead optimization scheme, which as an aside, I will just say a non-trivial to put together.

And they've done a fair amount of work both on our platform generally but also on 801, specifically in <unk>.

Terms of putting together the assays necessary to prosecute and effective lead optimization scheme, which.

As an aside I will just say a non trivial to put together.

They'd also made good progress on kind of enabling a structural biology approach to the target. So our view was it would very much jumpstart a program in the area to work with them rather than us trying to rebuild all that internally.

It also made good progress on kind of enabling and structural biology approach. The target. So our view was it would very much jumpstart program in the area to work with them rather than us trying to rebuild all of that internally.

So it's early days for the collaboration.

It's early days for the collaboration we're certainly excited to be to be at Mason I would often running through that we'll be able to update on progress at some point in the future.

We're certainly excited to be in it and have it off and running.

So hopefully we'll be able to update on progress at some point in the future.

Very super interesting.

Okay Super interesting. Thank you appreciate it.

Thank you. Thank you Paul next question.

Thank you.

Appreciate it.

Our next question comes from the line of NBC with William Blair. Your line is open.

Oh, great. Thanks for taking my question.

So one is, you know, maybe for, for Chris, just from a modeling standpoint, how should we think about DTC contribution, you know, in the grand scheme of things?

So I have three.

Two really quick ones. So one is.

Maybe for <unk>.

Chris just from a modeling standpoint, how should we think about.

DTC contribution.

In the Grand scheme of things.

Second one, maybe PJ, I think sometimes you talked about, you know, with these waves, sometimes you see contraction, normalization of the RCC market.

Second one maybe P. J I think sometimes that you talked about with these waves of TICC contraction is.

The normalization of the RCC market I'm just wondering.

What the current status that you've seen during the quarter and also maybe.

Your perspective, maybe a little bit in it.

In Q1.

And.

Lastly, maybe for for Vicki in terms of just thinking about XL overnight to and I think Mike has said this previously about.

Potentially positioning that in HCC.

And given the learnings from.

Cosmic 312, I'm just wondering if there is a way to.

Set a minimum for hepatitis B, driven HCC and also and or a maximum for hepatitis feature of the patients and the potential.

Potentially future trial just to really.

Maximize the probability of success.

Thank you.

Great Andy Thanks for the questions. This is P J I'll actually I'll say.

I'm just wondering what the current status that you've seen during the quarter, and also maybe, you know, your perspective, maybe a little bit in Q1.

Thank you.

The first two so.

So starting with DTC and kind of how we're thinking about.

That opportunity as I mentioned in my prepared remarks, we're really pleased with the with the launch and certainly.

In Q4, we saw more patients.

Starting therapy really than we anticipated.

Which is gratifying.

Area of significant unmet need.

We believe we're off to a fast start.

Towards becoming a standard of care in that setting.

The duration if you look at the PFS in the 311 trial, it's around 11 months so.

We believe there is a nice duration of therapy. There is we're kind of thinking about that opportunity at a high level, we're thinking it's about $100 million.

Give or take at peak, so that's kind of how we're thinking about DTC.

So with regards to your second question.

In terms of kind of how we're seeing the market.

One way to view that as just looking at the prescription data from <unk> over time, obviously in the pandemic, we saw some some ebbs and flows.

There, but I think we've really stabilized.

Over the second half of last year.

We did see the market expand in terms of <unk>.

I'd say the last few quarters of.

Of last year.

Okay.

I would expect as Iot <unk>.

Become more and more of a staple in frontline therapy, which they are becoming in combinations in general are really continue to grow in in the first line setting up to maybe close to 80% of patients receiving a combination therapy, but as more of those.

As those combinations of Iot cat become more prevalent I would just expect to see.

The longer duration of therapy, there that continues to drive overall growth of the <unk> market.

And that kind of.

That kind of goes in parallel to what we're talking about when we see.

The duration of therapy for 90 are continuing to provide.

Growth in 2022 and potentially beyond.

For Cabo medics.

Ill turn it over to Vicki for the third question.

And lastly, maybe for Vicky, in terms of just thinking about XL092, and I think Mike has said this previously about potentially positioning that in HCC, And given the learnings from COSMIC-312, I'm just wondering if there is a way to set a minimum for hepatitis B-driven HCC and also and or a maximum for hepatitis C-driven patients in the potentially future trial just to really maximize the probability of success.

Yes. Thank you.

So we're excited about the opportunity for <unk> <unk> two in many different tumor types, including HTC and other tumors where cabozantinib.

It has demonstrated activity.

To the point that you made we have seen that different etiologies.

Liver disease in HCC may respond differently to different therapies, including checkpoint inhibitors.

<unk> directed therapies, and we'll be taking all of those learnings into account as we build the development program for <unk> 192 antibodies cellular carcinoma.

Got it.

That's very helpful. Thank you so much.

Yes, Thanks, Andy.

Thank you.

Thank you, Michael.

Thank you. Our next question comes from the line of Jay Olson with Oppenheimer. Your line is open.

Great, Andy, thanks for the questions.

Our next question comes from the line of Andy Hsieh with Wim Blair.

Hey, congrats on the results and thank you for taking the questions.

Can you talk about how much runway you see for Cabo plus <unk> growth in the first line RCC setting and any feedback youre getting from clinicians on how Cabo plus <unk> compares to lend that near then plus <unk> in a real world setting and then maybe just to follow up on <unk>.

Okay. Thanks for the question. This is P. J I'll I'll take the first part there. So I think in terms of I wont quantify growth other than to say if you look at our guidance.

This is PJ.

Your line is open.

We're anticipating a robust growth.

For for demand underlying that in prescriptions in 2022 for Cabo medicine.

I'll actually, I'll take the first two.

Oh, great.

Thanks for taking my question.

So starting with DTC, and kind of how we're thinking about that opportunity, as I mentioned, in my prepared remarks, we're really pleased with the with the launch. And certainly, in Q4, we saw more patients starting therapy really than we anticipated, which is gratifying, it's an area of significant unmet need.

So I have three, two really quick ones.

<unk> with Novo lab.

And, you know, we believe we're off to a fast start towards becoming a standard of care in that setting.

So one is, you know, maybe for, for Chris, just from a modeling standpoint, how should we think about DTC contribution, you know, in the grand scheme of things?

As I mentioned earlier, the duration of therapy will continue.

Just a year on the market now so that's going to continue to drive growth going forward and we believe we have the opportunity to continue to.

Get more and more new patients on therapy.

You know, the duration, if you look at the PFS in the 311 trial, it's around 11 months.

Given our data and the story and kind of the strength of that resonating with physicians and the strong execution of our team.

I will say that.

I think the experience of prescribers with the combination of feedback we get either through market research advisory boards is very positive.

They view the balance of efficacy and safety in their hands as a positive.

Positive impression so I think that will also continue to augment our utilization going forward.

Turn it over to Vicki for the second question.

Thanks P J.

Second one, maybe PJ, I think sometimes you talked about, you know, with these waves, sometimes you see contraction, normalization of the RCC market.

I'm just wondering what the current status that you've seen during the quarter and also maybe, you know, your perspective maybe a little bit in Q1.

So we're looking to build a robust pivotal trial program for <unk> <unk>.

We're looking at various combination regimens, including novel mechanisms of action.

Beyond the first SKU that we're evaluating currently and stellar or wanted to.

So, you know, we believe there's a nice duration of therapy there.

Cosmic <unk>, one a signal finding study.

And as we're kind of thinking about that opportunity at a high level, we're thinking it's about $100 million, give or take, at peak. So that's kind of how we're thinking about.

Cabozantinib will help inform our plans for <unk> as I mentioned earlier, they have a very similar kinase profile. So we believe that there is an opportunity to develop <unk> in places, where we've seen activity with cabozantinib, including from various cohorts of cosmic <unk> 21, and so.

Cohorts as they readout will help inform our plans for moving into pivotal trials with a 92 beyond the CRC trial that we've already announced.

Okay, great. Thank you very much.

Thanks Jay.

Thank you.

So with regards to your second question, in terms of kind of how we're seeing the market, you know, one way to view that is just looking at the prescription data from Acuvia over time.

And lastly, maybe for Vicky, in terms of just thinking about Excel 092, and I think Mike has said this previously about potentially positioning that in HCC, And given the learnings from COSMIC-312, I'm just wondering if there is a way to set a minimum for hepatitis B-driven HCC and also and or a maximum for hepatitis C-driven patients in the potentially future trial, just to really maximize the probability of success.

Our next question comes from the line of Mike King with H C. Wainwright. Your line is open.

Obviously, in the pandemic, we saw some ebbs and flows there, but I think we've really stabilized, you know, over the second half of last year.

We did see the market expand in terms of TKIs, you know, I'd say the last few quarters of last year, of last year.

Thank you.

Hi, guys. Thanks for taking the question I just wanted to maybe to follow up on Jay's question about.

Use in first line RCC do you have more color on the proportion of probably use that as in conjunction with.

A checkpoint and I am just curious if those are what I would say add on therapy.

Regimen, starting whereas as a triple.

Yes, Mike. This is this is P J so.

And, you know, I would expect as IOTKIs, you know, become more and more of a staple in frontline therapy, which they are becoming, and combinations in general really continue to grow in the first line setting, you know, up to maybe close to 80% of patients receiving a combination therapy.

I guess, what I would say is that in the first line setting. We previously we've had the Cabo some sort of data in our label, which was mono therapy. When we got approved for.

Combination usage, a little over a year ago with <unk> in combination with <unk>.

In the first line.

We really have seen the majority of utilization of <unk> in the first line shift to that doublet.

Given the given the strength of the data.

And oncologists have been highly receptive of that.

So really that's what we're seeing primarily in the first line setting with regards to <unk> as utilization of the doublet I think as we think forward.

Two <unk>.

313 should that be a positive study.

And in terms of Cabo NEVA and it would be I think that just will potentially expand the market opportunity for <unk> in that first line setting there's certainly a lot of patients that do receive.

The combination of <unk> it would be now in the personal lines. So I think.

