Q3 2021 Mirati Therapeutics Inc Earnings Call

Okay.

Keith: Good afternoon, ladies and gentlemen. Welcome to the Mirati Therapeutics third quarter 2021 earnings call. My name is Keith, and I'll be your operator for today's call. All lines have been placed on mute to prevent any background noise. After the conclusion of the speaker's prepared remarks, there will be a question and answer session.

Good afternoon, ladies and gentlemen, and welcome to the Moratti Therapeutics third quarter 2021 earnings call. My name is Keith and I'll be your 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 session. If you would like to ask a question. During this time simply press the star key.

Followed by that number one on your telephone keypad, if you'd like to withdraw your question from the queue press the pound key and it's my pleasure to introduce Ryan <unk>, Vice President of corporate Affairs at Karate, Brian you may begin the call.

Keith: If you would like to ask a question during the...

Ryan: Thank you, Keith, and welcome, everyone, to this afternoon's call. With me today are David Meek, Mirati's Chief Executive Officer, Dr. Chuck Baum, Mirati's President, Founder, and Head of Research and Development, Dr. Jamie Christensen, Mirati's Chief Scientific Officer, and Vicki Reed, Mirati's Chief Accounting Officer. 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 Keith and welcome everyone to this afternoons call with me today are David <unk>, Chief Executive Officer, Dr. Chuck Baum.

President founder and head of research and development, Dr. Jamey Christiansen Rogers, Chief Scientific Officer, and Vickie Reed morality, Chief Accounting Officer. 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 for a full.

Ryan: For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended September 30th, 2021, and recent corporate news. This press release is available on the investor section of our website at mirati.com.

Discussion of these risks and uncertainties. Please review our annual report on Form 10-K, and our quarterly reports on Form 10-Q that are filed with the U S Securities and Exchange Commission.

This afternoon, we released financial results for the quarter ended September 32021, and recent corporate updates.

Press release is available on the investors section of our website at <unk> Dot com with that David ill turn the call over to you. Thank you Ryan and good afternoon, everyone and thank you for joining us on this afternoon's call I will provide some introductory remarks before asking Chuck to share an update on our clinical development programs, Jamie to comment on our preclinical program.

David D. Meek: With that, David, I'll turn the call over to you. Thank you, Ryan. Good afternoon, everyone, and thank you for joining us. On this afternoon's call, I will provide some introductory remarks before asking Chuck to share an update on our clinical development programs, Jamie to comment on our preclinical programs, and Vicky to.

Keith: This concludes today's conference. Thank you. I will then provide

And Vicki to summarize our financial results I will then provide an update on our operational plans before taking your questions.

David D. Meek: I will then provide an update on our operational plans before taking your questions. It has been a busy and rewarding two months since my announcement as Mirati's CEO. These first few weeks have confirmed my conviction about the near and long-term potential of this company. There is a relentless focus at Mirati on translating novel science into innovative therapies that bring hope to patients. Mirati is differentiated, and we are well on our way to creating a leading biotech company with one of the most exciting and tangible oncology portfolios in biopharma.

It has been a busy and rewarding two months since my announcement as Roddie CEO. These first few weeks have confirmed my conviction about the near and long term potential of this company.

There was a relentless focus at Marathi on translating novel Science, and innovative therapies that bring hope to patients.

<unk> is differentiated and we are well on our way to creating a leading biotech company with one of the most exciting intangible oncology portfolios and Biopharma.

David D. Meek: We continue to make significant progress on advancing our clinical and preclinical stage portfolio and rapidly expanding our capabilities as we prepare for the expected U.S. commercial launch of Adagrassive. We believe its clinical profile is best in class. In addition to the breakthrough therapy designation we announced in June, we recently submitted the first adigrassive data package as part of the Real-Time Oncology Review Pilot Program, or RTOR, new drug application submission process to the FDA for previously treated non-small cell lung cancer. We are on track to finalize the NDA submission before the end of this year.

We continue to make significant progress on advancing our clinical and preclinical stage portfolio and rapidly expanding our capabilities as we prepare for the expected U S commercial launch about aggressive.

We believe added glass its clinical profile is best in class. In addition to the breakthrough therapy designation, we announced in June we recently submitted the first out aggressive data package as part of the real time Oncology review pilot program or our tour new drug application submission process to the FDA.

For previously treated non small cell lung cancer.

We are on track to finalize the NDA submission before the end of this year.

Charles M. Baum: Our U.S. launch preparation for adagrassive in patients with KRAS and GTAL-C mutated advanced non-small cell lung cancer has been well underway, and we look forward to sharing specifics about our launch planning for this potentially transformational therapy next year. To recognize its full potential, we are aggressively evaluating adagrassive in a broad development plan, including in proof-of-concept phase two trials for first-line non-small cell lung cancer, a confirmatory phase three trial randomized to docetaxel in previously treated non-small cell lung cancer, and a registration-enabling phase three trial in second-line colorectal cancer.

Our U S launch preparation for autographs it in patients with K Ras <unk> mutated advanced non small cell lung cancer is well underway and we look forward to sharing specifics about our launch planning for this potentially transformational therapy next year.

So recognize its full potential we are aggressively evaluating added grass. It in a broad development plan, including a proof of concept phase III trials for first line non small cell lung cancer, a confirmatory phase III trial randomized to Docetaxel and previously treated non small cell lung cancer.

The registration, enabling phase III trial in second line colorectal cancer.

Charles M. Baum: Beyond non-small cell lung cancer and colorectal cancer, we are very pleased with the preliminary results we reported in pancreatic cancer and are continuing to assess aggressive and additional solid tumor settings to potentially help even more patients. To date, our capabilities have enabled us to execute across multiple programs, including adegrassib and citravacinib, on our own in key markets while partnering selectively in regions such as China. These capabilities have also enabled the development of novel drug combinations.

Beyond non small cell lung cancer and colorectal cancer. We are very pleased with the preliminary results. We reported in pancreatic cancer and are continuing to assess out a grass. It in additional solid tumor settings to potentially help even more patients.

To date, our capabilities have enabled us to execute across multiple programs, including <unk> and <unk> on our own in key markets, while partnering selectively in regions such as China.

These capabilities have also enabled development of novel drug combinations.

Charles M. Baum: When combined with the strength of our internal research team and novel portfolio of targeted oncology programs, we believe this provides us with the potential for long-term growth and sustainability. The strength, capabilities, and innovative mindset of our employees fuel our success, and I'm grateful for our dedicated and passionate team. I would like to acknowledge and thank them for all they're accomplishing. With that, I'll turn it over to Chuck.

When combined with the strength of our internal research team and novel portfolio of targeted oncology programs. We believe this provides us with the potential for long term growth and sustainability.

The strength capabilities and innovative mindset of our employees fuel our success and I am grateful for our dedicated and passionate team I would like to acknowledge and thank them for all they are accomplishing with that I'll turn it over to Chuck.

Charles M. Baum: Thanks, David. I will address our two late-stage registration-enabling programs, Atagrassis and Citravap. We continue to make significant progress and have seen best-in-class clinical results for adagrassate across multiple patient populations with solid tumors harboring a KRAS G12C mutation. Last month, we announced positive top-line results from our registration cohort of the CRYSTAL1 study in patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation following prior systemic therapy. The top line result showed that Atagrassif at a dose of 600 milligrams BID demonstrated an objective response rate of 43% and a disease control rate of 80% based on central independent review.

Thanks, David.

I will address our two late stage registration, enabling programs <unk> and <unk>.

We continue to make significant progress and have seen best in class clinical results for <unk> across multiple patient populations with solid tumors harboring K Ras G <unk> mutation.

Last month, we announced positive topline results from our registration cohort of the Crystal one study in patients with advanced non small cell lung cancer harboring the <unk> mutation following prior systemic therapy.

Top line results.

Show that <unk> at a dose of 600 milligrams PID.

Demonstrated an objective response rate of 43% and a disease control rate of 80% based on Central Independent review.

Charles M. Baum: Importantly, almost all (98.3% of patients in this trial) received Adagracib following treatment with both a checkpoint inhibitor and a platinum-based chemotherapy regimen, which is the standard of care in the United States. We reported that the safety and tolerability profile was consistent with previously reported results for adegravacib in patients with advanced non-small cell lung cancer. We plan to present the full data set at a medical congress in 2022 in advance of our anticipated U.S. commercial launch.

Importantly, almost 98, 3% of patients in this trial received at aggressive following treatment with both a checkpoint inhibitor and a platinum based chemotherapy regimen, which is the standard of care in the United States.

We reported that the safety and Tolerability profile was consistent with previously reported results for <unk> in patients with advanced non small cell lung cancer.

We plan to present, the full data set at medical Congress in 'twenty to 'twenty two in advance of our anticipated U S commercial launch.

Charles M. Baum: In addition to the top-line Phase 2 results, we also reported updated data from 19 patients treated with adegravacib at 600 milligrams BID in the Phase 1, 1B monotherapy cohort of the CRYSTAL1 study in patients who had received at least one prior systemic therapy. These patients had a median follow-up of 17 months. A median duration of response of 12.6 months in the 11 responders and a median progression-free survival of 8.3 months. However, the median overall survival has not yet been established.

In addition to the topline phase two results. We also reported updated data from 19 patients treated with <unk> 600 milligram PID in the phase one <unk> monotherapy cohort of the Crystal One study in patients who had received at least one prior systemic therapy. These.

Patients had a median follow up of 17 months.

Median duration of response of $12 six months in the 11 responders and a median progression free survival of eight three months. The median overall survival was not yet reached.

Charles M. Baum: Our Phase 3 confirmatory trial, CRYSTAL-12, is enrolling previously treated non-small cell lung cancer patients. As David mentioned in his opening remarks, we have initiated our new drug application as part of the RTOR pilot program and expect to complete the submission to the U.S. FDA by year's end. This is an important step for Mirati and patients with non-small cell lung cancer.

Our phase III confirmatory trial Crystal 12 is enrolling previously treated non small cell lung cancer patients.

As David mentioned in his opening remarks, we have initiated our new drug application as part of the art for pilot program and expect to complete the submission to the U S. FDA by year's end.

This is an important step for Marathi and patients with non small cell lung cancer.

Charles M. Baum: We have a broad and aggressive development plan for adagracid in patients with non-small cell lung cancer, as well as colorectal cancer and other solid tumors that express KRAS G12C mutations. For first-line non-small cell lung cancer, we have a multi-pronged development approach in both monotherapy and combination therapy. We are exploring the development of adagrassib in two unique patient populations as monotherapy in first-line non-small cell lung cancer patients whose tumors express a KRAS G12C mutation.

We have a broad and aggressive development plan for <unk> in patients with non small cell lung cancer as well as colorectal cancer and other solid tumors that express <unk> mutations.

In first line non small cell lung cancer, we have a multi pronged development approach in both monotherapy and combination.

We are exploring the development of allografts had been two unique patient populations as monotherapy in first line non small cell lung cancer patients, whose tumors express a <unk> mutation.

