Q4 2021 Mirati Therapeutics Inc Earnings Call

Okay.

Sarah: Good afternoon and welcome to the Mirati Therapeutics fourth quarter 2021 earnings call. My name is Sarah and I will be the operator for today's call. All lines have been placed on mute to prevent any background noise.

Good afternoon, and welcome to the Marathi Therapeutics fourth quarter 2021 earnings call. My name is Sarah and I will be the operator for today's call.

All lines have been placed on mute to prevent any background noise. After the conclusion of the speakers prepared remarks, there will be a question and answer Sachin. If you would like to ask a question. During this time simply press star followed by the number one on your telephone keypad.

Sarah: After the conclusion of the speaker's prepared remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press the star key followed by the digit two.

We would like to withdraw your question press the Star key followed by the digit too. It is my pleasure to introduce Brian AC Vice President of corporate Affairs cut Marathi Ryan you may begin your call.

Sarah: It is my pleasure to introduce Ryan Acey, Vice President of Corporate Affairs at Mirati. Ryan, you may begin the call. Thank you, Sarah.

Ryan Acey: Welcome, everyone, to this afternoon's call. With me today are David Meek, Mirati's Chief Executive Officer, Dr. Jamie Christensen, Mirati's Chief Scientific Officer, Ben Hickey, Mirati's Chief Commercial Officer, and Vicki Reed, Mirati's Chief Accounting Officer. Unfortunately, due to a last-minute acute stomach flu, Dr. Chuck Baum, Mirati's President, Founder, and Head of Research and Development, will not be able to participate in this afternoon's call. Please note that this conference call will include forward-looking statements because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements.

Thank you Sarah and welcome everyone to this afternoons call with me today are David Meek, Marathi Chief Executive Officer, Dr. Jamey Christian <unk>, Chief Scientific Officer, Ben Hickey, Marathi, Chief Commercial officer, Linda He read varieties, Chief accounting officer. Unfortunately, due to a last minute stomach flu doctor Chuck Baum bodies.

<unk> founder and head of research and development will not be able to participate in this afternoons call.

Please note that this conference call will include forward looking statements because such statements deal with future events and are subject to many risks and uncertainties actual results may differ materially from those in the forward looking statements.

Ryan Acey: For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K that is filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended December 31st, 2021, and recent corporate updates. This press release is available on the investor section of our website at mirati.com. With that, I'll turn the call over to David. Thank you, Ryan.

For a full discussion of these risks and uncertainties. Please review our annual report on Form 10-K filed with the U S Securities and Exchange Commission.

Afternoon, We released financial results for the quarter ended December 31, 2021, and recent corporate updates. This press release is available on the investors section of our website a variety dot com with that I'll turn the call over to David. Thank you Ryan Good afternoon, everyone and thank you for joining us on this afternoon's call I will provide some initial remarks before asking Jamie.

David Meek: Good afternoon, everyone, and thank you for joining us. On this afternoon's call, I will provide some initial remarks before asking Jamie to share an update on our clinical development program. Ben to comment on our commercial preparedness and Vicky to summarize our financial results. I will then provide a few concluding remarks before taking your questions. 2021 was an important year of growth, progress, and strong execution for Mirati. There are many achievements our team accomplished, and I'll highlight just a few of them here.

To share an update on our clinical development programs.

To comment on our commercial preparedness and they can just summarize our financial results I will then provide a few concluding remarks before taking your questions 2021 was an important year of growth progress and strong execution for variety.

David Meek: We received breakthrough therapy designation for adagrassive for the treatment of previously treated KRAS G12c mutated non-small cell lung cancer. We announced positive top-line monotherapy data from the Registrational Phase II Cohort of Adegraseb's CRYSTAL1 study and completed the submission of the Adegraseb new drug application in patients with previously treated non-small cell lung cancer under the FDA's Real-Time Oncology Review Pilot Program. We presented highly encouraging colorectal cancer data for adegrassin both as a single agent and in combination with cetuximab in late-line patients.

There are many achievements our team accomplished and I'll highlight just a few of them here.

We received breakthrough therapy designation product grass it for the treatment previously treated K Ras G. Tor <unk> mutated non small cell lung cancer.

That was a positive top line monotherapy data from the Registrational phase III cohort by the glass, it's Crystal one study.

We did the submission of the art aggressive new drug application in patients with previously treated non small cell lung cancer under the Fda's real time oncology review pilot program.

We presented highly encouraging colorectal cancer data for autographs it both as a single agent and in combination with Cetuximab in late line patients.

David Meek: We also share preliminary results from the combination of adegrassin and peprolithumab and first-line non-small-cell lung cancer, which provided strong support for our continued prioritization of this combination. We initiated several additional potentially registrational studies with Adagrassi, including as a single agent in certain subpopulations of first-line non-small cell lung cancer, as well as in combination with cetuximab and second-line colorectal cancer. Beyond that aggressive, we continue to advance and expand our increasingly broad targeted oncology pipeline, including completing the submission of an investigational new drug application for MRTX1719, our MTA cooperative PRMT5 inhibitor.

We also share preliminary results from the combination of all the grass at Appaloosa Mab in first line non small cell lung cancer, which provided strong support for our continued prioritization of this combination.

We initiated several additional potentially registrational studies without aggressive.

Voting as a single agent in certain sub populations of first line non small cell lung cancer as well as in combination with Cetuximab in second line colorectal cancer.

Beyond that aggressive we continued to advance and expand our increasingly broad targeted oncology pipeline, including completing the submission of an investigational new drug application for M. R. T X 17 19.

Our MTA cooperative T O M. A C five inhibitor.

David Meek: In November, we bolstered our capital position with a secondary public offering, which gives us increased financial strength and flexibility to continue to appropriately invest for success across our pipeline and in preparation for a potential U.S. commercial launch later this year. We continue to build our corporate capabilities. We're a company with strong end-to-end expertise from early discovery through drug development and commercial with strong foundational enabling function. We're incredibly excited about the transformational year ahead of us. We are well prepared and have the resources to achieve our bold agenda.

In November we bolstered our capital position with a secondary public offering which gives us increased financial strength and flexibility to continue to appropriately invest for success across our pipeline and in preparation for a potential U S. Commercial launch later this year.

We continue to build our corporate capabilities. We're a company with strong end to end expertise from early discovery to drug development and commercial with strong foundational enabling functions. We're incredibly excited about the transformational year ahead of US we are well prepared and have the resources to achieve our bold agenda.

David Meek: Important potential milestones in 2022 include gaining FDA approval for adegrassive and rapidly launching our first commercial product to patients with lung cancer in the U.S., which remains our top priority. Adegresiv's profile has the potential to make a meaningful difference for patients with lung, colorectal, pancreatic, and other cancers. We remain confident that Atagrassiv has blockbuster potential.

Important potential milestones of 2022 include gaining FDA approval product grass, it and rapidly launching our first commercial product to patients with lung cancer in the U S, which remains our top priority.

Congrats its profile has the potential to make a meaningful difference for patients with lung colorectal pancreatic and other cancers. We remain confident that atlassian has blockbuster potential we.

David Meek: We expect to complete the submission of our European Regulatory Package for Adagrassive based on our Phase II results. With adagracid's blockbuster potential, we're advancing the broad development plan we have for adagracid, including exploring earlier lines of therapy and into additional tumors. We are aggressively moving forward the other important value drivers in our broader portfolio.

We expect to complete the submission of a European regulatory package Friday grass it based on our phase II results.

Without a grassroots blockbuster potential we are advancing the broad development plan, we have product grass it including exploring earlier lines of therapy, and then two additional tumors.

We are aggressively moving forward the other important value drivers and our broader portfolio.

David Meek: We now have three meaningful programs in clinical development, each with a large commercial opportunity and areas of high unmet need. We're on track to reach the number of events needed to trigger the interim readout of CITRAVACID in Phase 3 SAFIRE study in the second half of 2022. We initiated a Phase I clinical study for MRTX1719, our MTA cooperative PRMT5 program, and expect to submit INDs for MRTX1133, our KRAS G12D inhibitor, and MRTX0902, our SOS1 inhibitor, in the second half of 2022. We have established ambitious goals for ourselves this year.

With all its three meaningful programs in clinical development, each with a large commercial opportunity in areas of high unmet need Roger.

We're on track to reach the number of events needed to trigger the interim readout of <unk> phase III Sapphire study in the second half of 2022.

We initiated a phase one clinical study for <unk>, TX 17, 19, our MTA cooperative P. O N T. Five program and expect to submit <unk> for M. A R. T X 11, 33, or <unk> inhibitor, and <unk>, Oh nine O to our sauce, one inhibitor in the second half of 2000.

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We have established ambitious goals for ourselves this year, we see significant enthusiasm across all areas of the company as we continued to execute on these priorities and drive results with a sense of urgency and passion to transform the lives of patients with cancer I'm excited about our momentum and proud of the company we are building.

Jamie Christensen: We see significant enthusiasm across all areas of the company as we continue to execute on these priorities and drive results with a sense of urgency and passion to transform the lives of patients with cancer. I'm excited about our momentum and proud of the company we are building. With that, I'll turn it over to Jamie.

With that I'll turn it over to Jamie.

Jamie Christensen: Thanks, David. In Chuck's absence today, I will touch on our three programs in clinical development. Atagrassiv, Cetrabatnib, and MRTX1719 are MTA-cooperative PRMT5 inhibitors. We're pleased with the progress we're making in advancing adagrassic through clinical development, and we look forward to potentially delivering it to patients in the commercial setting this year. Earlier this month, we announced the FDA's acceptance of our NDA for adigrassib for accelerated approval under the Subpart H Regulatory Path, for the treatment of patients with non-small cell lung cancer who harbor the KRAS G12C mutation and have received at least one prior systemic therapy. The target action date is December 14, 2022.

Thanks, David and Chuck's absence today, I will touch on our three programs in clinical development.

The grass at Central <unk>, and <unk>, TX 17, 19, our MTA cooperatives appear empty five inhibitor.

We're pleased with the progress, we're making in advancing <unk> through clinical development, and we look forward to potentially delivering it to patients in the commercial setting this year.

Earlier this month, we announced the Fda's acceptance of our NDA for <unk> for accelerated approval under the Subpart H regulatory path.

The treatment of patients with non small cell lung cancer, who harbor H K Ras. She talks you mutation and have received at least one prior systemic therapy.

The target action date is December 14th 2022.

Jamie Christensen: We have breakthrough therapy designation status and expect to continue to have positive and collaborative interactions with the FDA through the NDA review process. We look forward to presenting the full data set from the Phase II Registrational Cohort from the CRYSTAL1 study, which was the primary basis of our NDA file, as well as initial clinical activity in patients with non-small cell lung cancer brain metastases from a separate cohort of patients in the CRYSTAL1 study, who had active and untreated brain metastasis.

We have breakthrough therapy designation status and expect to continue to have positive and collaborative interactions with the FDA through the NDA review process.