There is an opportunity to add <unk> with.

And appropriate risk benefit profile to that to those patients we can get more and more patients should that study be positive. So hopefully that helps.

Frame frame that for you.

Great, Andy, thanks for the questions.

Great I appreciate that and maybe one for.

Perfectly on on contact all one I'm just wondering how we ought to think about.

Is that the combo of Cabo and <unk>.

No.

There hasnt been a development of anti VEGF and non small cell in a while.

Thinking about how that.

That Mike.

Provide some upside that really hasnt been widely discussed here.

Yes. Thank you for the question. So so bright contact a one is a combination of cabozantinib with a Tesla lithium mab.

This is PJ.

Versus docetaxel, which remains the standard of care in non small cell lung cancer after treatment.

With the checkpoint inhibitor plus or minus chemotherapy, it's really an underserved area with a lot of unmet need.

I'll actually, I'll take the first two.

The primary endpoint here is overall survival and we're expecting a readout of an interim analysis on overall survival.

Sometime later this year again.

Docetaxel is an old therapy.

With not particularly good outcomes and so we really believe this is an area of high unmet need and.

So starting with DTC and kind of how we're thinking about that opportunity, as I mentioned in my prepared remarks, we're really pleased with the with the launch. And certainly, in Q4, we saw more patients starting therapy really than we anticipated, which is gratifying, it's an area of significant unmet need.

And an opportunity.

To demonstrate further benefit for these patients. So we're looking forward to that readout later this year.

Thanks, so much appreciate it.

Thank you.

Our next question comes from the line of Jaap Van Weber with Cowen Your line is open.

And, you know, we believe we're off to a fast start towards becoming a standard of care in that setting.

Thanks very much this is gabe on for your own.

You know, the duration, if you look at the PFS in the 311 trial, it's around 11 months.

My questions are on the pipeline first what kind of data can we expect for the CDK seven program ex sell one or two in the second half specifically will it will be data from multiple cohorts in multiple dose cohorts do you expect to see monotherapy activity with objective responses.

Sure.

So, you know, we believe there's a nice duration of therapy there.

Thanks for the question, so I'll take the one or two first.

And as we're kind of thinking about that opportunity at a high level, we're thinking it's about $100 million, give or take, at peak. So that's kind of how we're thinking about.

So with regards to your second question, in terms of kind of how we're seeing the market, you know, one way to view that is just looking at the prescription data from Acuvia over time.

Obviously, in the pandemic, we saw some ebbs and flows there, but I think we've really stabilized, you know, over the second half of last year.

Yes, thank you.

We did see the market expand in terms of PKI's, you know, I'd say the last few quarters of.., of last year.

But as more of those, as those combinations of IOTKI become more prevalent, I would just expect to see, you know, longer duration of therapy there that continues to drive overall growth of the TKI market.

And, you know, that kind of, that kind of goes in parallel to what we're talking about when we see the duration of therapy for 90 are continuing to provide growth in 2022 and potentially beyond for Cabo Mato.

Turn it over to Vicki for the third.

So we're excited about the opportunity for XL092 in many different tumor types, including HCC and other tumors where cabozantinib has demonstrated activity.

To the point that you made, we have seen that different etiologies of liver disease and HCC may respond differently to different therapies, including checkpoint inhibitors and VEGF-directed therapies, and we'll be taking all of those learnings into account as we build a development program for XL092 in hepatocellular carcinoma.

Got it.

That's very helpful.

93.

Regarding your question on.

The phase III plan phase III in colorectal cancer for <unk> two.

This is a.

This is a study in patients with third line.

<unk> stable metastatic colorectal cancer, so they failed other therapies.

We are requiring documented Ras mutation status.

And basically randomize them to either sell or two with the Tesla lithium nab.

<unk>.

The data that are supporting this study come from two studies that were presented at <unk> Gi as I mentioned earlier in my remarks, one was a cohort.

Cosmic <unk> 21, and the other was in.

An investigator sponsor trial called the <unk> study.

So I can quickly run through some of those results for you.

Cosmic <unk> 'twenty, one colorectal cancer cohort.

Sponsor rate overall was 10%, but what we saw was a 25% response rate in patients two of Ras Wild type.

That was in combination with the cursor lithium mab in patients who had no known MSI high or DMR so semi.

A similar population to what we plan to study in 303, Likewise and Camilla. The overall response rate in the overall population was 28%, but again in Ras Wild type patients did better with a 50% response rate and this was a <unk> combo also in microsatellite stable patients.

So as a result of these findings we believe that the place where most likely to see benefits is the wild type <unk>.

Patient population and so the primary overall survival endpoint.

We will be focused on Ras wild type. However, we will also look at the population overall.

And thanks, very much maybe I'll add just for point of reference the typical <unk> response rate is about 2%.

Great. Thank you.

Thank you so much.

Thank you.

Yeah, thanks, Andy.

Thank you.

Our next question comes from Carlos <unk> with Jefferies. Your line is open.

Our next question comes from the line of Jay Olson with Oppenheimer.

This is Amy on cash thanks, so much for taking our question.

Your line is open.

Just wanted to contextualize your 2022, Cabo revenue guidance of $1 375 billion at midpoint with your prior expectations or public hitting a $1 5 billion run rate at the end of this year are you still comfortable with this run rate. Additionally have you seen any seasonality around copper demand and channel inventory and is there any.

Oh, hey, congrats on the results and thank you for taking the questions.

Can you talk about how much runway you see for CABO plus NEVO growth in the first line RCC setting?

And any feedback you're getting from clinicians on how CABO plus NEVO compares to LENVAT-NIV plus PENBRO in a real world setting?

Color you can provide on the overall median duration of treatment for Cabo in RCC. Thanks, so much.

Yes, thanks for the question Amy.

And then maybe just to follow up on 092.

With the initiation of a pivotal study in CRC, are you planning to initiate additional pivotal studies this year for O9-2 and how would you prioritize the various opportunities for O9-2 in your clinical development plans?

From a from an inventory perspective, I'll start with that one.

On it during the day.

In my prepared remarks.

Inventory stayed relatively flat Q3 versus Q4, it actually was flat all year.

But from a weeks on hand perspective, but it has been growing in line with demand throughout the year as demand increased.

The first question is.

This seasonality, but that's part of the inventory.

So the one five sorry.

So on the $1 5 billion run rate, yes, I mean, if you think about where we're.

We guided it does it does get you into that.

That range of getting to a run rate of $1 as we exit the year.

Okay, Great just to Oh, sorry. This is P. J just to kind of take the question.

With regards of duration of therapy that.

Our thoughts about the Cabo <unk> combination in first line setting.

We've been on the market for a year or so.

And the trial, we see year and a half give or take.

And, you know, that kind of, that kind of goes in parallel to what we're talking about when we see the duration of therapy for 9ER continuing to provide growth in 2022 and potentially beyond for CABOMED.

Or more of <unk>.

So it's really early to be able to have a look back to see.

The significant duration, we're expecting from 90 are but as I mentioned.

We believe that's a driver of significant growth for us and I would just say that we are.

We're certainly pleased with what we're seeing thus far.

Great. Thank you so much.

Thank you Amy.

Thank you. Our next question comes from the line of do Kim with Piper Sandler Your line is open.

Turn it over to Vicky for the third.

Thank you.

Yes, thank you.

Okay, thanks for the question.

Hi, Thanks for taking my questions.

First on contact zero one.

I was hoping you could frame for us the.

Expected median survival for the control arm.

And.

Maybe provide what your expectation or.

Or the hazard ratio that the study is powered to show.

Yes so.

So we're excited about the opportunity for XL092 in many different tumor types, including HCC and other tumors where cabozantinib has demonstrated activity.

This is PJ, I'll take the first part there.

There really arent great data in this setting of second line so as.

Got it.

As standard of care has changed.

The.

That's very helpful.

Thank you so much.

There isn't great data Docetaxel is used because it was the second line therapy.

Yeah, thanks, Andy.

Following platinum therapy in the past and has continued to be a second line therapy in patients who received generally speaking.

Nio and <unk>.

And platinum combination so.

Thank you.

So, you know, I think, in terms of, I won't quantify growth other than to say, you know, if you look at our guidance, we're anticipating robust growth, for for demand underlying that and prescriptions in 2022 for CaboMedix.

And the reason I say that is really the majority of our growth, I mentioned DTC earlier, that's obviously some growth.

I can speak to the fact that for patients who had.

Our next question comes from the line of Jay Olson with Oppenheimer.

But outside of that, the majority of that growth is due to first line combination usage, as we think about it, of CaboMedix with Novolumab.

You know, as I mentioned earlier, the duration of therapy will continue, you know, we're just a year on the market now.

So that's going to continue to drive growth going forward.

Lung cancer in the past.

Metastatic lung cancer, the median survivals, we're less than a year in the first line.

Obviously substantially shorter than that in the second line.

And.

We're shooting really for a substantial clinical effect here with respect to the Cabo.

And we believe we have the opportunity to continue to, you know, get more and more new patients on therapy.

Cabo combination and so again, we will see the first data from an interim analysis of overall survival.

Your line is open.

Later this year.

Okay. Thanks.

Oh hey, congrats on the results and thank you for taking the questions.

I have another question on <unk>.

Seasonality for Cabo sales.

As we look to 2022.

Should we start seeing your typical first quarter seasonality due to reimbursement factors.

Looking back at the.

The sales for Cabo you see to grow through any potential impact.

Is this something we should start considering now or do you manage the gross to net to offset those factors.

Can you talk about how much runway you see for CABO plus NEVO growth in the first line RCC setting and any feedback you're getting from clinicians on how CABO plus NEVO compares to LENVAT-NIB plus PENBRO in a real world setting?

Hey, Joe its Mike probably not wise for us to be giving.

Q1 guidance in the middle of Q1 so.

Stay tuned in the numbers when we have the Q1 call in May we feel really good about how the brand is doing.

Again timing with <unk> GE you on the call are.

But for <unk>, but we have a lot of support out there both in.