Charles M. Baum: The first approach is in first-line patients whose tumors have a co-mutation of KRAS G12C and SDK11, where we have an ongoing, potentially registrational, single-arm trial. The second monotherapy approach is in first-line patients whose tumors have TPS scores of less than 1%, in whom we have initiated a potentially registrational single-arm study. Patients with STK-11 co-mutations or GTS scores of less than 1% have a poor prognosis with standard of care therapies, with objective response rates in the first line of approximately 30% and median progression pre-survival of less than six months.

The first approach is in first line patients, whose tumors have a co mutation of <unk> and SDK 11, where we have an ongoing potentially registrational single arm trial.

The second monotherapy approach is in first line patients, whose tumors have TPS scores of less than 1% and who we initiated a potentially registrational single arm study.

Patients with SDK 11, co mutations or TPS scores of less than 1%.

A poor prognosis with standard of care therapies with objective response rates in the first line of approximately 30% and median progression free survival of less than six months.

Charles M. Baum: In patients with STK-11 co-mutations, published real-world data suggests that the median progression-free survival is approximately two months. Collectively, these two patient subgroups represent greater than 40% of the total first-line KRS-G12c non-small cell lung cancer patient population. We are discussing the potential registration pathways for each of these patient populations with the FDA.

In patients with SDK 11, co mutations published real World data suggests that the median progression free survival is approximately two months.

Collectively these two patient subgroups represent greater than 40% of the total first line <unk> non small cell lung cancer patient population.

We are discussing the potential registration pathways for each of these patient populations with the FDA.

Charles M. Baum: In addition to monotherapy approaches, we are advancing combination approaches in front-line, non-small-cell limits. One key area of focus in the frontline setting is to evaluate the combination of Adagracib with Pemberlis. We began this evaluation using the 600 milligram BID dose of Adegrazib with full-dose Pemberlis.

In addition to monotherapy approaches we are advancing combination approaches in front line non small cell lung cancer.

One key area of focus in the frontline setting is to evaluate the combination of <unk> with timber lithium atom.

We began this evaluation using the 600 milligram tid dosing that aggressive with full dose <unk> mab.

Charles M. Baum: We assessed the combination in patients with prior checkpoint inhibitor therapy as well as first-line patients in the CRYSTAL-1 and CRYSTAL-7 clinical trials. We later added a phase 1B cohort to the CRYSTAL1 study to evaluate the combination of pembrolizumab at an aggressive dose of 400 milligrams BIP. Collectively, we have evaluated the combination of adegrassib with full-dose pumperlizumab in over 40 patients across the CRYSTAL-1 and CRYSTAL-7 clinical trials. After comparing the overall tolerability profile of the combination of adegrassib at both 400 and 600 mg BID dose levels, we have identified 400 mg BID as the go-forward dose of adegrassib. Of note, the 400-milligram BID dose of Atagrasta breaches our target plasma concentration threshold for achieving complete target coverage for the full dose cycle.

We assessed the combination in patients with prior checkpoint inhibitor therapy as well as first line patients with Covid in the Crystal and.

And Crystal seven clinical trials.

We later added a phase one cohort to the Crystal one study to evaluate the combination of <unk> at an aggressive does 400 milligrams PID.

Collectively we have evaluated the combination of out aggressive with full dose <unk>.

40 patients across the Crystal and Crystal seven clinical trials.

After comparing the overall tolerability profile of the combination of that aggressive at both 400 600 milligram B I D.

Dose levels, we have identified 400 milligram B I D is the go forward dose of ad across it.

Of note the 400 milligram dose about aggressive breaches are target plasma concentration thresholds for achieving complete target coverage for the full dose cycle.

Charles M. Baum: Of the patients enrolled, eight treatment-naive, non-small cell lung cancer patients were enrolled at the 400 mg BID dose level of adegracin, and seven of these patients were valuable for response as of the October 21st data cutoff. These preliminary Phase 1B results indicate that the combination of full-dose pembrolizumab with aggressive therapy at 400 milligrams BID has a manageable tolerability profile and And no grade 4 or grade 5 adverse events were observed.

Of the patients enrolled eight treatment naive non small cell lung cancer patients were enrolled at the 400 milligram dose level of <unk> and seven of these patients were evaluable for response as of the October 21st data cutoff.

These preliminary phase one b results indicate that the combination of full dose <unk> without aggressive that 400 milligram PID has a manageable tolerability profile and no patients having treatment related adverse events, leading to treatment discontinuation and.

No grade four or grade five adverse events were observed.

Charles M. Baum: Of the seven response-evaluable patients, four had a confirmed partial response. And one additional patient, who is still on study, experienced a 49% tumor regression in the first scan, which allowed for tumor resection before the response could be confirmed according to The disease control rate was 100%, with all seven patients exhibiting tumor regression ranging from 37 to 92%. To put our results in perspective, the overall response rate reported in the Keynote 189 clinical trial that resulted in the approval of Pembrolizumab combined with platinum-based chemotherapy was 47.6% across all PPS scores.

Of the seven response Evaluable patients four had a confirmed resist partial response.

One additional patient who was still on study experienced a 49% tumor regression in the first scan which allowed for tumor resection before the response could be confirmed according to resist.

The disease control rate was 100% with all seven patients exhibiting tumor regression ranging from 37% to 92%.

To put our results in perspective, the overall response rate reported in the keynote 189 clinical trial that resulted in the approval of <unk> combined with platinum based chemotherapy was 47, 6%.

Ross all TPS scores.

Charles M. Baum: While the data are not yet mature, with a medium follow-up of 9.9 months, five of the seven patients remained on treatment as of the data cutoff and had been on treatment for 8 to 11 months and are still ongoing.

While the data are not yet mature with a median follow up of $9 nine months five of the seven patients remained on treatment as of the data cutoff and had been on treatment for eight to 11 months and are still ongoing.

Charles M. Baum: Now, we are now enrolling patients at the 400 mg BID dose of adegracib in the Phase 2 CRYSTAL7 combination trial, which is stratified by TPS score, and are planning to initiate a Phase III registration study of Adagracib with Pembrolizumab in 2022. In addition to the combination of adagressive and comparatilizumab, we are pursuing other combination approaches Based on extensive non-clinical work, our focus includes EGFR, SHIP-2, and SOS-1 inhibition, and we'll be continuing to explore combination strategies based on emerging science.

Now we are now enrolling patients at the 400 milligram B I D dose of autographs. It in the phase two crystal seven combination trial, which is stratified by TPS score.

And are planning to initiate a phase III registration study of that aggressive with <unk> in 2022.

In addition to the combination of that aggressive in Burleson fab. We are pursuing other combination approaches that may have benefit in the first line setting.

Based on extensive non clinical work our focus includes egfr shift to in source one inhibition and.

And we will be continuing to explore a combination strategies based on emerging science.

Charles M. Baum: We recently signed a non-exclusive clinical collaboration agreement with Sanofi to evaluate the combination of adagrastib with Sanofi's investigational SHIP2 inhibitor and have an ongoing Phase 2 study with Beringer-Ingelheim's SOS-1 inhibitor. We look forward to sharing additional updates about our non-sponsored lung cancer program next year, including additional clinical data supporting aggressive clinical activity in patients with brain metastasis. During the 2021 European Society for Medical Oncology Congress, or ESMO, we shared compelling results from the colorectal cancer cohort of the Phase 1, 2, Crystal 1 study, evaluating adagracib at a dose of 600 milligrams VID as monotherapy and in combination with cituximab in heavily pretreated patients harboring a KRAS-G12C mutation. The results showed that Adegresib alone or with Cetuximab demonstrated significant clinical activity and broad disease control with a favorable tolerability profile.

We recently signed a non exclusive clinical collaboration agreement with <unk> therapy to evaluate the combination of that aggressive with <unk> investigational <unk> inhibitor and have an ongoing phase two study with beringer ingelheim sauce, one inhibitor.

We look forward to sharing additional updates about our non small cell lung cancer program next year, including additional clinical data supporting out aggressive clinical activity in patients with brain metastasis.

During the 2021 European Society for medical Oncology Congress or ESMO, we shared compelling results from the colorectal cancer cohort of the phase one two crystal one study evaluating out aggressive at a dose of 600 milligrams B I D as both monotherapy and in combination with Rituxan.

And heavily pre treated patients harboring <unk> mutation.

The results showed that at aggressive alone or with Cetuximab demonstrated significant clinical activity and broad disease control with a favorable tolerability profile.

Charles M. Baum: We can continue to enroll patients and plan to discuss these results with the FDA to determine a potential pathway for accelerated approval in late-line colorectal cancer for adagressive vasomotor therapy or in combination with tuxedoctrin. Our Phase 3 Global Registration Enabling Randomized Study of Adagrassive Plus Cetuximab, called CRYSTAL-10, is enrolling second-line patients with colorectal Overall, we are well-positioned with Adagast as a best-in-class therapy in patients with colorectal cancer. Beyond non-small cell lung cancer and colorectal cancer, we also recently shared positive preliminary phase one to efficacy results in KRAS G12C mutated pancreatic cancer, which are highly encouraging and warrant further study.

We continue to enroll patients and plan to discuss these results with the FDA to determine a potential pathway for accelerated approval in late line colorectal cancer for <unk> as a monotherapy or in combination with cetuximab.

Our phase III global registration, enabling randomized study of that aggressive plus cetuximab called Crystal 10 is enrolling second line patients with colorectal cancer.

Overall, we are well positioned without aggressive as a best in class therapy and patients with colorectal cancer.

Beyond non small cell lung cancer and colorectal cancer. We also recently shared positive preliminary phase two efficacy results in <unk> mutated pancreatic cancer.

Which are highly encouraging and warrant further study.

Charles M. Baum: In addition to pancreatic cancer, we are evaluating patients with other tumor types, including cholangiocarcinoma, endometrial, ovarian, and any other solid tumor that has a KRAS G12C mutation. And we will be exploring potential registration pathways with the FDA. Now, I'll provide an update on Citra.

In addition to pancreatic cancer, we are evaluating patients with other tumor types, including Cholangiocarcinoma endometrial ovarian and any other solid tumor that has a <unk> mutation.

And we will be exploring potential registration pathways with the FDA.

I'll now provide an update on <unk> Avenue.

James G. Christensen: We recently presented Phase I results from our MRTX500 study of citravatinib in combination with nivolumab at this year's ESMO conference. The combination demonstrated durable responses in long-term survival, including 32% of patients alive at two years in patients with second or third-line non-squamous, non-small cell lung cancer who experienced clinical benefit on a prior checkpoint inhibitor with subsequent disease progression. On the phase three, registration-enabling SAFIRE study in combination with nivolumab in second- or third-line non-small-cell lung cancer patients who have documented progression following treatment with a checkpoint inhibitor is on track to reach the number of events needed to trigger an interim analysis of overall survival in the second half of 2020. With that, I will turn it over to Jamie to describe our preclinical pipeline program. Thanks, Chuck.

