Mirati Therapeutics Inc (MRTX) 2021 Q3 法說會逐字稿

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. (Operator Instructions)

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

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 Vickie 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. 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 30, 2021, and recent corporate updates. This press release is available on the Investors section of our website at mirati.com.

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

It has been a busy and rewarding 2 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.

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 adagrasib. We believe adagrasib's clinical profile is best-in-class. In addition to the breakthrough therapy designation we announced in June, we recently submitted the first adagrasib 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.

Our U.S. launch preparation for adagrasib in patients with KRAS G12C 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 adagrasib in a broad development plan, including in proof-of-concept Phase II trials for first-line non-small cell lung cancer, a confirmatory Phase III trial, randomized to docetaxel in previously treated non-small cell lung cancer and a registration-enabling Phase III trial in second-line colorectal cancer.

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 adagrasib in additional solid tumor settings to potentially help even more patients. To date, our capabilities have enabled us to execute across multiple programs, including adagrasib and sitravatinib, on our own in key markets while partnering selectively in regions such as China. These capabilities have also enabled development of novel drug combinations.

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 their accomplishing. With that, I'll turn it over to Chuck.

Thanks, David. I will address our 2 late-stage registration-enabling programs, adagrasib and sitravatinib. We continue to make significant progress and have seen best-in-class clinical results for adagrasib 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 KRYSTAL-1 study in patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation following prior systemic therapy. The top line results showed that adagrasib 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.

Importantly, almost all 98.3% of patients in this trial received adagrasib 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 adagrasib 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.

In addition to the top line Phase II results, we also reported updated data from 19 patients treated with adagrasib at 600 milligram BID in the Phase I/Ib monotherapy cohort of the KRYSTAL-1 study in patients who had received at least 1 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. The median overall survival was not yet reached. Our Phase III confirmatory trial, KRYSTAL-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. We have a broad and aggressive development plan for adagrasib in patients with non-small cell lung cancer as well as colorectal cancer and other solid tumors that express KRAS G12C mutations.

In first-line non-small cell lung cancer, we have a multipronged development approach in both monotherapy and combination. We are exploring the development of adagrasib in 2 unique patient populations as monotherapy in first-line non-small cell lung cancer patients whose tumors express a KRAS G12C mutation. The first approach is in first-line patients whose tumors have a co-mutation of KRAS G12C and STK11, 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 initiated a potentially registrational single-arm study. Patients with STK11 co-mutations or TPS 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-free survival of less than 6 months.

In patients with STK11 co-mutations published real-world data suggests that the median progression-free survival is approximately 2 months. Collectively, these 2 patient subgroups represent greater than 40% of the total first line KRAS 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 addition to monotherapy approaches, we are advancing combination approaches in frontline non-small cell lung cancer. One key area of focus in the frontline setting is to evaluate the combination of adagrasib with pembrolizumab. We began this evaluation using the 600 milligram BID dose of adagrasib with full dose pembrolizumab. We assess the combination in patients with prior checkpoint inhibitor therapy as well as first-line patients with -- in the KRYSTAL-1 and KRYSTAL-7 clinical trials.

We later added a Phase Ib cohort to the KRYSTAL-1 study to evaluate the combination of pembrolizumab at an adagrasib dose of 400 milligrams BID. Collectively, we have evaluated the combination of adagrasib with full dose pembrolizumab in over 40 patients across the KRYSTAL-1 and KRYSTAL-7 clinical trials.

After comparing the overall tolerability profile of the combination of adagrasib at both 400 and 600 milligram BID dose levels, we have identified 400 milligram BID as the go-forward dose of adagrasib.

Of note, the 400 milligram BID dose of adagrasib reaches our target plasma concentration threshold for achieving complete target coverage for the full dose cycle. Of the patients enrolled, 8 treatment-naive non-small cell lung cancer patients were enrolled at the 400 milligram BID dose level of adagrasib and 7 of these patients were evaluable for response as of the October 21 data cutoff.

These preliminary Phase Ib results indicate that the combination of full dose pembrolizumab with adagrasib that 400 milligram BID has a manageable tolerability profile, and no patients having treatment-related adverse events leading to treatment discontinuation and no Grade 4 or Grade 5 adverse events were observed.

Of the 7 response evaluable patients, 4 had a confirmed RECIST partial response, and 1 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 RECIST. The disease control rate was 100% with all 7 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 TPS scores.

While the data are not yet mature, with a median follow-up of 9.9 months, 5 of the 7 patients remained on treatment as of the data cutoff and have been on treatment for 8 to 11 months and are still ongoing. We are now enrolling patients at the 400 milligram BID dose of adagrasib in the Phase II KRYSTAL-7 combination trial, which is stratified by TPS score and our planning to initiate a Phase III registration study of adagrasib with pembrolizumab in 2022.

In addition to the combination of adagrasib and pembrolizumab, we are pursuing other combination approaches that may have benefit in the first-line setting. Based on extensive nonclinical work, our focus includes EGFR, SHP2 and SOS1 inhibition, and we'll be continuing to explore combination strategies based on emerging science.

We recently signed a nonexclusive clinical collaboration agreement with Sanofi to evaluate the combination of adagrasib with Sanofi's investigational SHP2 inhibitor and have an ongoing Phase II study with Boehringer Ingelheim's SOS1 inhibitor.

We look forward to sharing additional updates about our non-small cell lung cancer program next year, including additional clinical data supporting adagrasib's 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 I/II KRYSTAL-1 study, evaluating adagrasib at a dose of 600 milligrams BID as both monotherapy and in combination with cetuximab in heavily pretreated patients, harboring a KRAS G2C mutation. The results showed that adagrasib alone or with cetuximab demonstrated significant clinical activity and broad disease control with a favorable tolerability profile.