And the academic and community setting and we feel like based on the data and based on the strong team that we have we're going to continue to be able to educate physicians to the benefits of that combination so but Q1 statement.

And then maybe just to follow up on 092, With the initiation of a pivotal study in CRC, are you planning to initiate additional pivotal studies this year for O9-2 and how would you prioritize the various opportunities for O9-2 in your clinical development plans?

Given our data and the story and kind of the strength of that resonating with physicians and the strong execution of our team, I will say that, You know, I think the experience of prescribers with the combination of feedback we get either through market research or advisory boards is very positive.

Understood.

And then last question.

For XO 114.

How are you thinking about the opportunity for a <unk> inhibitor.

Is it primarily overcoming.

Let's see cell lymphomas.

That have PTK inhibitor resistance or are you expecting to see.

The drug.

<unk> better than a PTK inhibitor in aggressive NHL.

Yes. This is Peter let me, let me take that one.

Correct me identify <unk> resistance is a significant settings.

For one one for the <unk>.

This action is clearly downstream of BT K in terms of.

Inhibiting activation of.

The card Bcl multiple and complex.

So that's certainly.

Area of interest.

There are also subtypes of lymphoma, B cell lymphoma, specifically PTK inhibitors are not active.

Whether other mutations in the California, including in <unk> itself.

Where we believe will move four could have activity, where BK inhibitors wounds. So those are two kind of early stage initial stage opportunities that.

It could be it could be limited.

Great. Thank you. Thanks for taking my question and congrats on the quarter.

Thank you ma'am.

Thank you. Our next question comes from the line of Peter Lawson with Barclays. Your line is open great. Thank you. Thanks for taking the questions.

Thank you.

Okay, thanks for the question.

<unk>.

So one or two CDK <unk> inhibitor, where should we think about as success.

And what should we be looking for in that data.

Thanks to this year.

Yes, Peter it's Mike.

This is PJ, I'll take the first part there.

Probably premature to give you that level of guidance.

It's early in the year and we will.

We will have a pretty fulsome update when we do present that later in the year.

Peter I want to say a few words.

So, you know, I think, in terms of, I won't quantify growth, other than to say, you know, if you look at our guidance, we're anticipating robust growth, for for demand underlying that and prescriptions in 2022 for CaboMedix.

Oh sure yeah. So.

And the reason I say that is really the majority of our growth, I mentioned DTC earlier, that's obviously some growth.

But outside of that, the majority of that growth is due to first line combination usage, as we think about it, of CaboMedix with Novolumab.

I think if you look at that.

I guess, we have CDK inhibitor development, we're at a pretty pretty interesting stage right now one way or another people have been trying to advanced CDK inhibitors.

20 years.

If you look at the CDK family. They really forward broadly speaking into two buckets. Those CDK that are primarily involved in cell cycle regulation.

CDK is wanting to CDK four six where obviously we have clinical proof of concept.

The mechanism and then CDK seven also clearly falls into that group.

Upstream of CDK four six <unk> very clearly has a role in controlling entry into various phases of both the sales cycle.

So.

There were a lot of interesting opportunities for a CDK <unk> inhibitor CDK four six inhibitor resistance.

One of those.

Other tumor types, such as triple negative breast or ovarian.

Possible opportunities.

Just to add in addition to CDK regulatory role CDK seven will serve directly.

And houses transcription from both <unk> and <unk>. So then that leads to opportunities in combination in <unk>.

<unk> tumors as well.

In terms of the profile of a CDK <unk> inhibitor.

Yes, we obviously have all of you, what's an ideal profile and excellent wanting to fix that.

Some of the important characteristics of first needs to be highly selective in X <unk>.

Second I think this is a mechanism of action, where you're really going to want to have maximal dosing flexibility to give you the best chance of optimizing therapeutic index.

I wanted to as a covalent inhibitor, but at least in preclinical models cleared out all of the plasma out of the circulation very rapidly.

So you don't have a lot of it hanging around in the circulation, but you do have a prolonged pharmacodynamic duration of action based on the covalent covalent mechanism.

So maybe I'll just finish by kind of segway segway into a sort of related program.

The second bucket of kind of CDK is not that much involved in cell cycle regulation, but they are involved in regulating transcription and various subsets of genes and that would include CDK nine but also CDK 12.

13.

If you take all of the teams we have a program ongoing pre clinically with origin.

Again, the clinic to get for a CDK <unk> inhibitor.

It's very interesting based on a lot of biology.

Part of which is the CDK 12 is very much involved in regulating the transcription of DNA damage response genes.

Things like <unk> 51 breaker underlying so there's also potential directions to which and which can take a CDK <unk> inhibitor hopefully if things go well, we will be advancing wanting to preclinical development.

Today's and future.

Thank you and the CDK <unk> inhibitor that you think could have.

Simulation activity, we're really requires combination.

Well I can tell you is certainly pre clinically what we've seen is we've seen robust single agent activity.

And a number of different models.

As Vicki commented would it takes a willing to we're fairly early in the dose escalation of this at this point a point in time. So suddenly there is a rationale both both of the single agent and in combination, but time will tell with respect to the development of clinical data.

Got you. Thank you.

Just a final question around.

Hence you see that.

Filing for.

302 is that.

Dependent upon.

It's been significant.

<unk> way of doing.

To move.

Yes, so for 312, we'll be seeing the final OS analysis later this quarter.

And we will be evaluating the totality of the data.

And in consideration of the evolving treatment landscape before deciding whether or not it's appropriate to file and yes to answer. Your other question, we do see potential for <unk> cellular carcinoma as we do in other tumor types, where cabozantinib has demonstrated activity and we will be thinking about.

<unk>.

Development plans for <unk> in that tumor as well.

Perfect. Thank you so much thanks, Steve Thank you Peter.

Thank you. Our next question comes from the line of Kennan Mackay with RBC capital markets. Your line is open.

Hey, Thanks for taking the question for Mike or maybe.

How quickly do you think the cosmic 313 data can be turned around into an NPA.

Fixed asphalt if that data is.

In the first half impact.

It's something that could happen later this year and then maybe for P. J.

With three category one in CCM recommendations for frontline treatment of favorable risk for poor.

Poor and intermediate risk what happened that the drivers of physician preference for one regimen over another that's going on that is there anything in the longitudinal checkmate 90, our data adaptor to you because we've done that you think could impact physician choice here. Thanks.

Thank you.

I'll take that one.

The 313.

Yes, sure happy to write so.

We are expecting to see the cosmic 313.

Progression free survival primary endpoint readout.

In the first half of this year.

We're obviously working with a partner on this study Bristol Myers Squibb, and we'd be very motivated to work very closely with them and get that filing and as soon as possible data dependent.

Great.

P J Kevin.

With regards to your question.

In terms of physician preference and kind of what we're seeing in first line, our Utica utilization as I've mentioned is as broad.

You know, they view the balance of efficacy and safety in their hands as a positive impression.

And thats really cuts across the the clinical risk groups of favorable intermediate and poor.

Chorus disease.

We're also seeing broad uptake whether its community.

Or academic settings, and I think that's really it's really driven by the balance of.

Kind of efficacy tolerability and quality of life data that we.

We see a 90 or and I think thats resonating really well with prescribers.

So I think that will also continue to augment our utilization going forward, turn it over to Vicky for the second.

And they're seeing good results in their patients so I think that.

You know, as I mentioned earlier, the duration of therapy will continue, you know, we're just a year on the market now.

So that's going to continue to drive growth going forward.

We're only a year into this so I think.

The experience they're getting.

US further opportunities.

<unk>.

And we believe we have the opportunity to continue to, you know, get more and more new patients on therapy.

To continue to kind of grow in that perspective, what I will say with regards to the data. This weekend is we're certainly pleased with it.

You know, they view the balance of efficacy and safety in their hands as a positive impression.

So I think that will also continue to augment our utilization going forward.

Turn it over to Vicky for the second.

In terms of the longer follow up.

I think the.

Shows the durability of the data data set overall the complete response rate.

Increasing to about 12% certainly is a plus.

Importantly.

Nothing that really changed the perception of the Tolerability profile. So I think there's just more follow up gives it gives our story.

A little more.

A little more power behind it so we're very pleased with that and.

As I mentioned, we're very optimistic towards the.

The momentum of the business this year.

Hey, Thanks, Kevin.

Thanks, PJ.

Thank you.

Our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open.

We're looking to build a robust pivotal trial program for XL092.

Thank you for taking the question most of my questions have been asked so maybe one on partnerships. Since you mentioned that you expect to bring additional clinical partnerships.

We're looking at various combination regimens, including novel mechanisms of action beyond the first few that we're evaluating currently in Stellar 001 and 002.

COSMIC-021, a signal finding study of cabozantinib, will help inform our plans for O9-2. As I mentioned earlier, they have a very similar kinase profile, so we believe that there's an opportunity to develop O9-2 in places where we've seen activity with cabozantinib, including from various cohorts of COSMIC-021.

And so those cohorts, as they read out, will help inform our plans for moving into pivotal trials with O9-2 beyond the CRC trial that we've already had.

Thanks, PJ.

Thanks Peter.

Okay, great.

We're looking to build a robust pivotal trial program for XL092.

Yes.

I kind of alluded to earlier.

Discovery preclinical side, we've been we continue to look broadly both on the biotherapeutics in small molecule side. Both for platforms that we think will be complementary to what we have access to now that may kind of broaden our ability to.

We're looking at various combination regimens, including novel mechanisms of action, beyond the first few that we're evaluating currently in Stellar 001 and 002.

Tracon will tackle various targets would target classes.

So.

We're happy to do those as as they make sense for us.

Arnaud partners.

Well of course, we continue to look at assets as well individual emphasis particularly ones that are either late preclinical late preclinical early clinical but I think as we've said a number of times before on that frontier has to be an asset that we have conviction behind in terms of being able to mount.

COSMIC 021, a signal-finding study of cabozantinib, will help inform our plans for 092. As I mentioned earlier, they have a very similar kinase profile, so we believe that there's an opportunity to develop 092 in places where we've seen activity with cabozantinib, including from various cohorts of COSMIC 021.