We recently presented phase one results from our <unk> 500 study of <unk> in combination with Diwali Nab at this year's ESMO Conference.

The combination demonstrated durable responses and long term survival, including 32% of patients alive at two years in patients with second or third line non squamous non small cell lung cancer, who experienced clinical benefit on a prior checkpoint inhibitor with subsequent disease progression.

On phase.

Our phase three registration, enabling Sapphire study in combination with Nickelodeon Mab in second or third line non small cell lung cancer patients who have documented progression following treatment with a checkpoint inhibitor is on track to reach the number of events needed to trigger an interim analysis of overall survival in the second half.

2022.

With that I will turn it over to Jamie to describe our preclinical pipeline programs.

James G. Christensen: We have built a highly productive discovery and preclinical development capability at Mirati that is focused on the advancement of novel targeted cancer therapies that further complement our existing pipeline and that also offer potential practice-changing opportunities for cancer patients. First, I'll speak about our Next Generation PRMT5 program. This program was founded based on the principle of synthetic lethality via targeting MTAP gene deletions. These gene deletions are present in nearly 10% of all human cancers. As presented for the first time at the AACR-NCI ERCC International Conference, also known as

Thanks, Chuck we have built a highly productive discovery and preclinical development capability at Marathi.

It is focused on the advancement of novel targeted cancer therapies that further complement our existing pipeline and I would also offer potential practice changing opportunities for cancer patients.

First I'll speak to our next generation peer empty five program.

This program was founded based on the principle of synthetic lethality via targeting <unk> gene deletions.

Gene deletions are present in nearly 10% of all human cancers.

As presented for the first time at the ACR NCI <unk> International Conference also known as Eni.

James G. Christensen: MRTX171719 is the clinical development candidate.

<unk> hundred 717, 19 is the clinical development candidate for this program.

James G. Christensen: In contrast to first-generation PRMT5 inhibitors, 1719 was designed to selectively target the PRMT5 MTA complex. This targeting strategy leverages the abnormally elevated levels.

In contrast, the first generation <unk> inhibitors 17, 19 was designed to selectively target appear empty five MTA complex.

This targeting strategy leverages, the abnormally elevated levels of a metabolite known as metal tayo adenosine or MTA.

James G. Christensen: Metabolite, known as methylthioadenosine, or MTA, which is a unique characteristic of MTAP-deleted cancer. Thus, 1719 is able to selectively target MTAP-deleted cancer cells while sparing healthy non-tumor cells. 1719 is among the leading edge of PRMT5 MTA cooperative inhibitors and exhibits high-quality pharmaceutical properties and strong predicted human PK characteristics, together supporting a possible best-in-class opportunity. In addition, we have significant work ongoing in developing targeted therapies directed at KRAS mutations beyond just KRAS G12.

Which has which is a unique characteristic of <unk> tap deleted cancers.

Thus 17, 19 is able to selectively target <unk> cancer cells, while sparing healthy non tumor cells <unk>.

2019, as among the leading edge of PMT, five MTA cooperative inhibitors and exhibits high quality pharmaceutical properties.

Strong predicted human PK characteristics together supporting of the possible best in class opportunity.

In addition, we have significant work ongoing and developing targeted therapies directed at K Ras mutations beyond just <unk>.

James G. Christensen: At last month's ENA conference, I provided an overview of the discovery and preclinical development of MRTX1133, our highly selective and potent first-in-class inhibitor of KRAS G12. We are encouraged by the profile and characteristics of 1134, which includes single-digit nanomolar potency for inhibition of KRST-12D. The Ability to Bind G12t Protein in Both Active and Inactive

At last months in a conference I provided an overview of the discovery and preclinical development of <unk> 133.

Highly selective and potent first in class inhibitor of <unk>.

We are encouraged by the profile and characteristics of $11 33, which.

Which includes single digit nanometer potency for inhibition of <unk>.

The ability to bind <unk> protein and both active and inactive states a one.

James G. Christensen: A 1,000-fold selectivity ratio for KRAS G12DE versus wild-type KRAS, high-intrinsic solubility, and a long-predicted human half-life. We continue to assess long-acting IV formulations, including liposomal strategies, which are designed to maximize the extent and duration of target coverage, and have generated encouraging proof-of-principle non-clinical PK data.

1000 fold selectivity ratio for <unk> versus wild type K, Ras high intrinsic salary ability and a long predicted human half life.

We continue to SaaS long acting IV formulations, including life is almost strategies, which are designed to maximize the extent and duration of target coverage and have generated encouraging proof of principal non clinical PK data.

James G. Christensen: Last month's ENA presentation also included proof-of-concept data for spectrum-selective mutant KRAS inhibitors, including the observation of marked tumor regression observed in preclinical tumor models. We view this KRAS targeting strategy as a potential platform approach, which could eventually yield multiple development candidates targeting various KRAS mutations. Each inhibitor with distinct selectivity profiles for targeting KRAS mutant variants. Our platform-based spectrum-selective KRAS inhibitor programs are in the lead optimization stage, with specific compounds and multiple lead series under evaluation in various stages of preclinical development.

Last month's Eni presentation also include that proof of concept data for spectrum selective mutant K Ras inhibitors.

Any observation of market tumor regression observed in preclinical tumor models.

We view this <unk> targeting strategy as a potential platform approach, which could eventually yield multiple development candidates targeting various K Ras mutations.

Each inhibitor with distinct selectivity profiles for targeting K Ras mutant variance.

Our platform based spectrum selective <unk> inhibitor programs are in the lead optimization stage with specific compounds in multiple lead series under evaluation in various stages of preclinical development.

James G. Christensen: Finally, we continue to progress our discovery program targeting SOS-1. This program leverages SAS 1's utility as a KRES signaling modifier and is in the candidate selection stage. We have two unique SOX1 inhibitor lead candidates, which each exhibit high-quality pharmaceutical properties and strong predicted human PK characteristics, and are currently progressing through IND-TRAC preclinical development. With that, I will turn it over to Jamie. Thank you, Jamie.

Finally, we continue to progress our discovery program targeting sauce one.

This program Leverages SaaS once utility as a K Ras signaling modifier and isn't candidate selection stage.

We have two unique SaaS one inhibitor lead candidates.

Each exhibit high quality pharmaceutical properties and strong predicted human PK characteristics and are currently progressing through R&D track preclinical development.

With that I will turn it over to Vicky.

Thank you Jamie we ended the third quarter with approximately one $2 billion in cash cash equivalents and short term investments, which includes net proceeds of $6 3 million.

Vicki Reed: We ended the third quarter with approximately $1.2 billion in cash, cash equivalents, and short-term investments, which included net proceeds of $6.3 million from the upfront fee from our recent collaboration and license agreement with Zylab. Research and development expenses for the third quarter of 2021 were $116.1 million compared to $79.9 million for the same period in 2020. The increase in research and development expense is primarily due to an increase in expenses associated with the development of adegrassis, an increase in preclinical and early discovery activities, as well as an increase in salaries and other employee-related expenses.

From our research collaboration and license agreement with <unk> lab.

Search and development expenses for the third quarter of 2021 were $116 1 million compared to $79 9 million.

The same period in 2020.

Increase in research and development expenses, primarily due to an increase in expense associated with the development of <unk>, an increase in preclinical and early discovery activity as well as an increase in salaries and other employee related expense.

Vicki Reed: General and administrative expense for the third quarter of 2021 was $35.2 million compared

General and administrative expense for the third quarter of 2021, $35 $2 million compared to 22 million.

The same period last year.

Vicki Reed: The increase is due to an increase in commercial readiness activity, growth in salaries and related expenses from increased headcount, and an increase in other costs related to the growth of our business.

The increase is due to an increase in commercial readiness activity growth in salaries and related expense from increased headcount and increase in other costs related to the growth of our business.

Vicki Reed: The net loss for the third quarter of 2021 was $80.1 million, or $1.55 per share based compared to a net loss of $87.3 million, or $1.96 per share, basic and diluted, for the same period in time. Please see our press release from earlier this afternoon for additional details about our third quarter financial... With that, I'll hand it back. Thanks, Vicky.

Net loss for the third quarter of 2021 with $81 million, Alright, $1 55 per share basic and diluted.

Here to a net loss of $87 $3 million or $1 96 per share basic and diluted for the same period in 2020. Please see our press release from earlier. This afternoon for additional details about our third quarter financial results with that I'll hand, it back to David Thanks Vicki.

David D. Meek: We continue to make significant operational progress across our pipeline and organizational capability. In addition to the internal capabilities we have built, we are enhancing and accelerating our progress through selected partnerships. This is particularly true with Adagrassive, where we are focused on maximizing the potential of this best-in-class agent with a broad and robust development plan. We have a number of significant milestones ahead of us. For Adagrassive, by year end, we will complete the NDA submission for patients with KRES, G12c mutated second line and beyond non-small cell lung cancer.

We continue to make significant operational progress across our pipeline and organizational capabilities. In addition to the internal capabilities. We have built we are enhancing and accelerating our progress through selected partnerships. This is particularly true without aggressive where we are focused on maximizing the potential of this best in class agent to abroad.

Rod and robust development plan, we have a number of significant milestones ahead of us for autographs. It by year end, we will complete the NDA submission in patients with <unk> mutated second line and beyond non small cell lung cancer and we plan to present detailed results from the phase two registration.

David D. Meek: And we plan to present detailed results from the phase two registration enabling cohort at a medical congress ahead of our expected U.S. commercial launch in 2022. We also plan to provide additional clinical insights into Adagastib's ability to penetrate the CNS in the first half of next year. We will provide an update on the Phase II CRYSTAL7 study of the combination of adagrassid with pembrolizumab when we have enrolled enough patients with sufficient follow-up.

Enabling cohort at a medical Congress ahead of our expected U S commercial launch in 2022.

We also plan to provide additional clinical insights into autographs <unk> ability to penetrate the CNS and the first half of next year.

We will provide an update on the phase III Crystal <unk> study of the combination Nevada grass it with <unk> when we have enrolled enough patients with sufficient follow up.

David D. Meek: Based on our recent SHIP-2 clinical trial agreement with Sanofi, we will take time to generate data with that combination, and in 2022, we will provide additional guidance on future disclosures for clinical data targeting SHIP-2, SOS-1, EGFR, or CDK4 slash 6 in non-small cell lung cancer after we have generated further proof-of-concept combination data. In the first half of next year, we also expect to provide additional clarity on a potential pathway for accelerated approval of adagressive and late-line colorectal cancer as monotherapy or in combination with cetuximab, as well as share next steps in other solid tumors, including pancreatic cancer.

Based on our recent ship to clinical trial agreement with Sanofi, We will take time to generate data with that combination and in 2022, we will provide additional guidance on future disclosures for our clinical data targeting ship to source, one egfr or CDK four slash six in non small cell lung cancer after.

We have generated further proof of concept combination data.