We look forward to presenting the full data set from the phase II Registrational cohort from the Crystal One study, which was the primary basis of our NDA filing.

As well as initial clinical activity in patients with non small cell lung cancer brain metastases.

A separate cohort of patients in the Crystal One study who had active in untreated brain metastases.

Jamie Christensen: We expect to present both of these data sets at a medical meeting and are targeting ESCO as the potential venue this year. We continue to enroll patients and add aggressive clinical studies and are generating additional data and patients with a wide range of cancer. In first-line non-small cell lung cancer, we continue to explore adagressive as a single agent in certain underserved subpopulations.

We expect to present both of these datasets at a medical meeting and are targeting ESCO as a potential venue this year.

We continue to enroll patients in an aggressive clinical studies and are generating additional data in patients with a wide range of cancers.

In first line non small cell lung cancer, we continue to explore attic RASM as a single agent in certain underserved sub populations. These include patients harboring <unk> SDK 11 call mutations as well as K Ras mutated patients with TPS scores of less than 1%.

Jamie Christensen: These include patients harboring G12C and SDK11 co-mutations, as well as KRAS-mutated patients with TPS scores of less than 1%. We expect to provide additional clarity on a potential pathway for accelerated approval of adagressive as a monotherapy in these patients this year, as well as sharing initial data from these cohorts in 2023. Also in systemic therapy, naive, non-small cell lung cancer.

We expect to provide additional clarity on a potential pathway for accelerated approval of <unk> as a monotherapy in these patients this year as well as sharing initial data from these cohorts in 2023.

Also and systemic therapy naive non small cell lung cancer and aggressive is being studied in combination trials.

Jamie Christensen: Adagrassive is being studied in combination trials. The most advanced and highest priority combination is with pembrolizumab, where we continue to enroll patients at the 400 milligram BID dose of adagracid in the CRYSTAL7 study. We plan to share an update from the ongoing Phase II CRYSTAL7 study in the second half of this year, including the analysis of patients stratified by TPS score. We are also actively planning to start a phase three trial evaluating the adagrassive and pembrolizumab combination and treatment naive patients later this year.

The most advanced and highest priority combination is what campbellism app, where we continue to enroll patients at the 400 milligram B I D Dallas, Atlanta grass, it and the Crystal seven study.

We plan to share an update from the ongoing phase II Crystal seven study in the second half of this year, including the analysis of patients stratified by TPS score.

We are also actively planning to start a phase III trial evaluating at a grassroots embolism combination and treatment naive patients later this year.

Jamie Christensen: This is subject to results from the ongoing K7 study. We also continue to enroll patients with colorectal cancer, both in late-line CRC as a single agent and in combination with Cytuxanthin. We are also continuing to enroll the Registration Enabling Phase 3 study in combination with Cetuximab in second-line CRC patients. We're also pleased with the favorable results we recently presented at the ASCOGI Cancer Symposium in pancreatic cancer and other gastrointestinal cancer.

This is subject to results from the ongoing <unk> studies.

We also continue to enroll patients with colorectal cancer. Both in late line CRC as a single agent and in combination with Cetuximab.

We're also continuing to enroll the registration enabling phase III study in combination with Cetuximab in second line CRC patients.

We're also pleased with the favorable results. We recently presented at the ESMO Gi cancers symposium in pancreatic cancer and other gastrointestinal cancers.

Jamie Christensen: We are continuing to enroll patients with KRAS mutations and other solid tumors, and we'll continue to explore potential accelerated regulatory approval pathways in these patient populations. We expect to provide additional clarity on a potential pathway for accelerated approval of adegracib and late-line CRC, as well as sharing next steps and other solid tumors, including pancreatic cancer, this year. We continue to pursue a broad combination development program for adegrassive beyond the combinations with pembrolizumab and citoxamab. These include combinations with SHP2, SOS1, or CDK4,6 inhibitors, as well as VS6766, a MEKGRAF pathway inhibitor with a unique mechanism of action.

We are continuing to enroll patients with K Ras mutations and other solid tumors and will continue to explore potential accelerated regulatory approval pathways in these patient populations.

We expect to provide additional clarity on a potential pathway for accelerated approval of adequate acid in late line CRC.

Well as sharing next steps and other solid tumors, including pancreatic cancer this year.

We continue to pursue a broad combination development program for <unk> beyond the combinations with parallelism admin cetuximab.

Include combinations with ship to Cyrusone or CDK, four six inhibitors as well as the six 760, <unk> Mcgrath pathway inhibitor with a unique mechanism of action.

Jamie Christensen: We expect to have initial data readouts for some of these proof-of-concept combination studies in 2023 after we've generated additional data. We will continue to explore the potential of additional novel combination options beyond those we are currently evaluating. Now moving on to CITRAVAD.

We expect to have initial data readouts for some of these proof of concept combination studies in 2023 after we've generated additional data.

We will continue to explore the potential of additional novel combination options beyond those we are currently evaluating.

Now moving onto Citral bad we are enthusiastic about the program based on the 14.9 months overall survival demonstrated in the phase III am Archie X 500 study of central bed and in combination with no volume at and non small cell lung cancer patients previously treated with checkpoint inhibitor therapy.

Jamie Christensen: We are enthusiastic about the program based on the 14.9-month overall survival demonstrated in the Phase II MRTX500 study of citravadinib in combination with nivolumab in non-small cell lung cancer patients previously treated with checkpoint inhibitor therapy. The Phase 3 SAFIRE study is on track to reach the number of events needed to trigger an interim analysis of overall survival in the second half of 2022. If positive, this trial could be the basis of regulatory submissions for full approval in the U.S. and Europe. Now, moving on to MRTX1719.

The phase III Sapphire study is on track to reach the number of events needed to trigger an interim analysis of overall survival in the second half of 2022.

If positive this trial could be the basis of regulatory submissions for full approval in the U S and Europe .

Now moving onto our TX 17, 19 again. This is the second generation or next generation MTA cooperatives to guarantee five inhibitor.

Jamie Christensen: Again, this is the second generation or next generation MTA cooperative PRMT5 inhibitor. First, we're very pleased to have advanced another program into clinical development. 1719 is based on the principle of synthetic lethality through targeting of MTAP gene deletions, which are present in nearly 10% of all human cancer. In contrast to first-generation PRMT5 inhibitors, 1719 is designed to selectively target the PRMT5 MTA complex. This leverages the abnormally elevated levels of MTA uniquely found in MTAP-deleted cancers.

Jamie Christensen: 1719 selectively targets MTAP-deleted cancer cells while sparing healthy non-tumor cells. 1719 is orally bioavailable, and its unique ability to bind to the PRMT5 MTA complex is predicted to spare patients from toxicities observed with first-generation PRMT5 inhibitors. For this program, we recently initiated a Phase I clinical study in our actively enrolling patients. The clinical development plan includes moving through Phase I dose escalation, then into Phase Ib dose expansion cohorts, followed by a number of Phase II cohorts across several tumor types. These include mesothelioma, pancreatic cancer, lung cancer, malignant peripheral nerve sheet tumors, also known as MPNST, as well as a basket cohort of other MTAP-deleted tumor types.

First we're very pleased to have the best another program into clinical development.

17, 19 is based on the principle of synthetic lethality do targeting of Amtech English installations, which are present in nearly 10% of all human cancers.

In contrast, the first generation PMT five inhibitors 17, 19 is designed to selectively target the peer empty five MTA complex.

This leverages the abnormally elevated levels of MTA uniquely founded tap deleted cancers.

17, 19 selectively target untapped deleted cancer cells, while sparing healthy non tumor cells.

17, 19 is orally bio available and its unique ability to bind to the PMT five MTA complex is predicted to spare patients from toxicity observed with first generation, perhaps five inhibitors.

For this program, we recently initiated a phase one clinical study and are actively enrolling patients.

Clinical development plan includes moving through phase one dose escalation then enter phase <unk> dose expansion cohorts.

By a number of phase II cohorts across several tumor types decent click mesothelioma pancreatic cancer lung cancer.

Malignant peripheral nursing tumors also known as M. P N S T as well as a basket cohort of other amtech to lead to tumor types. We.

Jamie Christensen: We will explore 1719 as a single agent and have a number of rational combination strategies we're developing utilizing non-clinical translational studies that would also target next year. We expect to share initial clinical data in 2023 after we have a dose and have generated sufficient data to demonstrate clinical proof of concept. Finally, we continue to make significant progress with our preclinical programs, including MRTX1133, a KRES G12D selective inhibitor, and MRTX0902, an in-house SOS1 inhibitor, which leverages SOS1's ability to enhance the activity of KRES inhibitors, such as Etagrass. Both programs remain on track for IMDs in the second half of 2020. With that, I will turn it over to... Thanks, Jamie.

We will explore 17 19 as a single agent and have a number of rational combination strategies, we're developing utilizing non clinical translational studies that would also target next year.

We expect to share initial clinical data in 'twenty to 'twenty three after we have a dose and have generated sufficient data to demonstrate clinical proof of concept.

Finally, we continue to make significant progress with our preclinical programs, including <unk> 133, K Ras She 12 diesel active inhibitor and <unk>, our T X O in Idaho to an in house source, one inhibitor, which leverages sauce one's ability to enhance the activity of K Ras inhibitors, such as anti grass it.

Both programs remain on track for <unk> in the second half of 2022.

With that I will turn it over to Pat.

Ben Hickey: I'll touch briefly on our financial strategy for a successful launch subject to FDA approval of Atacrase. We initiated our launch preparations two years ago and we continue to execute on a staged approach to our launch readiness effort in anticipation of a launch as early as the third quarter of this year. There are several pillars that we believe will enable us to be highly competitive. First, Adagrassiv's unique molecular profile and 24-hour half-life have enabled us to generate meaningful clinical data across multiple lines of therapy and tumor types, and includes the potential for CNS penetration, which is a particularly important characteristic in lung cancer where up to 30% of patients will develop brain metastases.

Thanks, Jamie I'll touch briefly on our commercial strategy for successful launch subject to FDA approval about aggressive.

We initiated our launch preparations two years ago, and we continue to execute on a staged approach to our launch readiness efforts in anticipation of a launch as early as the third quarter of this year.

There are several pillars that we believe will enable us to be highly competitive.

At aggressive unique molecular profile and 24 hour half life have enabled us to generate meaningful clinical data across multiple lines of therapy in human science and includes the potential for CNS penetration, which is a particularly important characteristic in lung cancer, where up to 30% of patients will develop brain metastases.

Ben Hickey: Second, over the past two years we've attracted top talent across biotech, pharma and healthcare provider organisations. We've seen incredible interest in our commercialization roles, both because of AdAggressive's profile and because of Mirati's unique culture and targeted oncology pipeline. This has enabled us to recruit a team with extensive experience and demonstrate this success in launching some of the industry's top oncology products. Beginning in 2020, we have built an outstanding medical affairs capability, including a significant investment in customer-facing field medical.