And so those cohorts, as they read out, will help inform our plans for moving into pivotal trials with 092 beyond the CRC trial that we've already had.

Okay, great.

Mountain effective Clint.

Clinical development campaign, so basically it's the right molecule right time, right price condo mantra that we're still thinking through that.

Okay.

Thank you.

Thank you very much.

Thank you Jeff.

Thank you. Our next question comes from the line of Chris Schott from Tony <unk> with Goldman Sachs. Your line is open.

Thanks, Jay.

Great. Thank you for the questions.

Thank you.

You described the first line RCC marketplaces being very competitive dynamic.

Two questions and it certainly has been where the regimens that have.

Taken primacy have shifted.

Use of the Io doublet Nemo.

In combination with AP.

What would you say is the outlook for what the share of use could be in the first line setting over the coming years I think you've previously said, it's about 2025% is that to be stable.

Is that likely to be greater or less.

Yeah, Hey, Chris It's P J.

It certainly is a competitive market.

And that's what we've seen in the data with regards to <unk> as far as predicting it given as you pointed out.

The competitive nature of the market I wouldn't endeavor to do that.

As I think about that.

Though in terms of potential positive 303 study I think it just really gives us a lot of opportunity.

To add <unk>, which is a mainstay of RCC treatment for.

15 years now to a potential.

I O doublet, which obviously has a solid place in the treatment regimen. So I think.

Yes, I think from more of a dynamic perspective, that's how I think about things going forward.

Got it and then a question for Vicki, perhaps Vicki I know you come from.

A lot of experience working at some of the leading players in oncology Merck Bristol as well as at the FDA.

Been observing more broadly across the industry some interesting decisions by the FDA, perhaps even over the last couple of weeks.

Where we're seeing this question of timelines for acceleration of approval.

We factored in with this question of unmet need and I'm asking this question in the context of how Youre thinking about.

The development strategy for <unk> two.

As it follows an.

Is that factoring into your thinking at all as you decide how to prioritize the next steps for <unk> hundred 92, I know that you have.

Talk about advancing into CRC, but there is other realms as well.

Yes, so as we're thinking about development plan. We're obviously looking at multiple factors I think clinical unmet need its a big focus.

So.

We're closely watching the FDA trends.

Of course, taking that into account.

As we are developing our plans realizing of course that we intend to develop our therapies.

Globally right. So we have to look at the regulatory climate around the world, but really we're focused on areas, where we believe.

That our experimental medicine may demonstrate benefit for patients with cancer.

Got it and then lastly, just one housekeeping in terms of the Cabo revenue line.

Just thinking back to over the past summer, where the clinical trial sales and you also did breakout within the $2, 95% that you had that $8 million or for clinical trial sales can you give us a sense for what that means.

Your visibility into clinical trial sales in 2022.

Is there anything in particular about quarters that can hit or miss or make things maybe.

Maybe unique one off events.

Yes, Chris it's Chris.

I'd say, we don't have.

Very good visibility is obviously up to those that are running the trial to place the purchase order with us so generally.

Those timings, we will find out few weeks few months in advance and so we don't have good visibility throughout the year, but it's not included in our guidance number.

Got it and then lastly, if I could squeeze one more in Mike. Congratulations you had a new add to the board at the end of the year I was intrigued to see it with someone from outside of healthcare in the tech sector tell us about how you were thinking about the overall composition of the board <unk> had some folks who've been around for a very long time Lance in stereo and whatnot and you made an addition here how should we be interpreting.

That thinking at the board level.

Sure. So we're very pleased to have Jackie Wright joined the board from from Microsoft She is a.

Amazing resource to us from a broad.

And digital technology perspective, and as I'm sure we've talked about at a high level previously part of our part of our corporate growth and part of our really expansion into digital.

As a key component to how we want to go not only by close to <unk>, but also globally going forward. So to have her engaged is just a tremendous resource for us we're going to learn a lot from her and look forward to engaging with her on all aspects of both her view of how to really digitize health care, but also been helping our business become.

A much more efficient digitally as well.

Great. Thank you for all the questions.

Chris.

Thank you as a reminder, ladies and gentlemen that star one to ask a question.

Our next question comes from the line of Stephen Willey with Stifel. Your line is open.

Our next question comes from the line of Mike King with HC Wainwright, your line is open.

Our next question comes from the line of Mike King with H.C. Wainwright.

Hey guys, thanks for taking the question.

Your line is open.

Yes, Thanks for squeezing me in.

I just wanted maybe to follow up on Jay's question about, Use in first line RCC.

Just a question on <unk> and then actually I just have a quick follow up.

With respect to <unk>. So I know the stellar 303 study was obviously predicated on the notion that you had this sort of good data with Cabo.

But I guess when we look at the GE <unk> development strategy with Bristol.

We have nebo Cabo plus <unk> combo.

Data in both RCC and bladder and we have a <unk> data in prostate.

Obviously, no IL two data yet but.

Just trying to better understand how the.

The <unk> strategy is I guess going a bit deeper on the expansion cohort side as opposed to go into a phase III like you did with stellar.

Vicki you want to take a shot at that and maybe I can provide some color commentary afterwards.

Yes, sure happy to.

Right. So we're looking at multiple potential combinations for <unk> I think as I said earlier.

We may in order to advance the program quickly look also at.

Data coming out of the cosmic <unk>, one trial, which is cabozantinib right to move forward in a limited number of steadying, the colorectal cancer being one of them.

And again, you may see additional phase III launch from there down the road, but we believe that Io checkpoint inhibitors in Io combos are important for the combination of <unk> and that study stellar or two which recently initiated enrollment will be important to evaluating the potential of <unk>.

Two in combination with those agents.

Yes, maybe I can just add Steve that we are in the business of raising the bar.

In terms of standard of care for patients everything we do is focused on that so less about generating meteor data, but it's more about go into the next level and I think things like <unk> or <unk>.

Good example of that first first company first trial and going against.

<unk> as the as the control arm.

Certainly with <unk>, two we have the opportunity to do that across.

Broad indications of process across narrow indications as we develop that program. So so I wouldn't look at the stellar <unk> as the first first wave really of that of that signal searching single validating type efforts, while we're launching a pivotal trial program. We have a variety of other discussions ongoing with other combination.

Partners other other combination.

Owners, if you walk into with different different Io and other types of molecules that we and they want to combine with <unk>. So the program is advancing.

<unk>.

Multi dimensional way and I think what you're seeing here is just the beginning.

Okay. That's helpful. And then just one quick follow up on.

On stellar so I know.

Camilo was a investigator sponsored trial.

But I know that study used a modified resist criteria.

And I've seen it used before in.

Yes, I don't know Steve.

Do you have anything you can say there.

Not really I don't know specifically, but what I would say is that having the two data sets, including our own internal dataset from cosmic <unk> 'twenty one.

Both trending in the same direction in terms of better overall response rate then we would expect with historic controls and although they are both single arm the PFS and OS.

And we're also encouraging.

Relative to what has been seen historically for <unk>.

Okay. Thanks for taking the questions.

Yes, Thanks, Steve.

Thank you.

Okay.

At this time there are no further questions in the queue I would now like to turn the call back over to today's host Susan Hubbard Ms. Hubbard, great. Yeah, great. Thank you I wanted to thank you all for joining US today, we certainly welcome your follow up calls with any additional questions you may have.

Do you have more color on the proportion of travel use that is in conjunction with a checkpoint?

Hey guys, thanks for taking the question.

And I'm just curious if those are what I say add-on therapy or is the regimen starting with as a triple?

I just wondered if maybe to follow up on Jay's question about, Use in first-line RCC.

Yeah, Mike, this is PJ.

Do you have more color on the proportion of travel use that is in conjunction with a checkpoint?

So I guess what I would say is that in the first line setting, you know, we previously we've had the Cabo Sun sort of data in our label, which was monotherapy when we got approved for combination usage a little over a year ago, with Cabo Medix in combination with Nivolumab in the first line, we really have seen the majority of utilization of Cabo Medix in the first line shift to that doublet, you know, given the given the strength of the data.

And I'm just curious if those are, what I say, add-on therapy or is the regimen starting with as a triple?

And, you know, oncologists have been highly receptive of that.

Um, Yeah, Mike, this is PJ.

So, but Q1, stay tuned.

Is that likely to be greater or less?

So really, that's what we're seeing, primarily in the first line setting with regards to Cabo Medix is, is utilization of the doublet, I think, you know, as we think forward, To 313, should that be a positive study in terms of CABO, NEVO, and IPPE, I think that just will potentially expand the market opportunity for CABO Medics in that first-line setting.

Understood.

Yeah, hey, Chris, it's PJ.

There's certainly a lot of patients that do receive the combination of NEVO, IPPE now in the first line, so I think if there's an opportunity to add CABO Medics with, you know, an appropriate risk-benefit profile to that, to those patients, we can get more and more patients should that study be positive, so hopefully that helps frame that for you.

In the first line, we really have seen the majority of utilization of Cabo Medix in the first line shift to that doublet, you know, given the strength of the data.

And last question.

You know, it certainly is a competitive market.

Great, I appreciate that.

And, you know, oncologists have been highly receptive of that.

For XL114, how are you thinking about the opportunity for a MALT1 inhibitor?

And that's what we've seen in the data with regards to to NEVO-ABA.

And maybe one for Vicky.

So really, that's what we're seeing primarily in the first line setting with regards to Cabo Medix is utilization of the doublet.

Is it primarily overcoming C-cellulophomas that have BTK inhibitor resistance?

As far as predicting it, given, as you point out, the competitive nature of the market, I wouldn't endeavor to do that.

On contact01, I'm just wondering how we ought to think about, you know, the combo of Cabo and Tezo.

I think, you know, as we think forward, To 313, should that be a positive study in terms of CABO, NEVO, and IPPE, I think that just will potentially expand the market opportunity for CABO Medics in that first-line setting.