In the first half of next year. We also expect to provide additional clarity on a potential pathway for accelerated approval about aggressive and late line colorectal cancer as a monotherapy or in combination with cetuximab as well as sharing next steps and other solid tumors, including pancreatic cancer for <unk>.

David D. Meek: For citravacinib, the key catalyst continues to be the interim analysis of overall survival from the Phase 3 SAFIRE trial in the second half of 2022, which could be the basis for regulatory submissions for full approval in the U.S. and Europe. For our other programs, we are on track to submit an IND by year end for MRTx1719, our Synthetic Lethal MTA Cooperative PRMT-5 program. We plan to file an IND for MRTX1133, our KRAS G12D inhibitor, in 2022.

<unk> the key catalyst continues to be the interim analysis of overall survival from the phase III Sapphire trial in the second half of 2022.

Which could be the basis for regulatory submissions for a full approval in the U S and Europe.

For our other programs we are on track to submit an IND by year end for <unk>, $17 19, or synthetic lethal MTA cooperative <unk> five program.

We plan to file an IND for <unk> 11, 33 R. K Ras <unk> inhibitor in 2022.

David D. Meek: From a capital allocation perspective, we are investing aggressively and outside of the grasp of U.S. commercial launch readiness, as well as a broad development plan to ensure optimal life cycle management as we move into earlier lines of therapy in non-small cell lung cancer and colorectal cancer. Additionally, we are investing in a sustainable growth profile to ensure rapid advancement of our robust, innovative targeted therapy pipeline.

From a capital allocation perspective, we.

We are investing aggressively in that aggressive U S commercial launch readiness as well as a broad development plan to ensure optimal lifecycle management as we move into earlier lines of therapy in non small cell lung cancer and colorectal cancer.

And we are investing in a sustainable growth profile to ensure rapid advancement of our robust innovative targeted therapy pipeline.

David D. Meek: We are incredibly pleased with the progress we have made and look forward to the many important milestones we are approaching.

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

David D. Meek: Milestones we are approaching. With that, Operator, we're ready to take questions. Thank you.

With that operator, we're ready to take questions.

Keith: Ladies and gentlemen, I'd like to remind everyone that if you'd like to ask a question during this time, simply press the star key followed by the digit 1 on your telephone keypad. If you'd like to withdraw yourself from the queue, please press the pound key. We'll hold for a moment while we poll for questions. We'll take our first question from Gina Wang from Barclays. Please go ahead. Thank you

Thank you, ladies and gentlemen, if you like I'd like to remind everyone that if you'd like to ask a question. During this time simply press star followed by the digit one on your telephone keypad. If you don't like to withdraw yourself from the queue. Please press the pound key.

We will hold a moment, while we poll for questions.

We will take our first question from Gena Wang from Barclays. Please go ahead.

Charles M. Baum: Thank you for taking my questions. Congratulations on the data. So, I have a few questions regarding the other cohorts, 600-milligram BID data. For the 40 patients enrolled for the PD-1 combo from both CRISPR-1 and 7, how many were on 600-milligram BID? And what about the response data for the 600-milligram BID, as well as the toxicity profile compared to the 400-milligram BID PD-1 combo? And I have a second question regarding the rationale for expanding a 600-milligram BID mono treatment in first line with PPS less than 1%. Did you see any response that you've seen so far that makes you feel confident to go towards that indication as monotherapy?

Thank you for taking my questions. Congrats on the data. So I have a few questions regarding the other cohorts 600 milligram B I D data for the 40 patient load for the PD one combo from both Crystal one is Kevin how many will all 600 milligram B I D and <unk>.

What about the response data.

For the 600 milligram B I D.

As well as the toxicity profile compared to the 400 milligram B I D. PD, one combo and I have a second question regarding the rationale for expansion of our 600 milligram B I D. Mono in first line with Pts less than 1% did you see any.

The response that you see so far make you feel confident to go towards that indication as a monotherapy.

Charles M. Baum: Okay, so let's start with the combination. So, in terms of patient numbers, as we detailed, we had seven of those patients that were nave and treated at the 400-milligram BID dose, and then the majority were at 600-milligram BID with full-dose pembrolizumab. And the reason for that number was that we started the study, both the Phase 1b and the initial K7, the CRYSTAL7 study, with the 600-milligram VID dose. So that was the dose we were planning to go forward with if all went well.

Okay. So let's start with the combination so in terms of the patient numbers.

As we detailed we had seven of those patients that were treatment naive and treated at the 400 milligram B I D dose.

And the majority being at 600 milligram B I D with full dose <unk>.

And the reason for that number was that we started the study both phase one b.

And the initial case seven for Crystal <unk> study with the 600 milligram PID dose so that was.

We were planning to go forward with that dose if all went well. So what we found was that we had more adverse events than we had seen with single agent <unk> 600 milligram tid similar events, but a constellation of events that was leading to more tolerability issues that we wanted.

Charles M. Baum: So what we found was that we had more adverse events than we had seen with single-agent 600-milligram VID-related events, but a constellation of events that was leading to more tolerability issues, and that we wanted to explore the 400-milligram VID dose in combination with full-dose fembrolizumab as being an alternative path. So those are the seven patients that we reported on today. We didn't have any patients that withdrew due to treatment-related adverse events. And an overall favorable profile. Obviously, it's still early.

To explore the 400 milligram B I D dose in combination with full dose <unk> mab as being an alternative path. So that is the seven patients that we reported on today. So we didn't have any patients that withdrew due to treatment related adverse events.

And overall favorable.

Profile, obviously, it's still early so we have.

Charles M. Baum: So we have just those seven patients. We are continuing to enroll now in the K7 trial. We modified the trial, amended it, and are now enrolling 400-milligram VID patients. And so we have limited data currently, but we'll have a lot more data coming up as that's the primary focus.

Just those seven patients we are continuing to enroll now in the case of trial that we.

We modified the trial amended it and are now enrolling 400 milligram B I D patients.

And so we have limited data.

Currently, but we'll have a lot more data coming up.

That's the primary focus and just as a reminder, the K seven trial has one arm.

Charles M. Baum: And just as a reminder, the K7 trial has one arm that is patients with TPS of less than 1% treated with single-agent 600 milligram adegrassis, and then a second, which is the combination of 400 milligrams with Pembrolizumab in those with less than 1%. And then a third cohort, which is greater than 1% and is the combination of 400 milligrams BID with Pembrolizumab. So that is the design going forward, and we'll be able to update on that as we enroll more patients.

That is patients with less TPS with less than 1%.

Treated with single agent 600 milligram.

At aggressive and then second which is the combination of 400 milligrams with timberlands a map in the less than 1% and then third cohort, which is greater than 1% and is the combination of 400 milligrams B I D with timber lives in that so that is the design.

Going forward and we will we'll be able to update on that as we enroll more patients.

Charles M. Baum: And then the second one was in the less than 1% patient population; we think that there are two populations of interest, the STK-11, obviously, because as you've seen and what we've described previously, there's a low response to standard of care, but also, in the less than 1% patient population, that's the worst performing with the current standard of care. Those with a less than 1% TPS score do more poorly than others

And then the second one was the in the less than 1% patient population, we think that.

There's two populations of interest the SDK 11, obviously.

Because as you've as you've seen and what we've described previously there's a low response to standard of care, but also in the less than 1% patient population. That's the worst performing with current candidate standard of care.

Those with less than 1% TPS score do more poorly than others. So in terms of our overall strategy will felt that that was an area that we had a chance to see benefit relative to current standard of care. So with both the SDK 11 population.

Charles M. Baum: So in terms of our overall strategy, we felt that that was an area where we had a chance to see benefit relative to the current standard of care. So with both the STK-11 population and with the less than 1%, it was worth further exploring those to identify both the tolerability but also the response rates and overall clinical benefit relative to the current standard of care. And Chuck, if I can just build on that a little bit, you know, as noted in the earlier comments, if you look at Keynote 189 broken down by TPS score, you know, I think it's notable there that the response rate is about 30% in TPS less than one patient.

And with less than 1%, but it was worth further exploring those.

To identify both the.

The Tolerability, but also the response rates and overall clinical benefit relative to current standard of care.

And Chuck if I can just build on that a little bit I think you know as.

As noted in the earlier comments.

Look at keynote 189 broken down by TPS score I think it's notable there that the response rate is about 30% in TPS less than one patients.

Charles M. Baum: And then, you know, as you can imagine, we continue to explore correlative sciences as it relates to different co-occurring mutations or PD-L1 status. And we haven't presented on this publicly yet, but we'll just say that we're working with academic investigators and internally to determine if there may be an increased signal for adagrassive in certain patient subsets. Also, it's recognized that SDK11 is enriched in the TPS less than one population. So together, when we look at our own data, and if you dig through the supplemental figures for Sitoru's New England Journal article, you can see that there appears to be a trend towards potentially increased response rates in that TPS less than one population.

And then as you can imagine we continue to explore correlate of sciences as it relates to different co occurring mutations or PDL, one status and we havent presented on this publicly yet.

But would just say that we're working with academic investigators and internally to determine if there may be an increased signal for EDA grass and certain patient subsets also has recognized SDK 11 is enriched in the TPS less in one population. So together when we look at our own data and if you take through the supplemental figures for <unk>, New England Journal article.

You can see that there appears to be a trend towards potentially increased response rate and that TPS less in one population.

Charles M. Baum: So together, those two suggest that there may be a path forward as monotherapy, perhaps with a single-arm accelerated opportunity. Thanks, Tina. Keith, let's move on to the next question. We'll take our next question from Umar Rafat with Evercore.

So together those two suggests that there may be a path forward as a monotherapy, perhaps with a single arm accelerated opportunity.

Thanks, Tina Keith let's move onto the next question.

We'll take our next question from Omar <unk> with Evercore. Please go ahead.

David D. Meek: Hi guys, thanks for taking my question. I think there are two broad themes here today, if I may. First, it will be helpful in a public forum like today's to hear just your thoughts on recent management departures, especially given how extensive street interactions were with both the folks that moved on, and just if you could lay some background for us on the departure. Secondly, is it reasonable? There's increasingly this base case expectation on the street that PD-L1 lows is where we should expect some synergy or better synergy in combination for a Keytruda combo with a digressive, but perhaps not so much in PD-L1 highs.

Hi, guys. Thanks for taking my question.

I think I think two broad themes here today, if I may 1st I it'll be helpful. On a public forum like today's to here just your thoughts on recent management departures, especially given.

How extensive street interactions blur with both the folks that moved on and just if you could lay some background for us on the departure.

Secondly is it reasonable.

<unk> there is increasingly this base case expectation on the street that PDL, one lows is where we should expect some synergy or better synergy in combination for keytruda combo with the diagnosis.

But perhaps not so much in PD lone highs would you agree or disagree with that and then finally, perhaps at a high level. If you could just share your thoughts.

David D. Meek: And then, perhaps, at a high level, if you could just share your thoughts and your confidence in your program's clinical profile relative to a bunch of big pharma companies reporting their Phase I results next year. Thank you so much.