Over the past two years, we've attracted top talent across biotech pharma and health care provider organizations, we've seen incredible interest in on commercialization roles, both because of that aggressive profile and because of Iraqis unique culture and talking about targeted oncology pipeline. This.

This has enabled us to recruit a team with extensive experience and demonstrates a success in launching some of the industry's top oncology products.

Beginning in 2020.

We have built an outstanding medical affairs capability, including a significant investment in customer facing field medical. This has resulted in ongoing engagement across top academic centers and community oncology networks and the initiation of an expanded access program.

Ben Hickey: This has resulted in ongoing engagement across top academic centers and community oncology networks, and the initiation of an expanded access program. We've established an experienced value and access team who continue to engage U.S. payers managing the majority of covered lives. We've also developed marketing, analytics, and insight capabilities, as well as all of the foundational capabilities required for a deep understanding of customer needs, and ultimately a successful launch. Third, because we've built our team from scratch, we've been able to optimize how the team is designed with a focus on integration and speed of execution across key functions at the account level.

We've established an experienced value and access team, who continue to engage with payers managing the majority of covered lives. We have also developed marketing analytics and insight capabilities as well as all of the foundational capabilities required for a deep understanding of customer needs and ultimately a successful launch.

Because we have built our team from scratch, we'd been able to optimize havent seen is designed with a focus on integration and speed of execution across key functions at the account level.

Ben Hickey: COVID has changed the way our industry engages with oncology providers, moving from a focus on repetition of live engagements to relevance and customization based on customer preference via digital or live channels. We view this as a fundamental shift that really levels the playing field among larger pharmaceutical and biotech companies like ourselves, and positions as well for long-term commercial success. Fourth, we have the capital necessary to invest for success both in terms of preparing for and successfully executing on the initial launch and to invest in the long-term growth and expansion of adagrassive across tumors, lines of therapy, and combination approaches.

Does this change the way our industry engages with oncology providers moving from a focus on repetition of live engagements to relevance and customization based on customer preference for digital all of our channels. We view this as a fundamental shift that really levels, the playing field among larger pharmaceutical and biotech companies like ourselves and positions us well for.

Long term commercial success.

We have the capital necessary to invest for success, both in terms of preparing for and successfully executing on the initial launch and to invest in our long term growth and expansion of an aggressive across Jim's lines of therapy in combination approaches.

Ben Hickey: We are very enthusiastic and excited about this potential launch and being able to deliver this important treatment option to patients who are living with this type of cancer. The physicians who treat patients with lung cancer are also waiting for new options to treat their patients. With that, I'll turn it over to Vicky. Thank you, Ben. We ended the fourth quarter with approximately $1.5 billion in cash, cash equivalents, and short-term investments, which includes net proceeds of approximately $475 million from a secondary capital raise we completed in November 2021.

We are very enthusiastic and excited about its potential launch and being able to deliver this important treatment option to patients who are living with this type of cancer.

The physicians, who treat patients with lung cancer are also waiting for new options to treat their patients.

With that I'll turn it over to Vicki <unk>.

<unk> been we ended the fourth quarter with approximately $1 $5 billion in cash cash equivalents and short term investments, which includes net proceeds of approximately $475 million from our secondary capital raise we completed in November 2021.

Vicky Reed: Research and development expenses for the fourth quarter of 2021 were $153.8 million compared to $82.7 million for the same period in 2020. The increase in research and development expenses is primarily due to increases in expenses associated with the development of adagrassive and citrobatinib, preclinical and early discovery activities, salaries, and other related costs, which includes an increase in share-based compensation expense, as well as other research and development costs, including one-ton costs associated with registrational manufacturing batches. General and administrative expenses for the fourth quarter of 2021 were $43.5 million compared to $25.3 million for the same period in 2020.

Research and development expenses for the fourth quarter at 'twenty, and 'twenty, one or 153 $8 million compared to $82.7 million for the same period in 2020.

The increase in research and development expenses is primarily due to increases in expenses associated with the development of that aggressive and Citron badness.

Clinical and early just every activity salaries and other related costs, which includes an increase in share based compensation expense as well as other research and development costs, including one time costs associated with Registrational manufacturing batches.

<unk> and administrative expenses for the fourth quarter of 2021 or 43.

Million dollar cause there to $25 $3 million for the same period in 'twenty. It's funny. The increase is due to growth in salaries and other employee related costs, which includes share based compensation expense professional services expense, which is primarily associated with commercial scale up and other cause.

Vicky Reed: The increase is due to growth in salaries and other employee related costs, which includes share based compensation expense, professional services expense, which is primarily associated with commercial scale up, and other costs related to the growth of our business. Net loss for the fourth quarter of 2021 was $199.6 million, or $3.72 per share, basic and diluted compared to a net loss of $101.1 million or $2.08 per share basic and diluted for the same period in 2020.

It's related to the growth of our business now.

Net loss for the fourth quarter of 'twenty, 'twenty, one with $199 $6 million or $3 72 per share.

Basis basic and diluted as compared to a net loss of $101.1 million or $2 eight per share basic and diluted for the same period in 2020.

Vicky Reed: Please see our press release from earlier this afternoon for additional details about our fourth quarter and full year 2021 financial results. David, I'll hand it back to you. Thanks Vicki. I'll conclude by reinforcing what exciting time it is for Mirati. We have a broad and sustainable targeted oncology pipeline across multiple targets and tumors and see significant long-term value in the operational and commercial synergies across our portfolio. We have the financial resources to continue to invest for long-term success.

Please see our press release from earlier this afternoon for additional details about our fourth quarter and full year 2021 financial results, David I'll hand, it back to you. Thanks, Vicki I'll conclude by reinforcing what an exciting time for this for a variety we have abroad and sustainable targeted oncology Pi.

Blind across multiple targets in tumors and see significant long term value in the operational and commercial synergies across our portfolio.

We have the financial resources to continue to invest for long term success, we are continuing to invest in that aggressive U S launch readiness as well as in a broad development plan to enable us to optimize the blockbuster potential of this important product.

Vicky Reed: We are continuing to invest in that aggressive U.S. launch readiness, as well as in a broad development plan to enable us to optimize the blockbuster potential of this important product. Our objective is to launch and further develop a market-leading KRAS G12C inhibitor. We are investing to drive sustainable growth and ensure rapid progression across the breadth of our innovative, Targeted Oncology Pipeline, BEYOND, AttaGrasp. In addition to the internal capabilities we have built, we are enhancing and accelerating our progress through selective partnerships.

Our objective is to launch and further develop our market leading <unk> inhibitor.

We are investing to drive sustainable growth and ensure rapid progression across the breadth of our innovative.

Targeted oncology pipeline beyond at aggressive.

In addition to the internal capabilities, we have built we are enhancing and accelerating our progress through selective partnerships in the fourth quarter, we announced two nonexclusive clinical collaboration agreements.

David Meek: In the fourth quarter, we announced two non-exclusive clinical collaboration agreements. The first is with Sanofi to evaluate the combination of adegrassif with Sanofi's investigational SHIP-2 inhibitor. The second is with Baristem Oncology to evaluate the combination of adagrassive with Baristem's investigational RAF MEK inhibitor.

First is what therapy to evaluate the combination Nevada aggressive with therapies investigational ship two inhibitor.

Second is with barrister in oncology to evaluate the combination of that aggressive with bear Stearns.

Instigation of RAF Mec inhibitor.

David Meek: We expect to continue to be active in pursuing opportunities to accelerate and expand our pipeline through partnerships. We are incredibly pleased with the progress we have made and look forward to the many important milestones we are approaching. I continue to be impressed by the team we have at Mirati.

We expect to continue to be active in pursuing opportunities to accelerate and expand our pipeline through partnerships.

We're incredibly pleased with the progress we have made and look forward to the many important milestones we are approaching.

I continue to be impressed by the team we haven't Marathi they have an incredible energy and passion for improving the lives of patients I. Thank them for their continued efforts and focus as we work to transform the lives of patients with cancer.

David Meek: They have an incredible energy and passion for improving the lives of patients. I thank them for their continued efforts and focus as we work to transform the lives of patients with cancer. With that, we're ready to take questions. Thank you. If you would like to ask a question, once again, please signal by pressing star 1 on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment.

With that we're ready to take questions.

Sarah: Again, that is star 1 to ask a question. We'll pause for just a moment. And we'll take our first question from Tyler Van Buren with Cohen and Company. Hey, guys. Great to see all the progress, and thank you for taking the questions. I had two.

Thank you if you would like to ask a question. Once again. Please take note by pressing star one on your telephone keypad. If you are using a speaker phone. Please make sure. Your mute function is turned off totally out of your signal to reach our equipment again that is star one to ask a question it will pass.

Just a moment.

We will take our first question from Tyler Van.

Baron with Cowen and company.

Hey, guys, great to see all the progress and thank you for taking the questions.

David Meek: First, could you elaborate on the recent site audits or site visits that have been conducted by the FDA as part of the RTOR process, and if this is occurring earlier than expected based on your conversations with regulatory consultants? And the second question is related to the full Phase 2 data release at ASCO. Well, obviously, you look to confirm positive results have been disclosed previously, but other than response data. Is there anything else that might be disclosed that could be differentiating, or should we primarily look to the TNS MET data for that? Hi, it's David.

Two first could you elaborate on the recent site audits or site visits that have been conducted by the FDA as part of the artwork process. If this is occurring earlier than expected based on your conversations with regulatory consultants and the second question is related to the full phase II data released at <unk> will obviously look to confirm positive results had been to score.

As previously, but other than response data.

Anything else that might be disclosed there could be differentiating or should we primary primarily look to the CNS med data for that.

David Meek: A couple things regarding the, you know, some of the site audits that are already occurring with Adagrassive. I think it's standard business. We certainly take it as a good sign that the FDA is engaged. You know, being part of the pilot program for the real-time ecology review, it certainly gives the agency a head start on the review. So the site audits that are happening right now, they have happened, some more will happen, but I think we're not going to discuss the ongoing interactions with the FDA, but we take it as a positive sign with that.

Hi, there hi, its David a couple of things regarding the you know some of the site audits that are already occurring without aggressive I think it's standard business, we certainly take it as a good sign that the fda's engaged you'll having being part of the pilot program for the real time oncology review. It certainly gives the agency a head start.

<unk> on the review so the slight orders that are happening right now they're they have have been some more will happen, but I think we're not going to discuss the ongoing interactions with the FDA, but we take it as a positive sign with that regarding having the data published at Ash go. So we're announcing for the first time that we.

David Meek: Regarding having the data, you know, published at ASCO, so we're announcing for the first time that we expect the data to be released at ASCO, we say, you know, stay tuned for the data. You know, we're going to announce a full data set for the cohort A of the registrational trial, and that will be presented at ASCO. We're presenting that data set as well as, you know, we intend to present brain meds data at the same time. Thank you. Thank you. And next we'll move on to Gina Wing with Berkeley. Hi, good evening. This is Hershida on for Gina. Can you hear me?

Check the data to be released at Astro, We say stay tuned for the data, you'll we're going to announce a full dataset.