Or are you expecting to see the drug, performed better than a BTK inhibitor in aggressive NHL.

You know, as I think about that, Though in terms of a potential positive 313 study, I think it just really gives us a lot of opportunity to add TKI, which is a mainstay of RCC treatment for.

Ladies and gentlemen that concludes today's conference call. Thank you for your participation you may now disconnect.

Ladies and gentlemen, that concludes today's conference call.

You know, there hasn't been a development of anti-veg Jeff in non-small cell in a while.

Yeah, this is Peter, let me let me take that one.

You know, 15 years now to a potential IO doublet, which obviously has a solid place in the treatment regimen.

I'm just thinking about how that, you know, that might, provide some upside that really hasn't been widely discussed here.

Great, I appreciate that.

I think you've correctly identified BTK resistance as a significant setting for 114.

So I think.

Yeah, thank you for the question.

And maybe one for Vicky.

The mechanism of action is clearly downstream of BTK in terms of inhibiting activation of the CARD-BCL-Mult1 complex.

Yeah, I think from more a dynamic perspective, that's how I think about things going.

So, so, right, contact 01 is a combination of cabozantinib with a tezolizumab versus docetaxel, which remains a standard of care in non small cell lung cancer after treatment with a checkpoint inhibitor, you know, plus or minus chemotherapy.

On contact 01, I'm just wondering how we ought to think about, you know, the combo of Cabo and Atezo.

So that's certainly an area of interest. There are also subsets of lymphomas, B-cell lymphomas specifically, where PTK inhibitors are not active, where there are other mutations in the pathway, including in MALT1 itself.

Got it.

It's really an underserved area with a lot of unmet need.

You know, there hasn't been a development of anti-VEGF and non-small cell in a while.

We believe 114 could have activity where BDK inhibitors wouldn't.

And then a question for Vicky perhaps.

The primary endpoint here is overall survival, and we're expecting a readout of an interim analysis on overall survival sometime later this year.

Just thinking about how that, you know, that might, provide some upside that really hasn't been widely discussed here.

So those are the two kind of early stage or initial stage opportunities that, could be could be examined.

Vicky, I know you come from a lot of experience working at some of the leading players in oncology, Merck Bristol, as well as at the FDA.

Again, you know, docetaxel is an old therapy with not particularly good outcomes.

Yeah, thank you for the question.

Great, thank you.

We've been observing more broadly across the industry some interesting decisions by the FDA, perhaps even over the last couple of weeks, where we're seeing this question of timelines for acceleration of approval be factored in with this question of unmet need.

And so we really believe this is an area of high unmet need and an opportunity to demonstrate, you know, further benefit for these patients.

So, so right, contact 01 is a combination of cabozantinib with a tezolizumab versus docetaxel, which remains a standard of care in non-small cell lung cancer after treatment with a checkpoint inhibitor, you know, plus or minus chemotherapy.

Thanks for taking my question and congrats on the quarter.

And I'm asking this question in the context of how you're thinking about the development strategy for 092 as it follows in.

So we're looking forward to that readout later this year.

It's really an underserved area with a lot of unmet need.

Thank you, Joe.

Is that factoring into your thinking at all as you decide how to prioritize the next steps for 092?

Thanks much, appreciate it, that mic.

The primary endpoint here is overall survival, and we're expecting a readout of an interim analysis on overall survival sometime later this year.

Thank you.

I know that you've talked about advancing into CRC, but there's other realms as well.

Thank you.

Again, you know, docetaxel is an old therapy with not particularly good outcomes.

Our next question comes from the line of Peter Lawson with Barclays.

Yes, so as we're thinking about development plans, you know, we're obviously looking at multiple factors.

Thank you.

And so we really believe this is an area of high unmet need and an opportunity to demonstrate, you know, further benefit for these patients.

Your line is open.

I think clinical unmet need is a big focus. Areas where we believe we have the opportunity to transform the care of patients with cancer.

Our next question comes from the line of Yaron Werber with Cowan, your line is open.

So we're looking forward to that readout later this year.

Great.

And of course, at the same time, as we're thinking about this, we are watching the regulatory landscape and thinking about how that may impact our development plans.

Thanks very much.

Thanks much, appreciate it, that mic.

Thank you.

So we're closely watching the FDA trends, of course, taking that into account as we're developing our plans, realizing, of course, that we intend to develop our therapies globally, right?

This is Gayvon for your own.

Thank you.

Thanks for taking the questions.

So we have to look at the regulatory climate around the world, but really we're focused on, you know, areas where we believe that our experimental medicines may demonstrate benefit for patients.

So my questions are on the pipeline.

Thank you.

XL102, so your CDK7 inhibitor.

Got it.

First, what kind of data can we expect for the CDK-7 program, XL102, in the second half? Specifically, will it be data from multiple cohorts, multiple dose cohorts?

Our next question comes from the line of Yaron Werber with Cowan.

What should we think about as success and what should we be looking for in that data later this year?

And then lastly, just one housekeeping in terms of the Cabo revenue line, just thinking back to over the past summer, where the clinical trial sales, and you also did a breakout within the 295 that you had that 8 million were for clinical trial sales.

Do you expect to see monotherapy activity with objective responses?

Your line is open.

Yeah, Peter, it's Mike, it's probably premature to give you that level of guidance.

Can you give us a sense for what that, you know, your visibility into clinical trial sales in 2022?

And then for XL092 in CRC, Vicky touched on a little bit, but could you please discuss a little more detail, maybe some of the early data that gives you confidence to go into the third line pivotal study versus reg rafnib?

Thanks very much.

It's, it's early in the year.

Is there anything in particular about quarters that can hit or miss or make things maybe unique, one-off events?

Thank you.

This is Gabon for your own.

And we'll, we'll have a pretty fulsome update when we do present that later in the year.

Thanks.

Sure.

So my questions are on the pipeline.

Peter, if you would like and can go through the basic biology there and give you a sense on how we think one or two is different.

Yeah, Chris, it's Chris.

Thanks for the question.

First, what kind of data can we expect for the CDK-7 program, XL102, in the second half? Specifically, will it be data from multiple cohorts, multiple dose cohorts?

But again, it's, it's, it's probably early to start opining upon what we might see in a presentation, you know, months and months from now.

So I'd say, you know, we don't have, you know, very good visibility.

So I'll take the 102 first.

Do you expect to see monotherapy activity with objective responses?

Peter, do you want to say a few words?

It's, it's obviously up to those that are running the trial to push place the purchase order with us.

Right now, we're in dose escalation with 102, and that's what we anticipate.

Oh, sure, yeah, so...

So, you know, generally, you know, that those timings will find out, you know, a few weeks, few months in advance.

We anticipate the dose escalation cohorts will be presented at a medical conference sometime later this year.

Thank you.

You know, I think if you look at the history of CDK inhibitor development, we're at a pretty interesting stage right now.

And so we don't have good visibility throughout the year, but it's not included in our guidance.

So, these will still be fairly early data, and we will also look forward to additional clinical updates on that molecule in 2023.

Sure.

You know, one way or another, people have been trying to advance CDK inhibitors for probably 20 years.

Got it.

Regarding your question on the phase 3, planned phase 3 in colorectal cancer for O9-2, So this is a study in patients with third line microsatellite stable metastatic colorectal cancer. So they've failed other therapies. We were acquiring documented RAF mutation status and basically randomizing them to either XL092 with the tezolizumab or to regARAF. The data that are supporting this study come from two studies that were presented at ASCO-GI, as I mentioned earlier in my remarks. One was a cohort of COSMIC-021, and the other was an investigator-sponsored trial called the CAMILA study.

Thanks for the question.

If you look at the CDK family, they really fall, broadly speaking, into two buckets. There are those CDKs that are primarily involved in cell cycle regulation. CDKs 1 and 2, CDK 4 and 6, where obviously we have clinical proof of concept for that mechanism.

And lastly, if I could squeeze one more in.

So I can quickly run through some of those results for you.

So I'll take the 102 first.

And then CDK 7 also clearly falls into that group. It sits upstream of both CDK 4 and 6 and 1 and 2, and very clearly has a role in controlling entry into various phases of the cell cycle.

Mike, congratulations, you had a new ad to the board at the end of the year.

The COSMIC-O21 colorectal cancer cohort response rate overall was 10%, but what we saw was a 25% response rate in patients who were RAS-WILD type. That was in combination with a tezolizumab in patients who had no known MSI high or DMMR. So, a similar population to what we plan to study in 303.

Right now, we're in dose escalation with 102, and that's what we anticipate.

So, you know, there are a lot of interesting opportunities for a CDK7 inhibitor, CDK4, 6 inhibitor resistance, you know, being just one of those.

I was intrigued to see it was someone from outside of healthcare in the tech sector.

Likewise, in Camila, the overall response rate in the overall population was 28%.

We anticipate the dose escalation cohorts will be presented at a medical conference sometime later this year.

Other tumor types such as triple negative breast or ovarian, other possible opportunities. Then I would just add, in addition to its CDK regulatory role, CDK7 also directly enhances transcription from both AR and ER, so then at least opportunities, combination in ER and AR dependent tumors.

Tell us about how you were thinking about the overall composition of the board.

But again, in RAS-WILD type, patients did better with a 50% response rate.

So these will still be fairly early data, and we will also look forward to additional clinical updates on that molecule in 2023.

Profile of a CDK7 Inhibitor, Second, I think this is a mechanism of action where you're really going to want to have maximal dosing flexibility to give you the best chance of optimizing therapeutic index.

You've had some folks who've been around for a very long time, Lance and Stelios and whatnot, and you made an addition here.

And this was a Dervalumab combo also in microsatellite stable patients.

Regarding your question on the Phase 3, planned Phase 3 in colorectal cancer for O9-2, So, this is a study in patients with third-line microsatellite-stable metastatic colorectal cancer. So, they've failed other therapies. We're acquiring documented RAS mutation status and basically randomizing them to either XL092 with the tezolizumab or to regARAS.

Excel 102 is a covalent inhibitor, but it, at least in preclinical models, clears out all the plasma out of the circulation very rapidly.