And your confidence and and and your programs clinical profile relative to a bunch of big pharma is reporting their phase ones next year. Thank you so much.

David D. Meek: Sure, I'll go first. First of all, let me touch on the management changes, and we're very grateful for the roles that Dan and Joe played in helping to advance Humirati to where it is today. And I would say, the changes that were made were not a result of any issues with our programs or with the fundamentals of the company, and the change wasn't based on any impropriety or disagreement concerning the company's goals or financials. So I just wanted to say that up front.

Sure I'll go first.

First of all let me.

Touch on the management changes.

We're very grateful for the roles of damage Yoplait in helping me that she brought it to where it is today and what I would say that the changes that were made they were not a result of any issues or with our programs or the fundamentals of the company and the change wasn't based on any input priority or disagreement concerning the company's goals or financial so I just wanted to say.

David D. Meek: These overlaps are really based on me joining and Chuck taking on a new role as head of R&D. With these changes, I'll have more direct visibility into important parts of the organization, such as finance, legal strategy, BD, and corporate affairs. Now those functions will report to me directly, and with Chuck in his role as president and head of R&D, he'll have a more direct line of sight into the R&D organization and the day-to-day activities within R&D.

That upfront.

These overlaps are really based on myself, joining and Chuck taking on a new role as head of R&D, where these changes all have more direct visibility into important parts of the organization such as finance legal strategy BD and corporate affairs now those functions will report to me directly and with Chuck in his role is.

President and head of R&D, who will have more direct line of sight into the R&D organization that day to day activities within R&D and then finally I'd say as is Marathi has grown and become more complex and we're rapidly approaching commercialization that we discussed today there is a need for a traditional.

David D. Meek: And then finally, I'd say, as Mirati has grown, become more complex, and we're rapidly approaching commercialization, as we discussed today, there's a need for a traditional CFO, if you will, when you think about that, and a CFO with commercial experience, for which we have an active search ongoing. I'll turn the second question over to Chuck.

Traditional CFO if you will when you think about that in a CFO with commercial experience, where we have an active search ongoing.

Alternatives second question over to choke, okay, great so or.

Charles M. Baum: Okay, great. So, Amar, I think that the way I would phrase it is that, as you know well, the less than 1%, the 1 to 49, and the greater than 50% TPS score populations have different outcomes currently. The outcomes for the less than 1% are the lowest, as we mentioned, right, with a 30% response rate and a shorter PFS and overall survival than the 1 to 49 or the greater than 50.

Think that basically the way I would phrase it is that the.

As you know well.

The less than 1% the 1% to $49 in the greater than 50% TPS score populations have different outcomes currently.

That the outcomes to the less than 1% or the lowest as we mentioned right with a 30% response rate.

And the shorter PFS and overall survival than the 1% to 49% of the greater than 50, so I wouldn't say it so much as the synergy would be better in the less than 1%, but rather that the trial. The conduct of the trial would be simpler and shorter smaller trials shorter duration to show a <unk>.

Charles M. Baum: So I wouldn't say it so much as that the synergy would be better in the less than 1%, but rather that the trial, the conduct of the trial would be simpler and shorter. Smaller trials, shorter duration, to show superiority over the less than 1%, then the one to 49, and then the greater than 50 would be a larger study and would take longer to finish. So in terms of a practical approach for us, we think that the best place is to focus our initial attention on the less than 1%, but also wanting to define better, which we will in phase two, what the performance of the combination is in the greater than 1% patients, and then we can design phase three accordingly.

Superiority over it for less than 1% than the one.

149, and then the greater than 50 would be a larger study and would take longer to finish. So in terms of a practical approach for us we think that the best places to focus our initial attention on what the less than 1%.

But also wanting to define better which we will in the phase two what the performance of the combination is in the greater than 1% patients and then we can design the phase III. Accordingly, So that's I think that's the best way to look at it from our perspective, and then maybe Jamie if you want to just comment on some of the other.

Charles M. Baum: So I think that's the best way to look at it from our perspective. And then, maybe, Jamie, if you want to just comment on some of the other KRAS competitions. Sure, yeah, before I do that, Chuck, just to build on your last comment.

The rest of the competition.

Yes, before I do that job just to build on your last comment.

James G. Christensen: From a scientific or biological perspective, some of you may recall a presentation that was given at the ELCC meeting this year, and parts of that presentation focused on patients with mutations like STK11 that are associated with an immune-suppressed microenvironment and may be more poorly responsive to checkpoint inhibitor therapy. Same story with PD-L1 scores of TPS less than 1%. And what that data illustrated was that we were seeing a tumor response but also a molecular response in tumors harboring these co-mutations or having low PD-L1 scores.

From a scientific or biologic perspective, some of you may recall, our presentation that was given at the LCC meeting this year in parts of that presentation focused on patients with mutations like SDK 11 that are associate with immune suppressive microenvironment, and maybe more poorly responsive to checkpoint inhibitor therapy same story with P.

One scores of TPS less than 1%.

And what that data illustrated this that we were seeing.

A tumor response, but also items molecular response and tumors harboring. These cold mutations are having all PD lone scores and this data indicated that we were seeing an immune response to our PD or <unk>.

James G. Christensen: And this data indicated that we were seeing an immune response or essentially an immune-related signature that was associated with having an immune response in those tumors, suggesting that adegrassin as a monotherapy can reawaken the immune response in tumors that are really poorly responsive to checkpoint inhibitor therapy overall. I'm going to ask for kind of clarification on the last question, if that refers particularly to KRAS inhibitors from other large pharma companies.

Essentially.

And our main related signature that was associated with having an immune response in those tumors, suggesting that <unk> as a model therapy can reawaken. The immune response in tumors that are really poorly responsive to checkpoint inhibitor therapy overall.

I'm going to ask for a kind of a clarification on the last question if that reversed particularly too.

K Ras inhibitors from other large pharma companies is that is that what was Matt here.

James G. Christensen: Is that what was meant here? Yeah, basically the competition for all the readouts next year, which includes Rathon as well, but do you expect clinical efficacy differentiation for any of those molecules, or do you feel reasonably comfortable with the profile you guys have? Sure, yeah. First, as it relates to competition from other pharmaceutical companies, we are aware of the programs from Roche, Novartis, Lilly, and some others. And, you know, really, there's very little public domain data out there on any, maybe with the exception of Novartis preclinical data. So we continue to keep a pulse on this. And, you know, as the data emerges,

Yeah.

Basically the competition for all the Readouts next year, which includes Ras on as well, but do you expect clinical efficacy differentiation for any of those molecules or do you feel reasonably comfortable with the profile you guys out.

Sure Yeah.

So first as it relates to competition from other pharmaceutical companies. We are aware of the programs from Roche Novartis Lilly and some others and really there's very little public domain data out there on any maybe with the exception of Novartis preclinical data. So we continue to just keep it to keep.

A pulse on this and.

As the data emerges.

James G. Christensen: We will learn from whatever that data is.

We will.

James G. Christensen: whatever that data is, and continue to let science drive our programs overall. With regard to some of the emerging things about KRAS-ON, or otherwise, there may be some advantages to KRAS inhibition. And I think I will remind you, at our ENA presentation for MRTx1133, as well as refer to our own KRAS program, which targets multiple spectrum mutations, our programs that are directed at least partially at the active state. And what may be of benefit here is that there may be less subject to feedback reactivation of KRAS upstream.

We're from whatever that data as and continue to let science drive our programs overall.

With regard to some of the emerging things about K Ras or otherwise.

May be some advantages to K Ras on inhibition and I think I will remind you.

At our Eni presentation for <unk>, $11, 33, as well as referring to our own K Ras program, which targets multiple spectrum mutations.

Our programs that are directed at the at least partially at the active state.

And what may be up benefit here.

Is that there may be less of a subject to feedback reactivation of K Ras upstream.

James G. Christensen: So, you know, we are interested in and pursuing those types of programs and opportunities. But I would just say that we are compelled by the continued appraisal of activity of adegracib as both monotherapy or in combination and believe that there's a path forward for both classes of these inhibitors. Thank you, and we're looking forward to the next question.

So we are interested in and pursuing those types of programs and opportunities.

But would just say that we are compelled by the continued appraisal of activity of allografts. It as both a monotherapy or in combination and believe that there is a path forward for both classes of these inhibitors.

Thank you for listening to your next question.

Keith: We'll take our next question from Salveen Richter at Goldman Sachs.

We will take our next question from Solvay <unk> Richter with Goldman Sachs. Please go ahead.

Keith: Goldman Sachs. Please go ahead.

Charles M. Baum: Good afternoon. Thanks for taking my questions. With regard to adagrassi.

Good afternoon. Thanks for taking my question with regard to <unk> and the combo with temporary do you think more dose optimization work is needed or are you really comfortable here with the 400 milligram B I D. And then if you could give us an update on the monotherapy use in third line positive CRC and whether you've reached alignment.

Charles M. Baum: and the combo with PEMBRO, do you think more dose optimization work is needed? Are you really comfortable here with the 400-milligram BID? And then, if you could give us an update on monotherapy use in third-line positive CRC and whether you've reached alignment there yet with the FDA on a path forward. And then, finally, I just would love your initial thoughts on Amgen's launch here and how you see yourselves, you know, prepared to launch and fitting in with the landscape, just given it could be approved pretty quickly. Yes, so why don't we start with the Pembroke combination?

There yet with the FDA on a path forward and then finally.

Just would love your initial thoughts on that.

<unk> launch here and how you see yourselves.

Paired to launch and fitting in into the AR that that landscape just I'm, giving you could be approved pretty quickly.

Yes, so why don't we start with the <unk> combination.

Charles M. Baum: So, yeah, just to say that we are, that the 400 milligram BID dose looks to be well tolerated. The results thus far with the partial responses, a patient who couldn't be classified as partial response but did have a good tumor reduction and then surgical resection, are encouraging. So, we believe that there is a path forward, but we're doing further investigation in phase two. So, the CRYSTAL-7 trial is a phase two trial where we're looking at that dose, and that will be phase two to establish the activity and the parameters that we would investigate in phase three.

So yes, just to say that we are.

The 400 milligram B I D dose looks to be well tolerated.

The results, thus far but with the partial responses in patients who couldn't be classified as a partial response, but did have a good tumor reduction in surgical resection is encouraging so.

We believe that there is a path forward, but we're doing further investigation.

In phase two so the Crystal seven trial is a phase II trial, where we're looking at that dose.

And that will be the phase two to establish the activity and the parameters that we would investigate in phase III. So we don't have the final answer yet, but but we think we're on the right track and that the data from Crystal seven ultimately will be will be used to decide exactly what the design of the <unk>.

Charles M. Baum: So, we don't have the final answer yet, but we think we're on the right track and that the data from CRYSTAL-7 will ultimately be used to decide exactly the design of the next set of trials in phase three. And then, in terms of CRC, we believe there are two options here, and we're going to, and we're discussing both with the agency.

Set of trials and the phase III to come.

And then in terms of CRC. So we believe there's two options here.