For the cohort of the Registrational trial and that will be presented at <unk>, we're presenting that data set as well as.

Ted do present brain Mets data at the same time.

Thank you.

Yes.

Thank you.

Thank you and next we'll move on to Gena Wang with Barclays.

Hi, Good evening. This is Christina on for Gino can you hear me okay.

Yes.

Jamie Christensen: Okay. Yes. Thank you. First, I just had a quick clarification, and then I have a follow-up question. Did I hear correctly that for the Monotherapy 1L first-line data sets, both STK-11 and TPS-GLO, these data sets will be presented sometime in 2023? Yeah, this is Jamie.

Thank you first I just had a quick clarification and then I have a follow up question did I hear correctly that for the mono therapy, one al first line dataset.

Both SDK 11 N P. P. S slow these datasets will be.

Presented in sometime in 2023.

Jamie Christensen: That would be our goal. And just to note that these are two separate cohorts or studies. One of them is with KRAS mutation and SDK11 co-mutation. The other one is in KRAS mutation with TPS score less than 1%. And yes, we would be planning on presenting that next year. Okay, great.

Yeah. This is Jamie that would be our goal and just to note that these are two separate cohorts for studies one of them is with K Ras mutation, an SDK 11 commutation. The other one is N K Ras mutation with TPS score of less than 1% and yes, we would be planning on presenting that next year.

Jamie Christensen: Thank you. Then the other follow-up I had is for the PD-1 combo data set in the second half, for the 400 mg cohort, is it fair to assume that the number of patients can be at least in the 20 to 30 patient range, given that, you know, at that time point, you'll have at least three quarters minimum to enroll patients? So it's David, I'll jump on that and ask Jamie to elaborate.

Okay, great. Thank you and then the other follow up I had a blood that PD one combo data set in the second half for the 400 milligram cohort.

Is it fair to assume that the number of patients can be at least in the 20 to 30 patient range. Given that you know at that time point, you will have at least three quarters minimum to enroll patients.

So it's David I'll jump on that to ask Jamie to elaborate so what we're gonna do so we're enrolling that trial right now as we announced in the fall when we switched protocol at a 400 milligrams B I D plus full dose <unk> about the trial is actively enrolling we're encourage with the.

David Meek: So what we're going to do is we're enrolling that trial right now, as we announced in the fall, when we switch the protocol to 400 milligrams BID plus full-dose Pembrolizumab. The trial is actively enrolling. We're encouraged with the ongoing recruitment.

Ongoing improvement so what are we going to do is we're going to get to a data set we think it'll be a meaningful number of patients. We can look at the safety and tolerability of the combination well maybe I'll have a couple of scans by this but it'll be a meaningful number of patients well into the double digit range for that patient population that will inform us.

David Meek: So what we're going to do is we're going to get to a data set. We think it'll be a meaningful number of patients. We can look at the safety and tolerability of the combination. You know, maybe I'll have a couple scans by this, but it'll be a meaningful number of patients and well into the double-digit range for that patient population. That will inform us going into the phase three program. And as you know, we're already actively preparing for that phase three start, and we'll use that data to make that decision to jump into phase three. Jamie, anything else?

Going to the phase III program and as you know we're already actively preparing for that phase III start and we'll use that data.

To make that decision to jump into phase III JV anything else okay.

Jamie Christensen: Okay, that helps. I appreciate it. Now, that's helpful. Thank you so much.

That all I appreciate it.

No. That's that's helpful. Thank you so much.

Sure.

Jamie Christensen: Sure. Thank you. Next we'll move on to Gavin Scott with J.P. Morgan.

Thank you next we'll move on to Gavin Scott with J P. Morgan.

Jamie Christensen: Okay, thanks for taking my question. Just a follow up on the PD1 combo. I guess are there any molecular underpinnings that would suggest a better response and patients previously treated with PD1 or PD1 chemo? I get them just asking in the context that you've highlighted that your registration trial has 98% of patients there while you're going to pass out around 80%. So just curious on your, Yeah, this is Jamie again.

Hi, Thanks for taking my question.

Just a follow up on the PD one combo I guess are there any molecular underpinnings that would suggest that a risk.

Launched in patients previously treated with PD one.

Oh, PD, one chemo and I guess I'm, just asking on the contracts that you highlighted that your Registrational trial is 98%.

Patience umbrella, while Democrats at around 80%.

Curious on your thoughts.

Jamie Christensen: You know, I think it's hard to, you know, fully answer that question today based on the information we have in hand, especially as it relates to prior therapies. We'll just say as a reminder that, you know, there is data out there suggesting the SDK-11 and KEEP-1 co-mutations as unmet medical need for chemo-amino therapy. The response rates, PFS and OS, are fairly low there.

Yeah. This is Jamie again.

I think it's hard to fully answer that question today based on the information we have in hand, especially as it relates to <unk>.

Prior therapies would just say as a reminder, that there is data out there, suggesting the SDK 11 in and keep one co mutations is unmet medical need for chemo immunotherapy.

Jamie Christensen: That's partially the premise of us going after the SDK-11 co-mutated subpopulation. If we continue to see strong activity there, we would suspect that the unmet medical need with standard of therapy would be a logical discussion point with the agency around making sure that we're developing the drug in a setting with, you know, enhanced unmet medical need. We're also looking at the TPS less than 1% population would say that, you know, we follow both Amgen's data and, of course, ours.

Response rates PFS and OS are fairly low there that's partially the premise of us going after the SDK all I've been called mutated subpopulation.

We continue to see strong activity there, we would suspect that the unmet medical need with standard of therapy would be a logical discussion point with the agency around making sure that we're developing the drug in a setting with enhanced unmet medical need.

Jamie Christensen: There's no reason to believe to date that the response rate wouldn't be at least as good as the rest of the population and the TPS less than 1%, kind of subset of patients. So that remains as an effort for us as a model therapy and would just say that, you know, we do believe based on preclinical data that the KRAS inhibitor could reawaken the immune response in tumors that may be somewhat immune cold.

<unk> response, and tumors that may be somewhat immune cold again, citing those patient populations that I've mentioned earlier. So do you believe that these populations like the S. T K L as in.

Jamie Christensen: Again, you know, citing those patient populations that I mentioned earlier. So do believe that these populations like the STK-11, KEEP-1 and TPS-less-than-1 would be subject to treatment with both combination therapies as well as monotherapies. And in fact, we'll be pursuing both angles there. And if that didn't answer your question, please... That was very helpful. Thank you, and next we'll move on to Umar Rafid with Evercore ISI. Hi, this is Eric on for.

Keep one in TPS less than one would be subject to treatment with both combination therapies as well as monotherapies and in fact, we're broke we'll be pursuing both angles there.

And if that didn't answer your question. Please let me know.

Now that was very helpful. Thank you.

Sure.

Thank you and next home move I'm cute in my rocket with Evercore ISI.

Hi, This is Eric on for humor, just two quick questions. The first on the PR empty five.

Jamie Christensen: Just two quick questions. The first on the PRMT-5. With the IMD submitted, what sort of details can you share on the trial? and What's the Expected Safety?

With the IMD submitted what sort of details can you share on the trial design and what do you expect it to safety or CD profile versus competitive agent.

Jamie Christensen: Profile, Versus Competit- Sure, yeah. First, regarding the trial design, we are utilizing the agency's guidance around 2019 on multi-cohort studies. And these studies are essentially designed to allow rapid development in multiple settings for targeted therapies that are essentially targeting subsets of patients. So, in a way, this study will be the first study and also a Swiss Army knife of studies with differing objectives.

Sure Yeah first regarding that trial design.

We are utilizing the agency's guidance around 2019, and multi cohort studies and these studies are essentially designed to allow a rapid development in multiple settings for targeted therapies and that are essentially targeting subsets of patients. So in a way. This study will be the first.

And also a Swiss army knife of studies with different with different objectives number. One is we will be pursuing dose escalation for the first part of this study we're pleased with the outcome of our toxicology studies, which allow us to start with a reasonably high dose and patients that would be approaching therapeutic concentrations.

Jamie Christensen: Number one is we will be pursuing dose escalation for the first part of the study. We're pleased with the outcome of our toxicology studies, which allow us to start with a reasonably high dose in patients that would be approaching therapeutic concentrations. Once we establish a recommended Phase 2 dose, or perhaps multiple doses, we would be breaking into Phase 1B studies, where we would be evaluating the monotherapy activity in any patient with an MTAP gene deletion to get an enhanced understanding of dose dependence, tolerability, as well as anti-tumor activity.

Once we establish a recommended phase two dose or perhaps multiple doses, we would be breaking into phase one b studies, where we would be evaluating the mono therapy activity in any patient with an <unk> gene deletion to get an enhanced understanding of dos dependents.

Tolerability as well as antitumor activity as soon as we're confident in moving forward with our recommended face who dose than we would be opening phase two expansion cohorts and essentially the four cohorts that I had mentioned the.

Jamie Christensen: As soon as we're confident in moving forward with a recommended Phase 2 dose, then we would be opening Phase 2 expansion cohorts, and they're, you know, essentially the four cohorts that I had mentioned, the pancreatic ductal adenocarcinoma, non-small cell lung cancer, including both adeno and squamous cell cancer, as well as the two kind of more niche indications, mesothelioma and malignant peripheral nerve C tumors, and finally, one additional cohort, which would be a catch-all, you know, anybody who doesn't have one of those, those first four primary malignancies, and we'll be looking at expanded activity in all of these different patient sets as a monotherapy. So I would say that's part one.

Pancreatic ductile adenocarcinoma, non small cell lung cancer, including both add note and squamous cell cancer.

As well as the two kind of more niche indications mesothelioma and malignant peripheral nursery tumors and finally, one additional cohort, which would be a catch all anybody who doesn't have one of those those first four primary malignancies, and we'll be looking at expanded activity and all of these different patient assesses a mono therapy.

Jamie Christensen: Part two is, you know, we are interested in combinations. I'm not going to go into much detail today, but I will say that the ongoing studies in the preclinical setting have pointed to a couple of interesting codependencies with PRMP5 inhibition that would be the substrate to start rational combinations as soon as we identify a recommended phase two dose. So that would also potentially be part of the first inhuman study or, depending on how regress we pursue, could be also a substrate.

So I would say that's part one part two is we are interested in combinations I'm not going to go into much detail today, but I will say that the ongoing studies in the preclinical setting have pointed to a couple of interesting co dependencies with.

<unk> five inhibition that would be the substrate to start rational combinations as soon as we identify our recommended phase II dose. So that would also potentially be part of the first in human study or depending on how we're aggressively pursue could be also a separate study.

Jamie Christensen: Then I think your last question was related to the molecular aspects and the PK-PD relationship relative to first-generation inhibitors. And, you know, one thing that has come out as interesting in our preclinical studies is suggesting that the maximally effective dose of a PRMT5 inhibitor, you know, with this particular mechanism of action is really associated with near completely inhibiting symmetrical dimethyl arginine, the primary pharmacodynamic marker or molecular marker which PRMT5 works through to regulate histones and gene expression.