How should we be interpreting that thinking at the board level?

So, as a result of these findings, we believe that the place we're most likely to see benefits is the wild-type patient population, and so the primary overall survival endpoint will be focused on RAS wild-type.

The data that are supporting this study come from two studies that were presented at ASCO GI, as I mentioned earlier in my remarks.

So you don't have a lot of it hanging around in the circulation, but you do have a prolonged pharmacodynamic duration of action based on the covalent, covalent, Maybe I'll just finish by kind of segwaying into a sort of related program.

For sure.

However, we will also look at the population overall.

One was a cohort of COSMIC-021, and the other was an investigator-sponsored trial called the CAMILA study. So I can quickly run through some of those results for you. The COSMIC-021 colorectal cancer cohort response rate overall was 10%, but what we saw was a 25% response rate in patients who were RAS-WILD type.

Yeah, well, the second bucket of kind of CDKs are not that much involved in cell cycle regulation, but they are involved in regulating transcription, and various subsets of genes, and that would include CDK9, but also CDK12 and 13.

So we're very pleased to have Jackie Wright join the board from Microsoft.

And just, sorry, maybe I'll add, just for point of reference, the typical regoraphanib response rate is about 2%.

That was in combination with a tezolizumab in patients who had no known MSI high or DMMR. So, a similar population to what we plan to study in 303.

Cdk12-13, as we have a program ongoing preclinically with AuraGene, nothing in the clinic yet for a Cdk12 inhibitor. I think it's very interesting, based on a lot of biology, but one part of which is that Cdk12 is very much involved in regulating the transcription of DNA damage response genes.

She is a just amazing resource to us from a broad IT and digital technology perspective.

Great, thank you.

Likewise, in Camila, the overall response rate in the overall population was 28%.

, Brad 51, BRCA, and the like.

And as I'm sure we've talked about at a high level previously, part of our corporate growth and part of our really expansion into digital is a key component to how we want to go not only bi-coastally, but also globally going forward.

Thank you.

But again, in RAS-WILD type, patients did better with a 50% response rate.

So there's lots of potential directions in which to take a CDK-12 inhibitor.

So to have her engaged is just a tremendous resource for us.

Our next question comes from Akash Tewari with Jeff.

And this was a Dervalumab combo also in microsatellite stable patients.

Hopefully if things go well, we'll be advancing one into preclinical development in another two days.

We're going to learn a lot from her and look forward to engaging with her on all aspects of both her view of how to really digitize healthcare, but also then helping our business become much more efficient digitally as well.

The line is open.

So, as a result of these findings, we believe that the place we're most likely to see benefit is the wild-type patient population, and so the primary overall survival endpoint will be focused on RAS wild-type.

Thank you.

Great.

This is Amy on for Akash.

However, we will also look at the population overall.

And the CDK7 inhibitor, do you think it could have single agent activity or really requires a combination?

Thank you for all the questions.

Thanks so much for taking your questions.

And just maybe I'll add, just for point of reference, the typical regoraphanib response rate is about 2%.

Well, I can tell you, certainly pre-clinically, what we've seen is we've seen robust single-agent activity in a number of different models.

Thank you, Chris.

Just wanted to contextualize your 2022 CABO revenue guidance of $1.375 billion at midpoint with your prior expectations of CABO hitting a $1.5 billion run rate by the end of this year.

Great, thank you.

Yeah, as Vicky commented, with Excel 102, we're fairly early in the dose escalation at this point in time.

Thank you.

Are you still comfortable with this run rate?

Thank you.

So, you know, certainly there's a rationale, both as a single agent and in combination, but time will tell with respect to the development of clinical trials.

As a reminder, ladies and gentlemen, that's Star 1 to ask a question.

Additionally, have you seen any seasonality around CABO demand and channel inventory?

Our next question comes from Akash Tewari with Jeff.

Thank you.

Our next question comes from Elana Stephen Willey with CFO.

And is there any color you can provide on real world median duration of treatment for CABO in RCC?

The line is open.

Just a final question around First Line HEC.

Elana, so.

Thanks so much.

This is Amy on for Akash.

The filing for 312, is that, dependent upon OS being significant and is HCC an area where 0.9.2 could move?

Yeah, thanks for squeezing me in.

Yeah, thanks for the question, Amy.

Thanks so much for taking your questions.

Yes, so for 312, we'll be seeing the final OS analysis later this quarter, and we'll be evaluating the totality of the data and in consideration of the evolving treatment landscape before deciding whether or not it's appropriate to file and yes to answer your other question we do see potential for O9-2 in hepatocellular carcinoma as we do in other tumor types where cabozantinib has demonstrated activity and we'll be thinking about development plans for O9-2 in that tumor as well.

Just a question on 092 and then actually just have a quick follow-up, but, With respect to ONIT, so I know the Stellar 303 study was obviously predicated on the notion that you had this surrogate data with Cabo.

So, um, from a from an inventory perspective, I'll start with that one. I touched on it during the, in my prepared remarks, the, you know, inventory stayed relatively flat, Q3 versus Q4. It actually was flat all year. It's it but from a weeks on hand perspective, but it has been growing in line with demand throughout the year as demand increased.

Just wanted to contextualize your 2022 CABO revenue guidance of $1.375 billion at midpoint with your prior expectations of CABO hitting a $1.5 billion run rate by the end of this year.

Perfect.

But I guess when I look at the GU development strategy with Bristol, you know, we have NEBO-CABO plus I think IPI-NEBO-CABO data in both RCC and bladder.

The first question is...

Are you still comfortable with this run rate?

Thank you so much.

We have a Tezo-CABO data in prostate.

That's seasonality, but that's part of the inventory.

Additionally, have you seen any seasonality around CABO demand and channel inventory?

Thanks for taking the question.

Obviously no IL-2 data yet, but, Just trying to better understand how the GU strategy is, I guess, going a bit deeper on the expansion cohort side as opposed to going into a phase three like you did with Stella.

On the $1.5 billion run rate, if you think about where we guided, it does get you into that range of getting to a run rate of $1.5 billion as we exit.

And is there any color you can provide on real world median duration of treatment for CABO in RCC?

Thank you, Peter.

Vicki, you want to take a shot at that?

Great.

Thanks so much.

Thank you.

Maybe I can provide some commentary afterwards.

And just to Oh, sorry, this is PJ just to kind of take the question with regards of duration of therapy that we were our thoughts about that and coblematics and combination of the first line setting it's, you know, we've been on the market for a year.

Yeah, thanks for the question, Amy.

Our next question comes from the line of Kenny McKay with RBC Capital Markets.

Yeah, sure.

So in the trial, we see year and a half, give or take, Or more of, you know, PFS.

Hey, thanks for taking the question.

Happy to.

So it's really early to be able to have a look back to see the significant duration we're expecting from 9ER.

The first question is...

For Mike or maybe Vicki, how quickly do you think the COSMIC 313 data could be turned around into an FNDA if it's successful?

Right, so we're looking at multiple potential combinations for XL092.

But as I mentioned, you know, we believe that's a driver of significant growth for us.

That's seasonality, but that's part of the inventory.

If that data is in the first half, is that SBLI something that could happen later this year?

I think, as I said earlier, we may, in order to advance the program quickly, look also at data coming out of the COSMIC-021 trial, which is cabozantinib, right, to move forward in a limited number of settings, the colorectal cancer being one of them, you know, and again, you may see additional phase 3s launched from there down the road.

And I would just say that we're, we're certainly pleased with what we're seeing thus far.

Oh, the 1.5, sorry.

And then maybe for PJ, with three Category 1 NCCN recommendations for frontline treatment of favorable risk, RCC, and four for poor and intermediate risk, what have been the drivers of physician preference for one regimen over another?

But we believe that I.O., you know, checkpoint inhibitors and I.O.

Great.

So the on the $1.5 billion run rate.

And echoing on that, is there anything in the longitudinal Checkmate 90R data at ASCA GU this weekend that you think could impact physician choice here?

combos are important for the combination of O9-2, and that study, STELLAR-002, which recently initiated enrollment, will be important to evaluating the potential of O9-2 in combination with those agents.

Thank you so much.

Yeah, I mean, if you think about where we guided it, it does, it does get you into that, into that range of getting to a run rate of 1.5 as we, Great.

Thanks.

Yeah, maybe I can just add, Steve, that, you know, we're in the business of raising the bar in terms of standard of care for patients.

Yeah, thank you, Amy.

And just to Oh, sorry, this is PJ, just to kind of take the question with regards of duration of therapy that we were our thoughts about that.

Vicki, do you want to take that one?

Everything we do is focused on that.

Thank you.

And CobbleMedix in combination in the first line setting, it's, you know, we've been on the market for a year.

You want to take the 313? Yeah, sure, happy to.

So less about generating Me Too data, but it's more about going to the next level.

Our next question comes from the line of Duke Kim with Piper Sandler.

So in the trial, we see year and a half, give or take, or more of, you know, PFS.

Right, so we are expecting to see the COSMIC 313 progression-free survival primary endpoint readout in the first half of this year.

And I think things like 3.13 are a good example of that.

Your line is open.

So it's really early to be able to have a look back to see the significant duration we're expecting from 9ER.

We're obviously working with a partner on this study, Bristol Myers Squibb, and we will be very motivated to work very closely with them and get that filing in as soon as possible, data-dependent.

First company, first trial is going against, you know, IOIO as the control arm.

Hi, thanks for taking my questions.

But as I mentioned, you know, we believe that's a driver of significant growth for us.

Great, and it's PJ Kennan.

And, you know, certainly with 09.2, we have the opportunity to do that across.

First, on contact 01, I was hoping you could frame for us the expected median survival for the control arm and maybe provide what your expectation or the hazard ratio that the study is powered to show.

And I would just say that we're, we're certainly pleased with what we're seeing thus far.

With regards to your question, In terms of physician preference, and kind of what we're seeing in first line, you know, our utilization, as I've mentioned, is, is broad.