We're going to we're discussing both with the agency so single agent.

Charles M. Baum: So a single agent with a 20, over 20% response rate is quite encouraging and certainly higher than anything else we've seen in this area as a single agent. But the Cetuximab data, as you saw, is also very encouraging. It's a little bit less mature than the single agent, so we continue to follow those results. And as we have more results to share with the agency, we will actually have a discussion of both potential approaches. The unique thing here is that with CRC, you wouldn't expect any activity of cituximab in KRAS-mutated patients. So, in essence, the combination is almost like the equivalent of a single IgG.

With a 20 over 20% response rate.

Is quite encouraging and certainly higher than anything else. We've seen in this area as a single agent.

But the <unk> data as you saw is also very encouraging its a little bit less mature.

Then the single agents. So we continue to follow those results and as we have more results to share with the agencies that we would have a discussion of both potential approaches actually.

The unique thing here is that with CRC you wouldn't expect any activity of cetuximab in K Ras mutated patients. So in essence, the combination is almost like the equivalent of a single agent.

Charles M. Baum: And so it's kind of a unique setting, and we want to make sure we bring forward data for both single-agent and combination, because either path is attractive and could result in an accelerated approval strategy. And then, of course, as we mentioned, we have already started the second-line study of the combination with tuximab versus standard-of-care chemotherapy, and that would serve as our confirmatory full approval study. So I think we're in a very good position in colorectal cancer, and based on our ongoing discussions, we expect to go well forward with regulatory agencies, in particular the FDA. And then for the launch question... Could I add one more thing on this here, C?

And so it's kind of a unique setting and we wanted to make sure that we bring forward data for both single agent and combination because either path is attractive and could result in an accelerated approval strategy and then of course as we mentioned we already started the second line study of the combination with <unk>.

Smith versus standard of care chemotherapy and that would serve as our confirmatory full approval study. So I think we're in very good position in colorectal cancer in our ongoing discussions.

We expect to go well.

Forward with with regulatory agencies in particular, the FDA and then for the launch question.

Could I add one more thing on the FERC I think it's also just important to note historical precedent and a targeted patient population in late line colon cancer. So some of you may recall that the biomarker of MSI high where PDL. One inhibitors are active has historical precedent as an accelerated approval.

Charles M. Baum: I think it's also important to note historical precedent in a targeted patient population in late-line colon cancer. So some of you may recall that the biomarker of MSI-HI, where PD-L1 inhibitors are active, has historical precedent as an accelerated approval in colon cancer. So Novolumab, with a 27% overall response rate, did receive that approval path. And then we would recognize, as a monotherapy, at a 22% response rate, we're essentially in range. I would say with the cetuximab combination, we're certainly well within the range of historical, great.

And colon cancer some of <unk> with a 27% overall response rate did received that that approval path.

And then we would recognize as a monotherapy at 22% response rate were essentially in range I would say with the Cetuximab combination, where we're certainly well in range of historical precedent industrially to focus on that path forward, great. Thank you Jamie and Chuck.

Charles M. Baum: Thank you, Jamie and Chuck. As stated, relative to the commercial launch, the NDA will be filed by the end of the year, and with breakthrough therapy designation and the RQR pilot program, we expect an approval by mid-year next year. So, we are aggressively planning

As stated relative to the commercial launch the NDA will be filed by the end of the year and with breakthrough therapy designation and the <unk> pilot program.

We expected approval by midyear next year. So we are aggressively planning and in launch mode already with our team.

David D. Meek: We've got folks already on the team across medical affairs, market access, and marketing. We've begun the hiring of sales managers.

We have a highly capable set of folks already on the team and across medical affairs market access marketing.

We've begun the hiring of sales management as well so as I mentioned, we are aggressively planning for this our medical affairs team has been in place already for a year for the medical affairs team educating the physicians entering questions from physicians.

David D. Meek: Our Medical Affairs team has been in place already for a year; a fully deployed Medical Affairs team.

David D. Meek: For more information on Mirati, please visit www.mirati.com.

Our highly capable team across the board.

Many folks want to join Marathi based on not just out aggressive, but the pipeline that we've talked about today.

David D. Meek: So, we have...

David D. Meek: They're joining our team with significant oncology experience, significant launch experience, and significant lung cancer experience. So we're excited about the team we have on board. And why are we most excited? We have a best-in-class asset. Without aggressive, what we're hearing from the physician community, when we look at the data across all the tumor types, we have a best-in-class asset without aggressive. So we're investing in that.

So we have folks that are joining our team was not significant oncology experience significant launch experience significant lung cancer experience. So we're excited about the team we have on board and why are we most excited we have a best in class asset with that aggressive what we're hearing from the physician community.

When we look at the data across all the tumor types, we have a best in class assay without aggressive so we're investing behind that best in class asset and we're also thinking about not just the launch of a beyond the typical launch where we.

David D. Meek: And we're also thinking about not just the launch but beyond the launch. We're investing heavily in the launch preparation for second lines, later lines of therapy for non-small cell lung cancer. But at the same time, we're...

We're investing heavily in the launch preparation for second line later lines of therapy for non small cell lung cancer, but at the same time, we are aggressively investing in first line non small cell lung cancer multiple pathways for that significant patient population over to colorectal cancer as well over to pancreatic cancer and other tumor types. So.

David D. Meek: for that significant patient population, over to colorectal cancer.

David D. Meek: as well as to pancreatic cancer and other tumor types. So the team will be ready when we're ready for approval and launch against any competition.

The team will be ready.

When we're when we're ready to for the approval and launch up against any competition that's out there.

David D. Meek: against any competition that's out there. Thanks, Salveen. Let's move on to the next question.

Thanks, Avi and let's move on to the next question.

And ladies and gentlemen, as a reminder, due to time constraints. We ask that you. Please limit yourself to one single question per queuing. Thank you.

Keith: And ladies and gentlemen, as a reminder, due to time constraints, we ask that you please limit yourself to one single question per question. Thank you. We'll take our next question from Anupam Rama with J.P. Morgan. Please go ahead.

We will take our next question from <unk>.

Brahma with Jpmorgan. Please go ahead.

Hey, guys. Thanks, so much for taking the question I'll limit mine to one.

Charles M. Baum: Hey guys, thanks so much for taking the question. I'll limit mine to one.

Which is on the <unk> pancreatic cancer for <unk>.

The opening comments you said warrants further study maybe you can expand on that on what the next steps are for that indication, how we should think about it.

Charles M. Baum: And the G12C pancreatic cancer for adagrassive, I think in the opening comments you said warrants

Charles M. Baum: Thank you.

Charles M. Baum: So, you know, we are very encouraged by the results, as we mentioned, and given the late-line nature of those patients, we think that a 50% response rate is quite good. We need to continue to enroll, which we are now, continue to enroll more patients, and then go back to the agency to talk specifically about pancreatic cancer. We also, as I mentioned, are continuing to enroll other solid tumor types that have G12C mutations.

Yeah. So we are very encouraged by the results as we mentioned and given late line nature of those patients. We think that a 50% response rate is quite good.

We need to continue to enroll which we are now continuing to enroll more patients and then go back to the agency to talk specifically.

Pancreatic cancer. We also so as I mentioned are continuing to enroll other solid tumor types that have <unk> mutations and so what we need to also discuss is sort of across different tumor types of solid tumors that have <unk> mutations is there an option to do.

Charles M. Baum: And so what we need to also discuss is, sort of, across different tumor types, solid tumors that have KRAS G12C mutations, is there an option to do a broader approach, similar to what was done, as you're familiar with, TRACK, where approvals were across different tumor types that had the same mutations. So we're exploring both. We don't have an answer to that yet, but we think it's worth pursuing further aggressively. Even though those patient populations are smaller than colorectal and non-small cell, when you add them all together, they actually are a substantial number of patients.

A broader approach similar to what was done as youre familiar with track.

Where.

Approvals were across different tumor types that had the same mutations. So we're exploring both we don't have an answer to that yet, but we think it's worth pursuing further aggressively.

Even though those patient populations are smaller than colorectal and non small cell when you add them all together they actually a substantial number of patients.

Charles M. Baum: And maybe just to add to that as well, one reason to study pancreatic cancer in more detail, in addition to being, you know, seeing an interesting signal, is that about 36% of pancreatic ductal adenocarcinoma is G12D positive, and 90% overall have KRAS mutations. If we can learn the path with G12C inhibition, there's really nice read-through to some of our future programs as well.

So maybe just to add to that as well.

One reason to study of pancreatic cancer in more detail in addition to being.

Seeing an interesting signal as we recognize at about 36% of pancreatic ductal adenocarcinoma ESG 12, D positive and 90% overall have K Ras mutations if we can learn the path with <unk> inhibition, there's really nice read through to some of our future programs as well. Thanks.

The next question.

We will take our next question from Juran Werber with Cowen. Please go ahead.

Hi, This is gabe on for your own thanks for taking our questions and congrats on the data.

Hoping to drill down a little as possible into some of the specific safety and Tolerability findings for the aggressive with <unk> data. So first what were the grade three adverse events at the 400 milligram tid dosing, how common where they and also if you can share any of the most relevant toxicity seen with the 600 milligram Tid combo cohort that led you to evaluate the lower dose.

Keith: Let's move on to the next question. We'll take our next question from Euron.

Keith: We have a question from Yaron Werber with Cowan. Please go ahead.

Charles M. Baum: Hi, this is Gabe on for your own. Thanks for taking our question and congrats on the data. I was hoping to drill down a little, if possible, into some of the specific safety and tolerability findings for the aggressive with PEMBRO data.

At aggressive as we try to better understand the most relevant.

Overlapping toxicities between the two drugs.

And then secondly, just if you could just quickly what's the historical.

Response rates that you look at for the kiosks Newton's first line patients.

Charles M. Baum: So first,

Charles M. Baum: But what were the great three adverse events that

Compared to the unselected populations treated with Keytruda. Thank you.

Charles M. Baum: [inaudible]

Charles M. Baum: Thank you. So, in terms of the overall picture, you know, there wasn't anything new, really, that came up. So, in the 600-milligram BID dose, as you know, that was our highest dose of a single agent. And the same kind of adverse events, so the most common were GI-related events like nausea, vomiting, and diarrhea. There's some overlap there with some of the pembrolizumab adverse events as well. And so, I think, in the overall picture, the combination of effects meant that it was less well-tolerated.

Great.

So in terms of the overall picture.

There wasn't anything new really that came up so in the 600 milligram PID does.

As you know that was our highest dose of single agent and the same kind of.

Adverse events, so the most common where Gi related.

It sounds like nausea, vomiting diarrhea.

Some overlap there with some of the Pembina as a matter of adverse events as well.

And so I think in the overall picture that the combination of effects.

Meant that that was less well tolerated.