Then I think your last question was related to the molecular aspects in the PK PD relationship relative to first generation inhibitors and.

One thing that has come out is interesting in our preclinical studies.

Is suggesting that the maximally effective dose of appear empty five inhibitor.

With this particular mechanism of action is really associate with near completely inhibiting symmetrical dimethyl arginine the primary pharmacodynamic marker or molecular marker, which pier empty fireworks due to regulate histones and gene expression.

Jamie Christensen: So we do believe that near complete or complete inhibition of SDMA for the full dose interval is going to be critical and do view the key differentiated factor with first and second generation inhibitors is essentially the ability to achieve that near complete inhibition. First generation inhibitors are somewhat limited by neutropenia, thrombocytopenia, anemia, and although they're able to achieve pretty good SDMA inhibition, you know, in our measure it's, you know, the full inhibition is going to be critical to drive monotherapy activity. Therein lies I think the value proposition and premise for development of this class of drugs. I think I hit all the key points. Did I miss any?

So we do believe that near complete or complete inhibition of Stm's.

For the full dose our goal is going to be critical and do view the key differentiator factor with second first first or second generation inhibitors is essentially the ability to achieve that near complete inhibition first generation inhibitors are somewhat limited by neutropenia, thrombocytopenia anemia, and although they are able to achieve pretty good.

STM ambition.

In our in our measure.

The full inhibition is going to be critical to drive mono therapy activity therein lies I think the value proposition on premise for development of this class of drugs.

I think I hit all the key points did I Miss anything.

David Meek: No, no, that's all. And just one follow-up question. Are there any updates to the commercial readiness plans given the longer review timeline or any change in competitive dynamics there? Sure. Hi, it's David.

No no that's all and just one follow up question are there any updates to the commercial readiness plan given the longer review timeline or any changing competitive dynamics there.

David Meek: Regarding the commercial launch preparedness, I tell you, we're real excited about where we've come so far. You know, we plan on being launch-ready by Q3 this year, and that, you know, we've got a medical affairs organization already in the field. We have a value and access team in the field. We have sales management in the field.

Sure it's David regarding the commercial launch preparedness tell you we're real excited about where we've come so far we plan on being a launch ready by Q3 this year.

And that we've got a medical affairs organization already in the field, we have about the value in excess team in the field. We have sales management of field. This timeline gives us even more time to prepare for.

David Meek: This timeline gives us even more time to prepare for a highly successful and rapid launch. So that's the approach we're taking right there for the launch planning, and we'll be... Really, really ready to go and look forward to a rapid launch and building a blockbuster. Ben, anything you want to add to that? No, I think you've framed it pretty well.

Highly successful and rub and launch so that's the approach we're taking right there before the launch planning it will be.

Really really ready to go and look forward to a rabid launch and the ability to blockbuster been anything you want to add to that I think you've primary pretty well no big changes, we'd get to show up and things will look more we've got a a few more interactions with our customers and really understand from the dynamics going on.

Ben Hickey: No big changes. We get to sharpen things a little more. We get a few more interactions with our customers and really understand some of the dynamics going on. And we feel, you know, very confident. So, I think that a little bit more time hopefully means that we can sharpen things even further. Great, thank you. Thank you. And next we'll move on to Salveen Richer with Goldman Sachs. Thanks for taking the question. This is Andrew for Salveen.

We feel very confident so.

A little bit more time, hopefully means that we can show up and things even further.

Great. Thank you.

In queue and neck per move on to for being richer with Goldman Sachs.

Thanks for taking my question.

Jamie Christensen: Two questions for us, please. The first, maybe as a follow-up to the prior question on the CNS data that you're expecting at ASCO, just wondering if you could help to frame expectations for that read and how meaningful you think this will be when you think about demonstrating differentiation against Lumicrost.

For solving.

Key question please.

Maybe as a follow up question on mechanic pain at the expecting it ASKO just wondering if you could have different expectations Homestead Street, and how meaningful you think that'll be when you think about demonstrating differentiation again.

Jamie Christensen: I'm going to be talking about the different classifications into this read and how meaningful you think this will be when you think about demonstrating differentiation against LumaCraft. Sure, yeah, you know, we look closely at, of course, the properties of our drug and we are aware of formerly presented with increased data. So, I think a few key points about anagrassif, you know, both preclinically and clinically, we've studied the ability of the drug to get into the CNS. And we previously commented on what's called a KPU value, which is essentially the level of drug in the cerebral spinal fluid relative to the free fraction adjusted plasma concentrations at a comparable time point.

Yeah.

Sure Yeah.

We've looked closely at of course, the properties of our drug and we are aware of formerly presented it wound crash data.

So I think a few key points about anagrams both preclinical.

Cynically and clinically we've studied the ability of the drug ticket into the CNS and we previously commented on what's called a <unk> value, which is essentially the level of drug and the cerebral spinal fluid relative to the free fraction adjusted plasma concentrations at a comparable time point and we've seen K P. <unk>.

Jamie Christensen: And we've seen KPU values approaching 0.5, which is meaningful, just a couple of, you know, kind of bars that have been set, a submersion is an example of a drug that has a KPU value of about 0.3 and very robust activity against brain metastases, the two drugs and the elk inhibitor space electinib and oral atinib are agents with KPU values of greater than 5 and get have very strong CNS penetrance. And again, have demonstrated activity in patients with brain metastases.

<unk> approaching five which is meaningful just a couple of kind of bars that have been set as <unk>. As an example of a drug that has a <unk> value of about three and very robust activity against brain metastases.

The two drugs in the Elk inhibitor space elected <unk> and or Latin at our agents with K P. U values of greater than five and can have very strong CNI spent address and again have demonstrated activity.

Jamie Christensen: That is, you know, pretty different or differentiated relative to first generation inhibitors. So in the EGFR space, let's note that oral atinib and confidinib are agents with response rates of around 10 percent in intercranial metastases and lung cancer patients. And then note, Krizatinib is an agent with about a 27 percent response rate in the elk inhibitor space, again a non brain penetrant inhibitor. You may be aware that our submersion, oral atinib, electinib are all agents that have demonstrated intercranial response, fairly consistent with their activity in peripheral disease.

Patients with brain metastases that is pretty different or differentiate relative to first generation inhibitors. So in the Egfr space, Let's note that our last name and can fit nabe, our agents with response rates of around 10% and intracranial metastases and lung cancer patients and then no <unk> as an agent.

With about 27% response rate and the outcome Hebeler space again, a non brand kind of turn inhibitor you may be aware that our subvert nib or Latin elect to never all agents that have demonstrated intercontinental response rates fair.

Fairly consistent with their activity and peripheral disease, so suggesting that if the drug can get into the CNS it can be differentiated and demonstrate.

Jamie Christensen: So, suggesting that if the drug can get into the CNS, it can be differentiated and demonstrate, you know, essentially robust activity there. As mentioned in the call, we believe we will have a substantial number of patients to talk about at the ASCO meeting or wherever we land. And, you know, essentially there, would note that we've had the open cohort with active brain metastases or untreated brain metastases. We will be talking about that.

Essentially robust activity there.

Jamie Christensen: We'll also be talking about subset analysis from our cohort A patients, which essentially have treated or controlled brain metastases. And, again, you know, think that the number of patients that we'll have to talk about will be meaningful to at least appraise the preliminary activity of the drug in this setting. And then, for a second question, maybe for Ben, just, you know, with the fourth quarter of Lumicrost cells being lighter than some had expected, despite diagnosis and patient identification being pretty robust, just curious what your sense is for what is slowing physician uptake here, and is there anything you can do to drive additional utilization when Atagrassi is on the market? Thanks so much.

As mentioned in the call. We believe we will have a substantial number of patients to talk talk about at the ESCO meeting or wherever we land and essentially there would note that we've had the open cohort with active brain metastases are untreated brain metastases, we will be talking about that will also be talking about subset analysis from our call.

Or in a patients, which essentially have treated or controlled Brandon metastases and again.

Think that the number of patients that will have to talk about will be meaningful to at least appraised the preliminary activity of the drug in this setting.

And then for a second question maybe <unk> just.

Just.

In the fourth quarter learn the craft out being late or anything.

Thanks.

Hi, agnostic and patient identification enquiring about that.

So your sentence filing possession uptake here and is there anything you can do to drive additional utilization one autograph that's on the market. Thanks, so much.

Ben Hickey: Sure, thanks for the question. I think just as a reminder with a novel class coming to bear, the people have to be reminded that most of the testing, almost 80% of it, does occur in front line. So those patients now, with the benefit of the 189 regimen, it's still taking 18 to 24 months for these patients to actually come into second line or beyond therapy, so that does take some time. And secondarily, we've done a lot of work about understanding the local dynamics and understanding that it does also take a while for the patients to be identified in the EMR, so physicians to see that it's an actual mutation and to be able to take action on it. So we expect that the market will take a little while to mature.

Sure. Thanks for the question.

I think just as a reminder, with the.

Noble class coming to bear the people have to be reminded of most of the testing almost 80% of it does occur in front of the line. So those patients now with the benefit of the one of non regiment. This is still taking 18 to 24 months for these patients to actually come into second line or beyond therapy. So that it does take some time and second.

Barely we've been a little work about understanding the local dynamics and understanding that it does also take awhile for the patients to be identified and the EMR. So physicians to see that it's an actual mutation and to be able to take action on it. So we expect the market will take a little while to mature we see continuing to ma'am.

Ben Hickey: We see it continuing to mature and those patients becoming available in second line and beyond. And I think that as we come to market, hopefully later this year, physicians will be looking for the preferred KRAS G12C inhibitor, so sometimes being second to market is not always the best, but sometimes it has its advantages, and in this case, having some of the testing or the foundational work completed, that's been something that we have not been or have not focused on so much.

Sure in those patients becoming available in the second line and beyond.

I think that as we come to market. Hopefully later this year physicians will be looking for the preferred.

<unk> 12 inhibitors. So we are.

So as far as being second to market is not always the best but sometimes it has its advantages in the in this case, having some of the testing or the foundational work completed.

That's been something that we have not.

Nope focused on so much to date would.

Ben Hickey: Yeah, I would add to that that certainly we're going to benefit by, you know, Lumicrafts doing those market-shaping, you know, building the market-shaping of KRES G12C testing. And by the time we're approved, you know, we think a lot of this will be behind us and we can then focus our efforts on, you know, communicating and educating the physicians on the clinical profile of Atagrassiv as a G12C inhibitor for their patients. Thank you. Next, we'll take our next question from Evan Saigerman with BMO Capital Markets. Hi, guys.

Would add to the certainly we're going to benefit by Yo lumen crafts during those market shaping.

Do building the market shaping of <unk> testing and by the time, we were approved.

We think a lot of this will be behind us and we can then focus all records on commute.

Communicating in educating the physicians on the clinical profile about aggressive.

<unk> inhibitor for their patients.