Broad indications, across narrow indications as we develop that program.

Yeah, so, There really aren't great data in this setting of second line.

Great.

And that's really cuts across the the clinical risk groups of favorable intermediate and poor, poor risk disease.

So I would look at the, you know, STELLAR-001, STELLAR-002 as the first wave, really, of that signal searching, signal validating type efforts while we're launching the pivotal trial program.

So, you know, as standard of care has changed.

Thank you so much.

You know, we're also seeing broad uptake, whether it's community, or academic settings.

We have a variety of other discussions ongoing with other combination partners, other combination, you know, owners, if you will, people with different IO and other types of molecules that we and they want to combine with 09.2.

The, You know, there isn't great data.

Yeah, thank you, Amy.

And I think that's really, it's really driven by the balance of kind of efficacy, tolerability and quality of life data that we see 90-R and I think that's resonating really well with prescribers and they're seeing good results in their patients.

So the program is advancing really in a multidimensional way.

Dosataxel is used because it was the second line therapy following platinum therapy in the past and has continued to be a second line therapy in patients who've received, you know, generally speaking in IO and platinum combination.

Thank you.

So I think that we're only a year into this.

And I think what you're seeing here is just the beginning.

So, I can speak to the fact that, you know, for patients who had lung cancer in the past, metastatic lung cancer, the median survivals were less than a year in the first line, and obviously substantially shorter than that in the second line, and.

Our next question comes from the line of Duke-Kim with Piper Sandler.

So I think the experience they're getting gives us further opportunity to.

Okay, that's helpful.

We're shooting really for a substantial clinical effect here with respect to the Atezo-Cabo combination.

Your line is open.

To continue to kind of grow in that perspective, you know, what I'll say with regards to the data this weekend is, you know, we're certainly pleased with it in terms of the longer follow-up, you know, I think the, it shows the durability of the data, data set overall, the complete response rate increasing to about 12% certainly is a plus, and, you know, importantly, you know, nothing to really change the perception of the tolerability profile.

And then just one quick follow up on, on stellar.

And so, again, we'll see the first data from an interim analysis of overall survival later this year.

Hi, thanks for taking my questions.

So I think just more follow-up gives our story, you know, a little more power behind it.

So I know, Camilla was a investigator sponsored trial. But I know that study used a modified resist criteria.

Okay, thanks.

First on contact 01, I was hoping you could frame for us the expected median survival for the control arm and maybe provide what your expectation or the hazard ratio that the study is powered to show.

So we're very pleased with that.

And I've seen it used before in Liver cancer but I guess I haven't seen it used before in colorectal and so just wondering if you guys know why a modified or assist response was used in this instance, Did patients all have liver meds or something?

And I have another question on seasonality for Cabo sales.

Yeah, so, There really aren't great data in this setting of second line.

And, you know, as I mentioned, we're very optimistic towards the momentum of the business this year.

I'm just trying to figure that out.

As we look to 2022, should we start seeing your typical first quarter seasonality due to reimbursement factors?

So, you know, as standard of care has changed.

Thanks Kenan.

Thanks.

Looking back at the sales for Cabo, you seem to have any potential impact?

The, You know, there isn't great data.

Thank you.

Yeah, I don't know, Steve.

Is it something we should start considering now?

Dosetaxel is used because it was the second-line therapy following platinum therapy in the past and has continued to be a second-line therapy in patients who've received, you know, generally speaking, NIO and platinum combination.

Our next question comes from the line of Jeff Hung with Morgan Stanley.

Vicki, do you have anything you can say there?

Or do you manage the growth to net to offset those factors?

Thank you for taking the question.

Not really.

Hey Joe, it's Mike.

We're shooting really for a substantial clinical effect here with respect to the Atezo-Cabo combination.

Most of my questions have been asked.

I don't know specifically, but what I would say is that having the two data sets, including our own internal data set from COSMIC-021, both, you know, trending in the same direction in terms of better overall response rate than we would expect with historic controls.

Probably not wise for us to be giving, you know, Q1 guidance in the middle of Q1.

And so, again, we'll see the first data from an interim analysis of overall survival later this year.

So maybe one on partnerships, since you mentioned that you expect to bring additional clinical partnerships forward, can you talk about your strategy going forward in terms of collaborations for additional technologies?

And although they're both single arm, the PFS and OS medians were also encouraging relative to what has been seen historically for regoraphanib.

So, you know, stay tuned on the numbers when we have the Q1 call in May.

Okay, thanks.

Is it more to be more opportunistic with new platforms and technologies?

Okay, thanks for taking the question.

You know, we feel really good about how the brand is doing.

And I have another question on seasonality for Cabo sales.

Or are there certain capabilities and technologies that you want to remain more focused on?

Yeah, thanks, Steve.

The, again, timing with ASCO-GU and the call are somewhat fortuitous.

As we look to 2022, should we start seeing your typical first quarter seasonality due to reimbursement factors?

Thanks, Peter.

Thank you.

But, you know, we have a lot of support out there, both in the academic and community setting.

Looking back at the sales for Cabo, you seem to grow through any potential impact.

Yeah, I mean, you know, as I kind of alluded to earlier, on the discovery preclinical side, we've been we continue to look broadly, both on the biotherapeutics and small molecule sides, both for platforms that we think will be complementary to what we have access to now, and that may kind of broaden our ability to, We're happy to do those as they make sense for us and our partners.

At this time, there are no further questions in the queue, so I would now like to turn the call back over to today's host, Susan Hubbard.

And we feel like, you know, based on the data and based on the strong team that we have, we're going to continue to be able to educate physicians to the benefits of that combination.

Is it something we should start considering now?

Of course, we continue to look at assets as well, individual assets as well, particularly ones that are either late preclinical or early clinical, but I think as we've said a number of times before on that front, it has to be an asset that we have conviction behind in terms of being able to mount an effective clinical development campaign.

Ms. Hubbard?

Or do you manage the growth in that to offset those factors?

Basically, it's the right molecule, right time, right price kind of mantra that we're still sticking to that.

Great.

Hey, it's Mike.

Thank you, Jeff.

Yeah, great.

Probably not wise for us to be giving, you know, Q1 guidance in the middle of Q1.

Thank you.

Thank you, Tawanda, and thank you all for joining us today.

So, you know, stay tuned on the numbers.

Our next question comes from a line of Chris Shibutani with Goldman Sachs.

We certainly welcome your follow-up calls if any additional questions you have.

When we have the Q1 call in May, you know, we feel really good about how the brand is doing.

Great.

The, again, timing with ASCO-GU and the call are somewhat fortuitous, but, you know, we have a lot of support out there, both in the academic and community setting.

Thank you for the questions.

And we feel like, you know, based on the data and based on the strong team that we have, we're going to continue to be able to educate physicians to the benefits of that combination.

You described the first line RCC marketplace as being a very competitive dynamic.

So, but Q1 stay tuned.

Two questions, and it certainly has been where the regimens that have taken primacy have shifted.

Understood.

The use of the IO doublet, NEBO, in combination with IPI, what would you say is the outlook for what the share of use could be in the first line setting over the coming years?

And last question.

I think you previously said it's about 20-25%.

For XL114, how are you thinking about the opportunity for a Malt-1 inhibitor?

Is that going to be stable?

Is it primarily overcoming C-cellulophomas that have BTK inhibitor resistance?

Is that likely to be greater or less?

Or are you expecting to see the drug, performed better than a BTK inhibitor in aggressive NHL.

Yeah, hey, Chris, it's PJ.

Yeah, this is Peter.

You know, it certainly is a competitive market.

Let me let me take that one.

And that's what we've seen in the data with regards to Nebo API.

I think you correctly identified BTK resistance as a significant setting for 114.

As far as predicting it, given, as you point out, the competitive nature of the market, I wouldn't endeavor to do that.

You know, the mechanism of action is clearly downstream of BTK in terms of inhibiting activation of the, you know, card BCL multibond complex.

You know, as I think about that, Though in terms of a potential positive 313 study, I think it just really gives us a lot of opportunity to add TKI, which is a mainstay of RCC treatment for.

So that's certainly an area of interest. There are also subsets of lymphomas, B-cell lymphomas specifically, where BTK inhibitors are not active, where there are other mutations in the pathway, including in MALT1 itself, where we believe 114 could have activity where BTK inhibitors wouldn't.

You know, 15 years now to a potential IO doublet, which obviously has a solid place in the treatment regimen.

So those are two kind of early stage, or initial stage opportunities that.., could be could be examined.

So I think.

Great, thank you.

Yeah, I think from more a dynamic perspective, that's how I think about things going.

Thanks for taking my question and congrats on the quarter.

Got it.

Thank you.

And then a question for Vicky perhaps.

Thank you.

Vicky, I know you come from a lot of experience working at some of the leading players in oncology, Merck Bristol, as well as at the FDA.

Our next question comes from the line of Peter Lawson with Barclays.

Your line is open.

And I'm asking this question in the context of how you're thinking about.

Great.

The development strategy for O9-2 as it follows in, is that factoring into your thinking at all as you decide how to prioritize the next steps for O9-2?

Thank you.

I know that you've talked about advancing into CRC, but there's other realms as well.

Thanks for taking the questions.

Yes, so as we're thinking about development plans, you know, we're obviously looking at multiple factors.

XL 102 so you see cdk7 inhibitors, What should we think about as success and what should we be looking for in that data in the data this year?

I think clinical unmet need is a big focus. Areas where we believe we have the opportunity to transform the care of patients with cancer.

Yeah, Peter, it's Mike.

And of course, at the same time, as we're thinking about this, we are watching the regulatory landscape and thinking about how that may impact our development plans.

It's probably premature to give you that level of guidance.

So we're closely watching the FDA trends, of course, taking that into account as we're developing our plans, realizing, of course, that we intend to develop our therapies globally, right?

It's, it's early in the year.

So we have to look at the regulatory climate around the world, but really we're focused on, you know, areas where we believe that our experimental medicines may demonstrate benefit for patients.

And we'll, we'll have a pretty fulsome update when we do present that later in the year.