Charles M. Baum: And that's why we investigated at the 400-milligram dose. As he said, there were not any treatment-related discontinuations at the 400-milligram dose and no grade 4 or grade 5 events. So, you know, other than that, the types of events were similar to what we've described previously for single agent adegrassin. So, nothing new has come up. Obviously, we need to continue to study. We're early in the process. There are seven patients. So we are enrolling patients now, as I said, into phase two to get a better handle on exactly what those differences are between the 400 milligram dose and 600. And we'll provide a full update later when we have that data to compare the two doses and decide on the next steps forward as we get closer to initiating a phase three study next year.

And that's why we investigated at the 400 milligram.

As he said there were not any treatment related discontinuation that the 400 milligram dose.

And no grade four grade five events so.

Other than that the types of events were similar to what we've described previously for single agent at aggressive.

So nothing new has come up obviously, we need to continue to study.

Early in the process of seven patients. So we are enrolling patients now as I said into the phase two to get a better handle on exactly what those differences are between the 400 milligram dose of 600, and we will provide a full update later when we have that data to compare the two doses and decide on.

Next steps forward as we get closer to a triggering a phase III study next year.

Keith: Thank you, Gabe. Let's move on to the next question. We'll take our next question from Michael.

I think Gabe, let's move on to the next question.

We'll take our next question from Michael Schmidt with Guggenheim. Please go ahead.

Yeah, Hey, guys. Thanks for taking my questions.

Keith: And from Michael Schmidt with Guggenheim, Please go ahead.

I was just wondering.

Charles M. Baum: Yeah, hey guys, thanks for taking my questions. I was just wondering if you had already had some preliminary FDA interactions regarding your

If you already had some preliminary FDA interactions regarding your your.

Plans for potential accelerated approval and in different subsets and.

Charles M. Baum: [inaudible]

Charles M. Baum: on small cell lung cancer and whether the 30% ORR is a reasonable hurdle, as you mentioned, for the PD-L1 neck.

First line non small cell lung cancer, and if the 30% or if that is a reasonable hurdle as you mentioned for the PD Lone negative just in the context of some data that was published that indicates that keytruda may potentially perform better and chaos non small cell lung cancer patients as opposed to all come.

Charles M. Baum: in the context of some data that was published that indicates that Keytruda may potentially perform better in KRAS non-tumor and lung cancer patients as opposed to all comers.

Yes.

Charles M. Baum: Yeah, so there's limited data on the KRAS subset, but I think as we go forward here, there will be more data available from real-world studies and other sources to better characterize the KRAS subset of patients. But I think in our thinking that the bar would be lowest for the TPS less than 1%, which is in that 30% range. SDK 11 may be even lower than that. And that's a highly selected population.

Yes, so there is limited data on.

<unk> subset, but I think as we go forward here there'll be more.

Data information available from real World studies, and other sources to better characterize the kiosks subset of patients.

But I think our thinking that.

Bar would be lowest.

For the less the TPS less than 1%, which is in the 30% range SDK 11, maybe even lower than that and.

And Thats a highly selected population. So we are in the process of discussing that approach to first line as we continue our discussions of the approval the current approval and submission of.

Charles M. Baum: So we are in the process of discussing that approach to first line as we continue our discussions of the approval, the current approval, and submission of adagrassive in non-small cell lung cancer. So we don't have an answer yet, but we think that there is a path forward. And we need to further define through those discussions what the hurdle is. But those are ongoing discussions now, and we should have more information coming soon.

Out aggressive in non small cell lung cancer. So we don't have an answer yet, but we think that there is a path forward and we need to further defined through those discussions what the hurdle is.

But that is those are ongoing discussions now and then we should have more information coming soon.

Charles M. Baum: And, yeah, I think just to add, you know, and just discussions with the agency, they freely acknowledge the unmet need for KRAS-mutated patients that have either a TPS 4-OS-1 or an SDK11 mutation. As mentioned earlier, the Keynote 189 subset analysis did indicate poor response in that particular TPS-defined subset. You may be also aware of the work coming out of Dana-Farber, Memorial Sloan-Kettering, and M.D. Anderson, both in second-line patients as well as in first-line patients with SDK11 co-occurring mutations with KRAS, where response rates are probably closer to 20%, and PFS is just insidiously low, you know, really around two to three months.

And just to add.

Discussions with the agency they freely acknowledge the unmet need for K Ras mutated patients that have either a TPS score of less than one or an SDK 11 mutation.

As mentioned earlier the keynote 189.

Subset analysis did indicate poor response in that particular TPS defined subset you may be also aware of the work coming out of Dana Farber Memorial Sloan Kettering and MD Anderson, both in second line patients as well as in first line patients with SDK 11, co occurring mutations with K, Ras where response rates are probably.

<unk> to 20% and PFS are seriously level really around two to two to three months.

Charles M. Baum: You know, as Chuck mentioned, we would really have to define what the threshold is with the agency, but I think, based on our second-line experience, we're encouraged by what we see, and if we see enhanced activity in the first-line setting, we do believe, based on the discussions with the agency, that there is a viable path. In the end, the devil's in the details, and it depends on the data.

As Chuck mentioned, we would really have to define what the threshold is with the agency, but I think based on our second line experience. We're encouraged by what we see and if we see enhanced activity in the first line setting we do believe based on the discussions with the agency that there is a viable path.

In the end the Devil's in the details and depends on what the data looks like.

Keith: That makes sense. Thanks so much.

Make sense. Thanks, so much well into the next question.

Keith: We'll take our next question from Yigal Nochomovitz with Citi. Please go ahead.

We'll take our next question from Yigal <unk> with Citi. Please go ahead.

James G. Christensen: Hi. Thanks for taking the questions. I just had one on your MTAP-deleted cancers program. Can you just give us a sense as to when you're planning to initiate a clinical program for the synthetic lethality program, and which tumor types do you think are the most compelling indications?

Alright, thanks for taking the questions just.

Just had one on your M tap deleted cancers program could you just give us a sense as to when Youre planning to initiate a clinical program for this synthetic with Audi program, and which tumor types do you think are the most compelling indications.

James G. Christensen: Sure. Yeah, so we will be filing an IND this year. We are working out plans for phase one, but it is fully within range to start within the first quarter, enrolling the first patient. So, the first quarter of 2022.

Sure Yeah. So we will be fire filing an IND. This year we are.

Working out plans for the phase one, but it is fully within range to start within the first quarter.

Enrolling the first patient so first quarter of 2022 with regard to your question on tumor types. So our goal and the.

James G. Christensen: With regard to your question on tumor types, so our goal in Phase 1, Phase 1B, and Phase 2 is to study a subset of tumors where preclinical data suggests that we may see enhanced activity. That includes lung adeno and lung squamous cell carcinoma. It includes mesothelioma, pancreatic ductal adenocarcinoma, and also a small subset of tumors, called peripheral nerve sheath tumors.

Phase one phase <unk> and phase III is to study a subset of tumors, where preclinical data suggests that we may see enhanced activity that includes one <unk> and lung squamous cell carcinoma and includes mesothelioma pancreatic ductal adenocarcinoma.

And also a SaaS small subset of tumors peripheral nerve sheath tumors. These are spots, where the disease biology may be particularly compelling and what we may expect to see monotherapy response rates based on the preclinical data so it'll be our goal to focus there, but we also have the opportunity to study in a basket any other.

James G. Christensen: These are spots where the disease biology may be particularly compelling and where we may expect to see monotherapy response rates based on the preclinical data. So, it'll be our goal to focus on those spots, but we also have the opportunity to study in a basket any other solid tumor type that has an MTAP gene deletion. Those include bladder cancer, head and neck squamous cell carcinoma, and others.

Solid tumor type that Hasnt amtech gene deletion those include bladder cancer head and neck squamous cell carcinoma, and otherwise collectively all tumors with amtech deletions start approaching around 10% so.

Charles M. Baum: Collectively, all tumors with MTAP deletions start approaching around 10%. So, that is our initial focus, but certainly, our Phase 2 component of the MTAP deletion study allows us to learn. We will adapt that study design to accommodate any emerging signals from the first set of patients. Thank you very much, Yigal. We'll take our next question from Maurice Raycroft with Jeffreys, please go ahead.

That is our initial focus but certainly our phase II component of the <unk> deletion study allows us to learn and we will adapt that study designed to accommodate any emerging signals from from that first set of patients great. Thanks Yigal.

Next question.

We will take our next question from Maury Raycroft with Jefferies. Please go ahead.

Charles M. Baum: Hi, thanks for taking my question. I'm just wondering where you are with enrollment for SDK 11 aggressive monotherapy. What could timing look like for getting to a robust update on this opportunity, and what's the bar for success in this population?

Hi, Thanks for taking my question.

Just wondering if you can say where you're out with enrollment for SDK 11, <unk> monotherapy, what could timing look like forgetting to a robust update on this opportunity and what's the bar for success in this population.

Charles M. Baum: Yeah, so it's enrolling currently in that arm of the study and is going well. We will provide an update. I think we'll get to that very soon as we get more patients enrolled and have a better idea of what the discussions are with the agency in terms of the number of patients that we'll need to enroll. Based on previous accelerated approvals, we think that something in the 80 patients, maybe 80 to 100 patients, is a reasonable target number, but that's something that we have to validate with them.

Yeah. So.

Enrolling currently.

In that arm of the study and going well.

We will provide an update soon as we get more patients enrolled and have a better idea of what the discussions are with the agency in terms of the number of patients that will need to enroll based on previous accelerated approvals. We think thats something you know in the 80 patients maybe 80 to 100 patients as a.

Reason, a bold target number but.

That's something that we have to validate with them in terms of the difference. That's also something obviously, we have to define with the agency, but when the bar is low like 20%.

Charles M. Baum: In terms of the difference, that's also something, obviously, we have to define with the agency, but when the bar is low, like 20%, obviously, we think that the results, even though we already have, which were in the 50 to 60% response rate in later line, sometimes the response rates are a little bit better in first line, we should be in the ballpark where that could be an acceptable result, but we need to verify that with the agency directly before we Thank you.

Obviously, we think that the results.

Even though we already have which were in the 50% to 60% response rate in later line.

And oftentimes the response rates are a little bit better in first line that where we should be in the ballpark where that could be.

Separable result, but we need to verify that with the agency directly before we can be sure.

Great. Thanks Marty.

Keith: We'll take our next question from Ben Burnett with Stiefel. Please go ahead.

Thank you.

Okay.

We will take our next question from Ben <unk> with Stifel. Please go ahead.

James G. Christensen: Hey, thank you very much. I was wondering if you could just talk about, just with regard to the first-line data that you just read out or talked about, Pembro plus Atagrassiv, the level of target engagement that you saw with the 400 mg dose, and I guess just how was it that you were able to maintain good pharmacodynamics and good target coverage? Is this basically because of the half-life of the drug, or do you see any change in the rate of drug metabolism or drug-drug interaction? I guess any color that you could offer on how you were able to maintain good target engagement at the lower dose. Thank you. Sure, I will answer that question in two parts.

Hey, Thank you very much.

I was wondering if you could just talk about just with regards to the the first line data that you just read talked.