Thanks connection.

Thank you next we'll take our next question from and then I come in with BMO capital Mark.

David Meek: Thank you so much for taking my questions. Just a few for you guys with updates. Can you expand on the bar for monotherapy in the frontline setting in patients with both the TPS less than 1 and the SDK 11 commutation? And if you had conversations with the regulators as to kind of what they're looking for here, then I do follow up question. Sure.

Hi, guys. Thank you so much for taking my question just a few for you guys with updates so can.

Can you expand on the bar for mono therapy in the frontline setting I'm in patients with both the TPS less than one in the UK 11 computation and if you had conversations with the regulators to kind of what they're looking for here than I to follow up questions.

Jamie Christensen: Regarding your first question, you know, noting, first of all, Keynote 189 as it relates to TPS scores. So Keynote 189, as you may recall, the overall patient set had a response rate of around 48 percent. And then when they did the subset analysis, the response rate was 32 percent. And essentially that represents our bogey or null hypothesis to improve upon for the TPS scores of less than 1 percent with KRAS co-mutations.

Sure regarding your first question.

Noting first of all keynote 189 as it relates to TPS score so.

89, as you may recall, the overall patients that had a response rate of around 48% and then when they did the subset analysis. The response rate was 32% and essentially that represents our bogey on hole hypothesis to improve upon for the TPS scores of less than 1% with K rash called mutations.

Jamie Christensen: Secondly, you know, the SDK11 KRAS subset, the bogey there has mostly been defined by academic analyses at major cancer centers. And I think the numbers that are coming out for SDK11 patients that have also a KRAS co-mutation is that the response rate there is gonna be about 20 to 25%. So again, that's essentially what we need to improve upon.

Secondly, SDK 11, kers subset. The bogey there is mostly been defined by academic analyses at major cancer centers and I think the numbers that are coming out for SDK 11 patients that have also K Roscoe mutation is that the response rate there is going to be about 20 to 25.

Percent. So again, that's essentially what we need to improve upon now I think when you look at.

Jamie Christensen: Now, I think when you look at prior drug approvals in the first-line setting, that also sets a bit of a precedent or a bar for us to shoot for. And so there have been drug approvals with response rates in the first-line setting of over 55 percent, perhaps over 60 percent in some cases. And so if you take those two parts of the equation together, you would expect to be able to hit a 55 to 60 percent response rate or higher.

Prior drug approvals and the first line setting that also sets a bit of a precedent or a bar for us to shoot for and so there have been drug approvals with response rates and the first line setting.

Over 55% perhaps.

<unk>, 60% in some cases and so if you take those two parts of the equation together you would expect to be able to hit a 55% to 60% response rate or higher would give a clear differentiation from how standard of care performs in those particular patient populations. We haven't had ongoing discussions with the agency Dave.

Jamie Christensen: That would give a clear differentiation from how standard of care performs in those particular patient populations. We have had ongoing discussions with the agency. They will, of course, never quote a particular number that we need to exceed.

Well of course never quote particular number that we need to exceed they call that a review issue, but I think they've encouraged us or should we present or provide compelling data and the target response rate ranges with reasonable duration responses that we would generally be in range to submit for those for those particular patient sites.

Jamie Christensen: They call that a review issue. But I think, you know, they've encouraged us if should we present or provide compelling data in the target response rate ranges with reasonable duration responses that we would generally be in range to submit for those particular patient sets. So that's really where we stand today. All of our discussions with the agency are considered preliminary.

So that's really where we stand today all of our discussions with the agency are considered preliminary and now the rest of our program is data driven.

Jamie Christensen: And now the rest of our program is data-driven. That's quite helpful. And then when you kind of talk about planning for a phase three PD-L1 combo, can you expand like what that actually means? And also touch on when the study may start and what you're waiting for here? So let me start, David, and that is, first of all, regarding the preparation for the phase three protocol. We want to be aggressive, and we want to move fast.

Oh, it's quite helpful. And then when you talk about planning coffees three P. D. O. One combo can you expand luck with that actually mean.

Also touch on when the study of my start in what you're waiting for here.

So let me start with David and that is first of all regarding the preparation for the phase III protocol.

We want to be aggressive when we want to move fast we realize that the opportunity in the frontline setting is significant for the patient population and we wouldn't be the first <unk> inhibitor to be studied in combination and ultimately improve the launch an available to patients over time. So that's why we're we're planning for success with 400 milligrams.

David Meek: We realize that the opportunity in the frontline setting is significant for that patient population, and we want to be the first G12C inhibitor to be studied in combination and ultimately approved and launched and available to patients over time. So that's why we're planning for success with 400 milligrams BID plus PEPRO. So we don't like to do things sequentially here. We like to do things in parallel and move as fast as we can.

Plus prempro so.

Don't like to do things sequentially here, we like to do things in parallel and move as fast as we can so that's the first part of that question I will turn it over to Jamie Yes, certainly agree I mean, we need to be poised first success here and I'll just note that planning a phase III study in its opening globally as an equation of greater than nine months.

David Meek: So that's the first part of that question. I'll turn it over to Jamie to. Yeah, I certainly agree. I mean, you know, we need to be poised for success here, and you know, let's note that, you know, planning a phase three study and it's opening globally is an equation of greater than nine months. So essentially, we are actively planning to be able to open that study. With regard to the statistical hypotheses, you know, I think we know what part of that equation is, and that is how Keynote 189 as a control regimen would perform NK-RAS mutated patients.

So essentially we are actively planning to be able to open that study.

With regard to the statistical hypotheses I think we know what part of that equation is and that is how keen on 189 as as a control regimen would perform and chaos mutated patients. So we're essentially basing some of our clinical trial design assumptions on that.

Jamie Christensen: So we're, you know, essentially basing some of our clinical trial design assumptions on that. And then, as you know, we have the ongoing CRYSTAL-7 study to help inform how Adagrassif and Pembrolizumab will perform, you know, initially with respect to tolerability, dose intensity, and otherwise, but also at least with regard to initial response rate. And with that data, we would be able to make some additional assumptions around the clinical trial design. So, you know, that's really where we stand at this point. We've been encouraged with what we've seen from the small number of 400 MAID-BID patients and are looking to better understand that as the year goes. Alright, thanks so much guys, appreciate it.

And then as you know we have the ongoing crystal seven study to help inform how at a grass and <unk> will perform.

Initially with respect to Tolerability dose intensity.

And otherwise, but also at least with regard to initial response rate and with that data, we would be able to make some additional assumptions around the clinical trial design. So that's really where we stand at this point, we've been encouraged with what we've seen from the small number of 400, Meg patients and are looking to better understand that.

A year comes along.

Alright, thanks, so much I appreciate it.

Jamie Christensen: Thank you and next we'll move on to my goshman with Google's. Thank you for taking my questions. Just a follow-up on the first line, lung cancer, monotherapy, you know, the two cohorts. I guess, in your preliminary discussions with the FDA, have you had any conversations about the sample size in those cohorts, how many? are targeted to be enrolled in either of these two cohorts. And then the other question was really about your potential plans in pancreatic cancer. Should we consider a third-line accelerated approval strategy potentially, or are there other options? Perhaps move into an earlier setting.

Thank you and next move on to Michael Smith with Guggenheim.

Thanks for taking my question.

Follow up on the first one.

Mono therapy.

The two cohorts I guess in your preliminary discussions with the FDA have you had any conversations about the sample size and melts cohort Tommy patients.

Are targeted to be enrolled in either of these two cohorts.

The other question was really about your potential plowed and pancreatic.

Or should we consider a third line tolerate approve a strategy potentially or are there opportunities to perhaps move into an earlier setting and PDOC. Thank you.

Jamie Christensen: Sure. Yeah, regarding the two cohorts. So, you know, we essentially know what the null hypotheses are. For PD-L1, less than one, it would be de facto around 32% response rate with a meaningful duration of response. For the SDK-11 subpopulation, it would be somewhere in the 20 to 25% range, you know, again, with a meaningful duration of response. You know, as noted in the discussions with the agency, they will not give us a number, what we need to accomplish with regard to response rate or duration of response, but we do have prior experience with the approval of other targeted therapies as monotherapies in these settings.

Sure here regarding the two cohorts so.

We essentially no what the no hypotheses are four PDL, one less than one it would be the fact all around 32%.

Response rate with a meaningful duration of response for the SDK 11, subpopulation it would be somewhere around the 20th of 25% range again with a meaningful duration of response.

As noted the discussions with the agency they will not give us a number what we need to accomplish with regard to response rate or duration of response, but we do have prior experience with the approval of other targeted therapies as monotherapies in these settings and essentially if we use though as targets the number of patients necessary.

Jamie Christensen: And essentially, if we use those as targets, the number of patients necessary to get approval wouldn't be unreasonable. We also recognize that we have a significant safety database as a monotherapy from all the other additional work we're doing.

To get approval wouldn't be unreasonable.

We also recognize that we have a significant safety database as a mono therapy from all the other additional we're doing so I can't really give you a number of today, but we essentially believe that.

Jamie Christensen: So I can't really give you a number today, but you know, we essentially believe that, you know, the enrollment of a, you know, kind of approvable data set could be in the range of other accelerated approvals or monotherapies for targeted therapies in the non-SMOS-L1 cancer setting. For your question on pancreatic cancer, you know, a, you know, I think you're aware of the data we presented at ASCO GI earlier this year. So just to note, when you look at standard of care, maintaining a 50% response rate and a progression-free survival or duration of response north of six to seven months is actually meaningful even for first line. Now, it would be challenging for us to start a development program in treatment naive patients.

Enrollment of a kind of a provable.

Data set could be in the range of other accelerated approvals are monotherapies for targeted therapies in the non small cell lung cancer setting.

For your question on pancreatic cancer.

A.

I think you are aware of the data we presented ESCO Gi earlier. This year. So just to know when you look at standard of care, maintaining a 50% response rate and a progression free survival or duration of response north of six seven months.

Is actually meaningful even for first line now it would be challenging for us to start a development program and treatment naive patients. So we will continue to focus on second and third line patients as we get more and more data will wait for that to mature along with a better understanding of the durability of response and otherwise we think of that data holds up.

Jamie Christensen: So we'll continue to focus on second and third line patients. As we get more and more data, we'll wait for that to mature, along with a better understanding of the durability of response. And otherwise, we think if that data holds up, you know, again, along with the safety database that we've generated and other types of cancer, that, you know, a accelerated approval would be a possibility in either one of those settings.

Again, along with the safety database that we've generated and other types of cancer that.

Jamie Christensen: And, you know, really the ongoing generation of data will help further inform that path. Let me just say something, just on the front line lung cancer, you know, with the STK11 co-mutation and the patients with a TPS score of less than 1%, you know, we're already moving very aggressively in that patient population as well because that represents about 40% of the first line non-small cell lung cancer patients with the G12C mutation.

An accelerated approval would be a possibility and either one of those settings and really the ongoing generation of data.

Will help further informed that path.

Okay.