Got it.

Peter, if you would like and can go through the basic biology there and give you a sense on how we think one or two is different.

And then lastly, just one housekeeping in terms of the Cabo revenue line, just thinking back to over the past summer where the clinical trial sales, and you also did a breakout within the 295 that you had that 8 million were for clinical trial sales.

But again, it's, it's probably early to start opining upon what we might see in a presentation months and months from now.

Can you give us a sense for what that, you know, your visibility into clinical trial sales in 2022?

Peter, do you want to say a few words?

Is there anything in particular about quarters that can hit or miss or make things maybe unique, one-off events?

Oh, sure, yeah, so...

Thanks.

You know, I think if you look at the history of CDK inhibitor development, we're at a pretty interesting stage right now. You know, one way or another, people have been trying to advance CDK inhibitors for, I don't know, probably 20 years.

Yeah, Chris, it's Chris.

So I'd say, you know, we don't have, you know, very good visibility.

And then CDK 7 also clearly falls into that group. It sits upstream of both CDK 4 and 6 and 1 and 2, and very clearly has a role in controlling entry into various phases of the cell cycle.

It's, it's obviously up to those that are running the trial to push place the purchase order with us.

So, you know, there are a lot of interesting opportunities for a CDK7 inhibitor and a CDK4, 6 inhibitor resistance, you know, being just one of those.

So, you know, generally, you know, that those timings will find out, you know, a few weeks, few months in advance.

Other tumor types such as triple negative breast or ovarian, other possible opportunities. Then I would just add, in addition to its CDK regulatory role, CDK7 also directly enhances transcription from both AR and ER. So then at least opportunities, combination in ER and AR dependent tumors.

And so we don't have good visibility throughout the year, but it's not included in our guidance.

Exxel 102, Exxel-107, Exxel-101, Exxel-107, Exxel-108, Exxel-109, Exxel-108 and Exxel-103.

Got it.

Second, I think this is a mechanism of action where you're really going to want to have maximal dosing flexibility to give you the best chance of optimizing therapeutic impact.

And lastly, if I could squeeze one more in.

Excel 102 is a covalent inhibitor, but it, at least in preclinical models, clears out all the plasma out of the circulation very rapidly. So you don't have a lot of it hanging around in the circulation, but you do have a prolonged pharmacodynamic duration of action based on the covalent.

Mike, congratulations, you had a new ad to the board at the end of the year.

Maybe I'll just finish by kind of segwaying into a sort of related program.

I was intrigued to see it was someone from outside of healthcare in the tech sector.

Tell us about how you were thinking about the overall composition of the board.

You've had some folks who've been around for a very long time, Lance and Stelios and whatnot, and you made an addition here.

Braga and the like.

How should we be interpreting that thinking at the board level?

So there's lots of potential directions in which to take the CDK12 inhibitor.

For sure.

Hopefully if things go well, we'll be advancing one into pre-clinical development in another, Thank you.

So we're very pleased to have Jackie Wright join the board from Microsoft.

And the CDK7 inhibitor, do you think it could have single agent activity or really requires a combination?

She is a just amazing resource to us from a broad IT and digital technology perspective.

Well, I can tell you, certainly pre-clinically, what we've seen is we've seen robust single-agent activity in a number of different models.

You know, as Vicky commented, with Excel 102, we're fairly early in the dose escalation at this point in time.

So to have her engaged is just a tremendous resource for us.

So, you know, certainly there's a rationale, both as a single agent and in combination, but time will tell with respect to the development of clinical trials.

Thank you.

Great.

Just a final question around First Line HEC.

Thank you for all the questions.

The filing for 312, is that.., dependent upon OS being significant and is HCC an area where 092 could move?

Thank you, Chris.

Yes, so for 312, we'll be seeing the final OS analysis later this quarter.

Thank you.

And we'll be evaluating the totality of the data and in consideration of the evolving treatment landscape before deciding whether or not it's appropriate to file.

As a reminder, ladies and gentlemen, that's stall one to ask the question.

And yes, to answer your other question, we do see potential for O9-2 in hepatocellular carcinoma, as we do in other tumor types where cabozantinib has demonstrated activity, and we'll be thinking about development plans for O9-2 in that tumor as well.

Our next question comes from Elana Stephen Willey with CFO.

Perfect.

Elana, so.

Thank you so much.

Yeah, thanks for squeezing me in.

Thanks for the question.

Just a question on 092 and then actually just have a quick follow-up, but, With respect to ONIT, so I know the Stellar 3L3 study was obviously predicated on the notion that you had this surrogate data with CABO.

Thank you, Peter.

But I guess when I look at the GU development strategy with Bristol, you know, we have NEBO-CABO plus, I think, IPI-NEBO-CABO data in both RCC and bladder.

Thank you.

We have a TESO-CABO data in prostate, obviously no IL-2 data yet, but, Just trying to better understand how the GU strategy is, I guess, going a bit deeper on the expansion cohort side as opposed to going into a phase three like you did with Stella.

Our next question comes from the line of Kenny McKay with RBC Capital Markets.

Vicki, you want to take a shot at that?

Hey, thanks for taking the question.

Maybe I can provide some commentary afterwards.

For Mike or maybe Vicki, how quickly do you think the COSMIC 313 data could be turned around into an SNDA if it's successful?

Yeah, sure.

If that data is in the first half, is that SBLI something that could happen later this year?

Happy to.

Right, so we're looking at multiple potential combinations for XL092.

And echoing on that, is there anything in the longitudinal Checkmate 90R data at ASCA GU this weekend that you think could impact physician choice here?

Thanks.

But we believe that I.O., you know, checkpoint inhibitors and I.O.

Vicki, do you want to take that one?

You want to take the 313? Yeah, sure, happy to.

Yeah, maybe I can just add, Steve, that, you know, we're in the business of raising the bar in terms of standard of care for patients.

Right, so we are expecting to see the COSMIC 313 progression-free survival primary endpoint readout in the first half of this year.

Everything we do is focused on that.

We're obviously working with a partner on this study, Bristol Myers Squibb, and we would be very motivated to work very closely with them and get that filing in as soon as possible, data-dependent.

So less about generating Me Too data, but it's more about going to the next level.

Great, and it's PJ Kennan.

And I think things like 3.13 are a good example of that.

With regards to your question, In terms of physician preference and kind of what we're seeing in first line, you know, our utilization, as I've mentioned, is, is broad.

First company, first trial is going against, you know, IOIO as the control arm.

And that's really cuts across the the clinical risk groups of favorable intermediate and poor, poor risk disease.

And, you know, certainly with 09.2, we have the opportunity to do that across.

You know, we're also seeing broad uptake, whether it's community, or academic settings.

Broad indications, across narrow indications as we develop that program.

And I think that's really, it's really driven by the balance of kind of efficacy, tolerability and quality of life data that we that we we see in 9ER. And I think that's resonating really well with prescribers. And they're, you know, seeing good results in their patients.

So I would look at the, you know, STELLAR-001, STELLAR-002 as the first wave, really, of that signal searching, signal validating type efforts while we're launching the pivotal trial program.

So I think that, you know, we're only a year into this.

So I think the experience they're getting, you know, gives us further opportunity to.

So the program is advancing really in a multidimensional way.

To continue to kind of grow in that perspective, you know, what I'll say with regards to the data this weekend is, you know, we're certainly pleased with it.

And I think what you're seeing here is just the beginning.

In terms of the longer follow up, you know, I think the it shows the durability of the data data set.

Okay, that's helpful.

Overall, the complete response rate increasing to about 12% certainly is a plus.

And then just one quick follow up on, on Stellar.

And, you know, importantly, you know, nothing to really change the perception of the tolerability profile.

So I know, Camilla was a investigator sponsored trial.

So I think just more follow up gives gives our story, you know, a little more, a little more power behind it.

But I know that study used a modify to resist criteria.

So we're very pleased with that.

And I've seen it used before in, Liver Cancer but I guess I haven't seen it used before in colorectal and so just wondering if you guys know why a modified or assist response was used in this instance?

And, you know, as I mentioned, we're very optimistic towards the momentum of the business this year.

Did patients all have liver meds or something?

Thanks Kenan.

I'm just trying to figure that out.

Thank you.

Thanks.

Our next question comes from the line of Jeff Hung with Morgan Stanley.

Yeah, I don't know, Steve.

Thank you for taking the question.

Vicki, do you have anything you can say there?

Most of my questions have been asked, so maybe one on partnerships, since you mentioned that you expect to bring additional clinical partnerships forward.

Not really.

Can you talk about your strategy going forward in terms of collaborations for additional technologies?

Is it more to be more opportunistic with new platforms and technologies, or are there certain capabilities and technologies that you want to remain more focused on?

And although they're both single arm, the PFS and OS medians were also encouraging relative to what has been seen historically for regoraphanib.

Thanks, Peter.

Okay, thanks for taking the question.

Yeah, thanks, Steve.

Of course, we continue to look at assets as well, individual assets there as well, particularly ones that are either late preclinical or early clinical.

Thank you.

But I think as we've said a number of times before on that front, it has to be an asset that we have conviction behind in terms of being able to mount an effective clinical development campaign.

At this time, there are no further questions in the queue, so I would now like to turn the call back over to today's host, Susan Hubbard.

And so basically, it's the right molecule, right time, right price kind of mantra that we're still sticking to there.

Ms. Hubbard?

Thank you, Jeff.

Great.

Thank you.

Yeah, great.

Our next question comes from a line of Chris Shibutani.

Thank you, Twanda, and thank you all for joining us today.

Goldman Sachs.

We certainly welcome your follow-up calls with any additional questions you may have.

Your line is open.

Great.

Thank you for the questions.

You described the first line RCC marketplace as being a very competitive dynamic.

Two questions, and it certainly has been where the regimens that have taken primacy have shifted.

The use of the IO doublet, NEBO, in combination with IPI, what would you say is the outlook for what the share of use could be in the first line setting over the coming years?

I think you previously said it's about 20-25%.

Is that going to be stable?

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