<unk> talked about Pembroke plus out of grass or could you just talk about the level of target engagement that you saw with the 400 Meg dose.

Just how is it that you were able to maintain good pharmacodynamics and good target coverage is this basically because of the half life of the drug or do you see.

Any change in the rate of drug metabolism or drug drug interaction I guess any color you could offer on how you're able to maintain good target engagement at the lower dose. Thank you.

Sure Let me answer that question in two parts so.

James G. Christensen: So, you know, first of all, our non-clinical data, we had modeled over a range of different dose schedules, different models, different doses what the target plasma concentration should be that we exceed for the entire dose interval. And that was approximately 1.5 micrograms per mil corrected for protein binding. At the dose of 600 megs BID, we achieve around 2,200 nanograms per mil above for the full dose interval. At the 400 meg dose level BID, the longer half-life allows us to achieve at or around that 1.5 micrograms per mil for the entire dose interval.

First of all our non clinical data.

We had modeled over a range of different dose schedules different models different doses.

The target plasma concentration should be that we exceed for the entire dose interval and that was approximately $1 five micrograms per mil corrected for protein binding.

At the dose of 600, Megs PID, we achieve around 2200 nanograms per ml above for the full dose interval at.

400 make dose level VIP the longer half life allows us to achieve at or around that one five micrograms per ml for the entire dose interval. So we are above our pre clinically defined.

James G. Christensen: So we are above our preclinically defined, you know, kind of target plasma concentration there and are confident that that is associated with near complete or complete engagement of KRAS for the entire dose interval and the vast majority of KRAS mutated. I think the second point to make here is, you know, as you can imagine, we're on the cusp of filing, so we have done a lot of exposure response analysis, and we've done that every way but loose, above or below median, by quartile or otherwise.

Kind of target plasma concentration there and are confident that that is associated with near complete or complete engagement of K Ras for the entire dose interval and the vast majority of K Ras mutated tumors.

I think the second point to make here is as you can imagine we're on the cusp of filing. So we've done a lot of exposure response analysis, and we've done that every which way, but loose above or below median by quartile or otherwise and particularly study <unk>, where the exposure would be around what we would <unk>.

James G. Christensen: And we've particularly studied quartiles where the exposure would be around what we would predict at the 400 meg dose level. And when we look at response rates or different clinical outcome parameters in those lower quartiles that would be associated with a lower dose, we essentially see no difference in response rates or other clinical outcome parameters. So we believe we, at 400 megs BID, are essentially at a very active dose. Of course, you know, more study is warranted, but the preponderance of the evidence indicates that we should be in very good shape at that dose. Super helpful. We'll take our next question from Jason Gerberry with Bank of America. Please go ahead.

At the 400, Meg dose level and when we look at response rates are different clinical outcome parameters in those lower quartile that would be associated with a lower dose we essentially see no difference in response rates or other other clinical outcome parameters. So we believe we are at 400 B I D.

E are essentially had a very active dose of course more study warranted, but the preponderance of the evidence indicates that we should be in very good shape at at that dose level.

Super Helpful last question.

Yeah.

We will take our next question from Jason <unk> with Bank of America. Please go ahead.

Charles M. Baum: I wanted to just come back to the frontline PEMBRO combo, the seven valuable patients. Can you comment, were the PD-1 levels sort of broadly across the full range of different levels? And really, what I'm getting at here is that in Keynote 42, this exploratory subgroup analysis showed that PEMBRO was closer to 60% in KRAS-rebuttated patients. So from an ORR perspective, just wanted to realize that we're dealing with really small numbers here. Just wanted to make sure how to evaluate these data.

Hi, guys. Thanks for taking my questions.

Wanted to just come back to the frontline Pembroke combo, the seven evaluable patients.

Can you comment where the PD, one levels sort of broadly across the full range of different levels and really what I'm getting at here is.

I know that <unk> 42. This exploratory subgroup analysis showed that <unk> was closer to 60% and K Ras mutated patient so from an or perspective, just wanted to realizing we're dealing with really small numbers here I just wanted to make sure.

How do you evaluate these data and then I think there was one patient then went on to surgery, so where their inclusion of stage.

Charles M. Baum: And then I think there was one patient that went on to surgery. So were there inclusion of Stage 3 patients, or were these all advanced metastatic patients that got enrolled? Just wanted to clarify those two points, thanks.

Stage three patients or were these all.

Advanced metastatic patients that got enrolled just wanted to clarify those two points.

I forget.

Firstly level.

The level of or sorry, the PDL Oh, yes, yes, yes, yes, so sorry.

Charles M. Baum: With the Phase 1B study, which is where we investigated the 400 mg dose, we did not type or select patients based on TPS scores. So we do not know what their TPS scores were. So that's why we didn't report on it.

With the phase one B study, which is where we investigated the 400 milligram dose we did not type or select patients based on TPS score. So we do not know what their TPS scores were.

So that's why we didn't report on it for the Crystal seven study that is the patients are typed upfront and they're put into different groups less than 1% in one two or greater than 1% and that's when we'll know what the correlation is between TPS score in.

Charles M. Baum: For the CRYSTAL-7 study, that is, the patients are typed up front, and they're put into different groups, less than 1%, or greater than 1%. And that's when we'll know what the correlation is between the TPS score and response rate. There's limited data available, as you know, and we still have limited data. So I think, you know, although the responses look good, that we need further study, as I said, to enroll more patients to define these parameters more carefully.

Right.

Limited data available as you know.

And we have still limited data so I think we're in.

Although the responses look good.

We need further study as I said to enroll more patients to define these parameters more carefully and then the other was.

Charles M. Baum: And then the other was related to the stage of disease. And These were all advanced metastatic patients. So, it wasn't a stage 3 resectable tumor, they, it was just the judgment of the investigator that they had gotten significant tumor reduction and that by a lobectomy they could benefit the patient, and that was the decision based on the investigator and the best, you know, their judgment about that particular patient. Oh, and that patient is still on study and still on drugs, so he's doing well.

Related to the stage of disease and these were all advanced metastatic patients. So it wasn't.

Stage three resectable.

It was just the judgment of the investigator that they had gotten significant tumor reduction in that by a lobectomy they could benefit the patient and that was the decision based on the investigator and the best.

Their judgment about that particular patient.

Great.

Thank you alone.

On study and still on drugs, so it's doing well.

Charles M. Baum: Okay, thanks. Thanks, Jason. It looks like we're just about out of time. Why don't we take one last call, and we'll cut it off at that point. Thank you. Our last question is from Andrew Burns with SVB Lyrinc. Please go ahead.

Okay. Thank you thanks, Jason it.

It looks like we're just about at time, when we take one.

One last fall and we'll cut it off at that point.

Sure.

Thank you our last question is from Andrew Burns with SBB Leerink.

Keith: All right, thanks for squeezing in the question, guys. In terms of the responders, you said all five of them are on therapy. Are they all still maintaining a response? And then just, I think in the press release, you said 37 percent was the lower boundary of shrinkage. What was the reason that all of them were not considered responders?

Please go ahead.

Alright, thanks for squeezing in the question guys.

In terms of the responders you said all five of them are on therapy or are they all still maintaining response and then just I.

I think in the press release, you said, 37% was the lower boundary of shrinkage what was the reason.

Got all of them are not considered responders.

Charles M. Baum: So yes, all four, plus the one that I just mentioned who had the resection, are on study, continuing to study, and continuing in response. So that's looking good.

Okay.

So yes, the all four plus the one that I just mentioned who had the resection are on study continue on study and continue in response.

So that's looking good and then.

Charles M. Baum: And then, in terms of what happened to, yes, so we had a couple of patients who had tumor reductions, and just part of it is around resistance criteria for whether they can be continued to be called as PRs. But we've seen this in other cases as well, in all of our other trials. There are occasionally patients who have tumor progression after initial response and therefore cannot be considered partial responses per resist. But the others, the other five that we discussed, they all continue to respond at this point. Okay, is there any more...

In terms of those who have happened to US yes. So we had a couple of patients who had.

Reductions in just part of it is around persists criteria.

For whether they can be continued to call as prs.

But we've seen this in other cases as well in all of our other trials. There are occasionally patients who have tumor progression. After initial response and therefore cannot be considered partial responses per resist so.

But the others. The other five that we discussed they all continue and in response at this point.

Okay is there any chance of going up on the dose might have kept them in our response.

Charles M. Baum: Okay, is there any chance that going up on the dose might have kept them in range?

I've made I made a missed your question.

Charles M. Baum: I may have missed your question. The dose? Well, these were 400. Yeah, these were 400 BIDs with concomitant K-truda. And it sounds like some of them had a 37% shrinkage, and then they lost that response. But it would have been possible to go up to a higher dose, and maybe they would have stayed in response. Yeah, that's a hard question to answer. I mean, certainly we've seen in other trials where we had patients that had an initial tumor reduction, some increase, some stayed on the study, and others didn't.

The dose.

Please we're 400, yes.

400, B I D.

Comment on Keytruda and it sounds like some of them had a 37% shrinkage and then they lost that response, but would have been possible could go up to a higher dose than maybe they would.

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Yeah, that's a hard question to answer.

Certainly we've seen in other trials, where we've had patients that had an initial tumor reductions some increase there.

Some stayed on study and others didn't.

Charles M. Baum: But, you know, so small numbers at this point. So it's not part of the protocol to re-escalate or to escalate from 400 to 600. So that's an outstanding question. We don't know the answer to that at this point. Thanks.

But it's a small numbers at this point. So we are not part of the protocol to re escalate or to escalate from 400 to 600. So that's announced any question. We don't know the answer to that at this point.

Keith: Ladies and gentlemen, this concludes today's question and answer session. At this time, I'll turn the conference back to your presenters for any additional or closing remarks. Well, thanks for joining me, Chuck, Jamie, and Vicki this afternoon. As you can tell, we're really

Okay, Thanks, and congrats on all the progress.

Thank you.

Okay.

Ladies and gentlemen, thank you for joining <unk> question and answer session. At this time I'll turn the conference back to your presenters for any additional or closing remarks.

Well, thanks for joining me Chuck Jami Vickie. This afternoon as you can tell we're real excited about the future of variety as we continue to progress toward our mission to discover design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. We look forward to speaking with many of you and sharing additional updates as we continue to progress toward our mix.

David D. Meek: We're really excited about the future of Mirati as we continue to progress toward our mission to discover, design, and deliver breakthrough therapies that transform the lives of patients with cancer and their loved ones. We look forward to speaking with you.

David D. Meek: We look forward to speaking with many of you and sharing additional updates as we continue to progress toward our mission to discover, design, and deliver our therapies to patients. So, thank you very much. This concludes today's call, and thank you for joining us. Ladies and gentlemen, this does conclude today's conference. We appreciate your participation. You may now disconnect.

<unk> to discover design and deliver our therapy to the patient. So thank you very much. This concludes todays call and thank you for joining.

Yes.

Ladies and gentlemen, this does conclude today's conference. We appreciate your participation you may now disconnect.

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