Oh, sorry, let me just say somebody goes on the frontline lung cancer.

Okay 11 until mutation of the patients with the TBO score of less than 1%.

We're already moving very aggressively patient population as well because the reference events represents about 40% of the first line non small cell lung cancer patients with the gene told C mutation. So.

Jamie Christensen: So the unmet need is high, and the opportunity is great in that patient population. Thank you. Just to clarify, are we thinking, you know, 100 patients per cohort in first-line lung cancer or something lower than that, just given that you already have a certain amount of data?

That need is high and the opportunities scraped and a patient population.

But you might have made.

Just to clarify are we thinking.

100 patients per cohort in firsthand.

Or or something.

Other than that just given that you already have a.

Certain amount of data and other places.

Jamie Christensen: Right. You know, again, I mean, you know, please take my response in the spirit that, you know, this is a review issue and it remains undefined. So, in a way, we've developed our statistical hypotheses and are targeting those hypotheses. And ultimately, depending on how the data shakes out, that would determine the number of patients necessary probably to present a convincing argument to the agency. But we just say, if you looked at this as a purely statistical argument, the number would be under 100.

Right again.

Again I mean, please take my response in the spirit that this is a review issue and remains undefined. So in a way we've developed our statistical hypotheses and are targeting those hypotheses and ultimately depending on how the data shakes out that would determine the number of patients necessary.

Probably to present, a convincing argument to the agency, but we just say if you looked at this as a purely statistical argument the number would be under 100.

Jamie Christensen: Again, assuming response rates of 55% to 60% or higher and assuming that the null hypotheses of 20% to 25% in SDK 11 or 32% in, you know, especially the TPS Lesson 1 were the assumptions beyond those statistical hypotheses. Thank you, and next we'll move on to Ben Burnett with Steve. Excellent. Thank you very much. I had a just a quick question on the CNS data. Just given the timing potentially at ASCO, is this is this something that might be included the adagrassive drug label if it's approved? Great question, Ben.

Again, assuming response rates of 55% to 60% or higher and assuming that the no hypotheses of 20% to 25% and SDK 11 or 32% in.

Essentially the TPS lesson, one where the assumptions beyond those statistical hypotheses.

Okay.

Thank you and next we move on to Dan Bern, It with people.

Excellent. Thank you very much I had a just a quick question on the <unk> stated just given the timing potentially to ask or is this something that might be included the at aggressive drug label, if if it's brute.

David Meek: We're certainly going to have that dialogue with the agency as the data emerges. We'll discuss that with the agency. We'll try to have as much data as possible put on the label, both preclinical and clinical data. No guarantees.

Great question, but I know, we're certainly going to have that dialogue with the agency is the data emerges.

We'll have that with the agency will try to have as much data as possible put on the label preclinical and clinical data you'll no guarantees.

David Meek: We're certainly moving to get Adagrassive approved as fast as possible. So I'd say, as a minimum, the data will be published. If it's not available in the label, we certainly would like to go for a compendia listing, listing of the guidelines, clinical pathways, until we're able to catch up with the label. Okay, understood.

We are certainly moving to get at aggressive approved as fast as possible.

So I'd say as a as a minimum the data will be published if it's not available to label. We certainly would like to go for a compendium listing listing of the guidelines clinical pathways until we're able to catch up with the label.

Jamie Christensen: That's helpful. And if I could just kind of piggyback on on the pancreatic discussion that we're just having. I guess what level of evidence is, are KRAS G12D, tumors equally as addicted as G12C tumors in pancreatic cancer. Just trying to get a sense for what to expect from a good G12D inhibitor in this setting and if the adagrassive data might be somewhat predictive here. Any thoughts there?

Okay understood that's helpful and if I could just kind of piggyback on the pancreatic discussion we were just having.

I guess what level of evidence is R. K rashed equal D.

Tumors equally as addicted as <unk> C tumors and pancreatic cancer.

Just trying to get a sense for what to expect from a good useful D inhibitor in this setting and it's if you add a grasp data might be somewhat predict appear in your thoughts there.

Jamie Christensen: Yeah, I think that's a really interesting question. We've been looking at that as well. And I think there are some commonalities between G12 C mutations in Pang versus G12 D. You know, I think one of those observations is that... These appear to be the founding genetic event in this class of cancers, you know, going back, you know, kind of now 20 years looking at the sequence of genetic events that move, you know, kind of pancreatic ductal adenocarcinoma from, you know, kind of pancreatic inner epithelial neoplasia, which is a very early lesion, those are caused by KRAS mutations.

Yeah, I think that's a really interesting question, we've been looking at that as well.

There are some commonalities between G 12, see mutations in paying versus G 12 D.

I think one of those observations is that.

These appear to be the founding genetic event in this class of cancers going back.

Now 20 years looking at the sequence of genetic advance that move.

Kind of pancreatic ductile adenocarcinoma from.

Of.

Pancreatic thinner and our empathy those neoplasia, which is a very early lesion. Those are caused by kers mutations. So at the very least we would expect the founder mutation to demonstrate that the vast majority of tumor cells. If not all of them are going to have the chaos mutation, it's not going to be a heterogeneous or wait.

Jamie Christensen: So at the very least, we would expect the founder mutation to demonstrate that the vast majority of tumor cells, if not all of them, are going to have the KRAS mutation. It's not going to be a heterogeneous or late acquisition of a genetic event.

Acquisition of a genetic match.

Jamie Christensen: Number two is when we look at disease modeling pre-clinically, we have, you know, tried to get our hands on every possible G12C pancreatic ductal adenocarcinoma model, looking both at topically and orthotopically with regard to implantation. We've looked, you know, certainly at a number of G12D models and the data stacks up pretty well. You know, the majority of those models are decreasing in tumor size at least 30% off and greater than 50%. So we have a paper that will likely be accepted here shortly, and it goes over the data in pancreatic ductal adenocarcinoma models for MRTX1133.

Number two is when we look at disease modeling preclinical Lee we have tried to get our hands on every possible G 12 seed pancreatic ductile adenocarcinoma model looking both at topically and Orthotopic Lee with regard to implementation. We've looked certainly at a number of G 12 D models.

The data stacks up pretty well the majority of those models are decreasing and tumor size at least 30% off in greater than 50%. So we have a paper that will likely be accepted here shortly and it goes over the data and pancreatic ductile adenocarcinoma models for <unk> 1133, and a lab.

Jamie Christensen: And 8 out of 11 of those models responded by tumor regression of at least 30% off and, again, higher than that. And then finally, if you look at, you know, kind of depth mapped project drive and a lot of these large kind of functional genomic studies that have looked across hundreds, if not, you know, over a thousand different tumor cell lines, looking at the systemic knockdown of genes. Certainly, G12D pops up as one of the strongest DEPMAP hits, including the enrichment for pancreatic to adenocarcinoma lines. It's one of the strongest dependencies found in those studies, if you look closely at DEPMAP mining. So you take those three pieces of information and triangulate.

Eight out of 11 with those models responded by tumor regression of at least 30% often again higher than that.

And then finally, if you look at that map project drive in a lot of these animals large kind of functional genomics studies that have looked across hundreds if not over 1000 different tumor cell lines looking at the systemic knocked out of genes both.

<unk> Pops up as one of the strongest that map hits, including the enrichment for pancreatic adenocarcinoma lines is one of the strongest dependencies found in those studies.

If you look closely at that map mining. So you take those kind of three pieces of information that triangulate. We do believe that <unk> is a very strong driver and pack and that there is likely supreme through for a parada grass.

Jamie Christensen: We do believe that G12D is a very strong driver in PANC, and that there is likely some read-through for adagrass. And the patient population is significantly larger. The G12T patient population or pancreatic prevalence is significantly greater than it is for G12C mutations.

As a patient population is significantly longer us significantly larger than <unk> patient population were patriotic so prevalent significantly greater than it is for <unk> mutations right <unk>, yeah, just to build that David's comment 36% of pancreatic pepto adenocarcinoma patients are going to have <unk>.

David Meek: Right. Yeah, just to build on David's comment, 36% of pancreatic ductal endocarditis patients are going to have a G12T mutation. I believe the overall US prevalence is around 40,000.

Haitian I believe the overall use prevalence somehow 40000 all of those are a strong.

Jamie Christensen: All of those are a strong amount. Okay, that's great, Kolar. I appreciate it. Thank you. Thank you, and we'll move on to Maury Raycroft with Jeffrey. Hi, this is Kevin Strang on for Morrie.

Medical need.

Okay. That's a great color I appreciate it thank you.

Okay.

You don't want to move on.

Murray Ray Crock with Jeffrey.

Hi, This is Kevin Strang on for Morey, Thanks for taking my questions.

Jamie Christensen: Thanks for taking my questions. Just first on the Phase 3, could you give any color into how the enrollment is going and whether or not you plan to open on any more sites than the 115 you have listed right now? And then how confident you are that you'd be able to enroll this prior to the December PDUFA? A couple things, if David and Jamie can jump in, too.

Just first on the on the phase III could you give any color into how the enrollments going.

And whether or not you plan to open on any more sites and 115, you have lifted right now and then how confident you are that you'd be able to enroll this prior to the December <unk>.

Yeah, a couple of things, it's David Jamie and jump into further confirmatory trial for autographs admitted second line non small cell lung cancer.

David Meek: For the confirmatory trial for adagrassive and second-line non-small cell lung cancer, for that, we're really encouraged by the increase in enrollment. With that, we've expanded the trial. It's a global trial at this time.

For that we are really encouraged by the increase in enrollment without we've expanded the trial. It's a global trial at this time, we better in a number of use sides excuse me European sides are partners I is helping us in Asia, So new recruitment is going well.

David Meek: We've added a number of U.S. sites, excuse me, European sites. Our partner, Zai, is helping us in Asia, so the recruitment is going well. Just for clarity, that trial does not need to be fully enrolled prior to an approval. That's per FDA regulations. However, we'll be well underway, well, we are well underway, and we'll be very well recruited by the time we think adagrassive should be approved later this year. Jamie?

Just for clarity that trial does not need to be fully enrolled.

Prior to approval.

Regulations, however will be well underway and we are well underway and will be variable recruited by the time, we think of aggressive should be approved later this year, Jamie the only thing I would add two is that.

Jamie Christensen: The only thing I would add, too, is that, you know, with the trial, you know, now opening globally, that's a major catalyst for enrollment. Those sites are really opening up, you know, en masse now, and we can certainly see an uptick in enrollment associated with the global opening of the trial. Yes, it does.

With the trial now opening globally, that's a major catalyst for enrollment those sites are really opening up.

And mass now and we can certainly see an uptick in enrollment associated with the global opening of the trial.

Venture.

Jamie Christensen: Thank you. And then just a quick one on, you know, you've opened a couple new arms for your crystal study on ct.gov for citoximab combinations in small cell and PDAC. You've spoken about, and you've shown data for, CRC.

Yes. It does thank you and then just a quick one on.

You opened a couple of new arms.

For your Crystal study on <unk> Dot Gov for talks about combinations.

In small cell on PDOC, you've spoken before about and you show data for CRC can you just talk about your rationale for.

Pursuing that combination in these indications.

Jamie Christensen: Can you just talk about your rationale for pursuing that combination in these indications? Sure, you know, EGFR and EGFR family have turned out to remain among the very top combinations that we've observed pre-clinically. There's a very strong link to EGFR biology and KRAS. Certainly that's been demonstrated first in colorectal cancer, but we also believe it to be important in lung and pancreatic cancers as well.

Sure.

Egfr and Egfr family have turned out to remain among the very top combinations that we've observed preclinically is a very strong linked egfr biology, and pay Ross certainly that stem and demonstrated first and colorectal cancer, but we also believe it to be important and.

Long and pancreatic cancers as well, so essentially want a double down and and make sure that we are covering all of the options to be able to block both of those pathways and due to the success of Cetuximab in CRC.

Jamie Christensen: So essentially we want to double down and, you know, make sure that we are covering all of the options to be able to block both of those pathways. And due to the success of Situximab and CRC, you know, it certainly opened up, you know, some interest for us to look at that and other malignancies as well. So that's really the basis of us looking at that. Great, thank you. Thank you. And next we'll take Mike Ulz with Morgan Stanley.

Certainly opened up some.

Some interest for us to look at that and other malignancies as well.

So that's really the basis of us looking at that.

Great. Thank you.

Thank you and next I'll take Mike <unk> with Morgan Stanley .

Jamie Christensen: Hey guys, thanks for taking the question. One quick one for me on Adagrassive in terms of... Combination Strategy Beyond the PD-1 and Cetuximab. You'd mentioned providing some of that data next year, but I'm just curious if you can remind us what dose of Adegresib you're using there. Is it the 600 milligram dose? considering using. You know, generally when we start a dose escalation, we're starting with 400, and then if that looks promising, we can go up from 400. So I would say we have combination trials ongoing right now with the 400 dose, and we have some combination studies that have escalated up to 600. So we're essentially looking at both.

Hey, guys. Thanks for taking the question just one quick one for me on at aggressive in terms of two combination strategy beyond the P D. One and tucks a map.

You'd mentioned, providing some of that data next year, but I'm. Just curious if you can remind us what dose of add aggressive you're using their is it the 600 milligram dose or are you considering using 400 as well.

Generally when we started dose escalation, we're starting with 400 and then if that looks promising we can go up from 400. So I would say we have combination trials ongoing right now with the 400 dose and we have some combination of studies that have escalated up to 600. So we're essentially looking at both.

Jamie Christensen: And just to say that, you know, we've done some analysis of the 400 dose with regard to PK exposures. And as you can imagine, we constantly look at things like exposure response analysis in any of the clinical data sets that we've generated and are highly confident that 400 makes BID is covering the target quite well. So any combination that we move forward with at a 400 milligram dose level, whether it be Pembrolizumab or otherwise, the data exposure response, you know, PK overall looks quite promising at that dose level. Yeah, thank you.

And just to say that.

We've done some analysis of the 400 dose with regard to pique exposures.

And as you can imagine we constantly look at things like exposure response analysis and any of the clinical data sets that we've generated and are highly confident that 400 makes it is covering the target quite well so.

So any combination that we move forward with it a 400 milligram dose level, whether it be <unk> or otherwise.

The data exposure response.

PK overall look look quite promising at that dose level.

Yeah. Thanks, So I'm certainly going to be a temperament.

<unk>. Thanks.

Oh that was it for me.

Thanks.

Sarah: Thank you, and we'll take a. One last question from Yigal Nopomovic with Citi. Great. Hi, this is Carly.

And can you take off.

One more question from your account no promote with city.

Carly: Thanks so much for taking our questions. We have two questions. First, I think you mentioned that you've begun medical affairs activities in preparation for the launch, so we're just curious if there are certain aspects of adagrassis differentiation that you believe are resonating most with physicians, whether it's the PK properties, long half-life, CNS penetrance, or something else. Any additional context you could provide there would be helpful.

Hi. This is currently on France. Thanks, so much for answering our questions. We have two questions first I think you mentioned that.

Medical affairs activities in preparation for the launch. So we're just curious if there are certain aspects of autographs differentiation that you believe are resonating messed with the question is whether it's the P. K properties half-light fiennes pattern or something else any additional potash.

Fantastic Alright, there would be helpful. And then the second question is just on G. 12 D. We were just hoping to get an update on where you stand.

David Meek: And then the second question is just on G12D. We were just hoping to get an update on where you stand with the formulation work for that program. Thank you. David, Ben, and Jamie will answer this.

A formulation whack for that program. Thank you.

So.

David Ben and Jamie will inches regarding medical Affairs Medical Affairs has been in the field since 2020, so their rapidly approaching.

David Meek: Regarding medical affairs, medical affairs has been in the field since 2020, so they're rapidly approaching two years in the marketplace, preparing the market for Atagrassiv as well as a KRAS G12C inhibitor. And part of the story that the physicians find very appealing is the unique molecular profile, the 24-hour half-life, the time on target that Atagrassiv has, you know, reading through to overall response rates. Physicians have been very appreciative and very excited about the 43% response rate that we have in our registration trials, so that's going over very well.

Two years in the marketplace of preparing the market for an aggressive as well as a K Ross <unk> inhibitor and the part of the story that the physicians fight very appealing is the unique molecular profile. The 24 hour halfway in the Taiwan target that out aggressive has really do too.

David Meek: Also, the unique molecular profile Jamie spoke about earlier regarding CNS and brain meds and the activity we have there is also very appealing to physicians. So there's a couple of data points regarding the medical affairs organization, the impact they're having. And, Ben, other comments you'd add? Yeah, I would just add one.

Overall response rates of physicians have been very appreciative and very very excited about the 42% response rate that we have on our registration trials. So that's going over very well also the unique vallecula profile, Jamie spoke about earlier regarding CNS and brain beds in the activity. We have there is also very appealing to a physician so there's a <unk>.

Double data points regarding the medical affairs organization impact they are having and then other comments you just.

Just add one.

Ben Hickey: They're doing a magnificent job, and we have folks in both the U.S. and the EU focused on driving enrollment of the studies. What we hear consistently back is that they are enthused by the molecular profile and the 24-hour half-life, and they do believe that that's part of the story and why we've seen some consistent results around response rates across tumors. And then on the brain meds from preclinical data, they're enthused and looking forward to seeing more of the clinical data. But they certainly ask us a lot about that data, and I'm looking forward to the upcoming data presentation. Michael Ulz, Benjamin Hickey.

Doing a magnificent job when we have folks in both the us and the EU focused on driving enrollment of the studies.

From.

What we hear consistently back is but they are enthused by the macula profile on the 24 hour 24 hour offline and they they do believe that's part of the story and what we've seen.

Some consistent results around response rates across tumors.

And then on the Raymond from obviously from a preclinical date for their enthused and looking forward to seeing more of the clinical data but.

But they sent me ask a lot of data and I'm looking forward to the upcoming data presentation.

And we have time, okay, yeah and on the <unk> front. So I think as we've previously communicated due to a D 1133 checks a lot of the boxes with respect to potency metabolic stability Sally ability to an otherwise.

Jamie Christensen: Okay, yeah, and on the G12 defraud, so I think as we've previously communicated... G12V1133 checks a lot of the boxes with respect to potency, metabolic stability, solubility, and otherwise. But the intrinsic oral vibability is fairly low. And we initially started developing this as a standard IV formulation, but just weren't really satisfied with the duration of target coverage necessary to drive monotherapy activity. So we shifted our gears into long-acting injectables. One example of a long-acting injectable is a liposome-based formulation.

But the intrinsic oral five ability is fairly low and.

And we initially started developing as a standard Ivy formulation, but just weren't really satisfied with the duration of target coverage necessary to drive mono therapy activity. So we've shifted our gears into long exiting Injectables. One example of long acting injectable as a liposomal based formulation.

Jamie Christensen: And we've been, I think, encouraged by the preclinical data we've seen thus far, where we see strongly differentiated PK properties, essentially extending the half-life of the 1133 in preclinical species that we've evaluated to date. And that is associated with achieving longer duration of target coverage.

And we've been I think encouraged by the preclinical data we've seen thus far where we see strongly differentiated PK properties.

Essentially extending the half life of the 11 33 and preclinical species that we've evaluated to date.

And that is associated with achieving longer duration of target coverage and if we can set that up in a way where we can deliver the drug once a week or somewhere in that range clinically I think it's going to be more clinically feasible for us to develop that as a as a formulation approach we.

Jamie Christensen: And if we can set that up in a way where we can deliver the drug once a week or somewhere in that range, clinically, I think it's going to be more clinically feasible for us to develop that as a formulation approach. We do have other long-acting injectables that we're looking at as well. And those are also in process. And then finally, we have discovered that there are some ways to enhance oral bioavailability or oral absorption of the drug. Those are ongoing and, I'd say, exploratory at this point.

We do have other long exiting injectables that we're looking at as well.

And those are also in process and then finally, we've had discovered that there are some waste enhanced oral.

By availability oral absorption of the drug those are ongoing and I'd say exploratory at this point, but if we can make progress there as possible that in addition to the long acting injectable Ivy that we're advancing towards the Indy track that there may be a lifecycle strategy with other formulations that we could eventually move forward with us as well.

Jamie Christensen: But if we can make progress there, it's possible that, in addition to the long-acting injectable IV that we're advancing towards the IND tract, that there may be a lifecycle strategy with other formulations that we could eventually move forward with this as well. Thank you, Jamie, and thank you everyone for joining us today, and also thank you very much for your questions. As you can tell from the team, we're real excited about the future of Mirati.

Thank you Jamie Okay.

Yes. Thank you everyone for joining us today and it also thank you very much for your questions.

Told from the team we're real excited about the future Marathi, we're well on our way to creating a leading biotech company with one of the most exciting and tangible target oncology portfolios and Biopharma.

David Meek: We're well on our way to creating a leading biotech company with one of the most exciting and tangible target oncology portfolios in biopharma. There is a relentless focus at Mirati on translating novel science into innovative therapies that bring hope to patients. And we look forward to speaking with many of you and sharing additional updates as we continue to progress toward a mission to discover, design, and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. Thank you. And that does conclude today's teleconference. We do appreciate your participation. You may now disconnect.

There is a relentless focus a variety of translating novel clients and then an innovative therapies that bring older patients and we look forward to speaking with many of you and sharing additional basis, we continue to progress toward admission to discover design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones.

Thank you and that does conclude today's teleconference. Let me give her appreciate your participation you may not disconnect.

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Sarah: The Mirati Therapeutics Inc. is a non-profit organization that focuses on the treatment of chronic pain and emotional distress. We provide free counseling and support services to patients and their families. We provide free education and support services to patients and their families. We provide free counseling and support services to patients and their families. [inaudible] by the pace of their pain and experience a myopic Mayo Crisis.