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 adagrasib as monotherapy or in combination with cetuximab.

Our Phase III global registration enabling randomized study of adagrasib plus cetuximab, called KRYSTAL-10, is enrolling second-line patients with colorectal cancer.

Overall, we are well positioned with adagrasib 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 I/II efficacy results in KRAS G12C mutated pancreatic cancer, which are highly encouraging and warrant further study. 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.

I'll now provide an update on sitravatinib. We recently presented Phase I results from our MRTX-500 study of sitravatinib in combination with nivolumab at this year's ESMO conference. The combination demonstrated durable responses and long-term survival, including 32% of patients alive at 2 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 III registration-enabling SAPPHIRE 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 2022.

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

Thanks, Chuck. 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 to 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-EORTC International Conference, also known as ENA, MRTX1719 is the clinical development candidate for this program.

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 of a metabolite known as methylthioadenosine or MTA, which has -- which is a unique characteristic of MTAP-deleted cancers.

Thus, 1719 is able to selectively target MTAP-deleted cancer cells while sparing healthy nontumor cells. 1719 is among the leading edge of PRMT5 MTA cooperative inhibitors and exhibit high-quality pharmaceutical properties and strong predictive human PK characteristics together supporting a possible best-in-class opportunity. In addition, we have significant work ongoing and developing targeted therapies directed at KRAS mutations beyond just KRAS G12C.

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 G12D. We are encouraged by the profile and characteristics of 1133, which includes single-digit nanomolar potency for inhibition of KRAS G12D, the ability to buy G12D protein in both active and inactive states, a 1,000-fold selectivity ratio for KRAS G12D 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 nonclinical PK data. 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.

Finally, we continue to progress our discovery program, targeting SOS1. This program leverages SOS1's utility as a KRAS signaling modifier and is in candidate selection stage. We have 2 unique SOS1 inhibitor lead candidates, which each exhibits high-quality pharmaceutical properties and strong predicted human PK characteristics and are currently progressing through IND track preclinical development.

With that, I will turn it over to Vickie.

Thank you, Jamie. We ended the third quarter with approximately $1.2 billion in cash, cash equivalents and short-term investments, which includes net proceeds of $6.3 million from the upfront fee from our recent collaboration and license agreement with Zai Lab.

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 expense associated with the development of adagrasib, an increase in preclinical and early discovery activities as well as an increase in salaries and other employee-related expense.

General and administrative expense for the third quarter of 2021 was $35.2 million compared to $20.2 million for the same period last year. 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.

Net loss for the third quarter of 2021 was $80.1 million or $1.55 per share basic and diluted compared 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, Vickie. 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 with adagrasib, where we are focused on maximizing the potential of this best-in-class agent to a broad and robust development plan. We have a number of significant milestones ahead of us.

For adagrasib, by year-end, we will complete the NDA submission in patients with KRAS G12C mutated second line and beyond non-small cell lung cancer, and we plan to present detailed results from the Phase II 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 adagrasib's ability to penetrate the CNS in the first half of next year.

We will provide an update on the Phase II KRYSTAL-7 study of the combination of adagrasib with pembrolizumab when we have enrolled enough patients with sufficient follow-up.

Based on our recent SHP2 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 SHP2, SOS1, EGFR or CDK4/6 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 adagrasib and late-line colorectal cancer as a monotherapy or in combination with cetuximab as well as sharing next steps in other solid tumors, including pancreatic cancer.

For sitravatinib, 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 MRTX1719, our synthetic lethal MTA cooperative PRMT5 program. We plan to file an IND for MRTX1133, our KRAS G12D inhibitor in 2022.

From a capital allocation perspective, we are investing aggressively in adagrasib 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. And we are investing in a sustainable growth profile to ensure rapid advancement of our robust innovative targeted therapy pipeline. We are incredibly pleased with the progress we have made and look forward to the many important milestones we are approaching.

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

(Operator Instructions) We'll take our first question from Gena Wang from Barclays.

Congrats 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 KRYSTAL-1 and 7. How many were on 600 milligram BID? And what about the response data for the 600 milligram BID and 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 expansion of a 600 milligram BID mono in first-line with TPS less than 1%. Did you see any response that you've seen so far make you feel confident to go towards that indication as a monotherapy?

Okay. So let's start with the combination. So in terms of the patient numbers, as we detailed, we had 7 of those patients that had -- that were treatment naive and treated at the 400 milligram BID dose. And then the majority being at 600 milligram BID with full dose pembrolizumab. And the reason for that number was that we started the study, both the Phase Ib and the initial K7, the KRYSTAL-7 study, with the 600 milligram BID 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 600 milligram BID similar events but a constellation of events that was leading to more tolerability issues, and that we wanted to explore the 400 milligram BID dose in combination with full dose pembrolizumab as being an alternative path.

That is the 7 patients that we report on today. So we didn't have any patients that withdrew due to treatment-related adverse events in an overall favorable profile. Obviously, it's still early. So we have just those 7 patients. We are continuing to enroll now in the K7 trial that we modified the trial, amended it and are now enrolling 400 milligram BID patients.

And so we have limited data currently, but we'll have a lot more data coming up as that's the primary focus. And just as a reminder, the K7 trial has 1 arm that is patients with less than 1 -- TPS of less than 1%, treated with single agent 600 milligram adagrasib. And then second, which is the combination of 400 milligrams with pembrolizumab in the less than 1%. And then a third cohort, which is greater than 1% and it's 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.

And then the second one was if the -- in the less than 1% patient population, we think that there's 2 populations of interest, the STK11 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 current standard of care, those with less than 1% TPS score do more poorly than others.

So in terms of our overall strategy, we felt that, that was an area that we had a chance to see benefit relative to current standard of care. So with both the STK11 population and with less than 1% that it was worth further exploring those to identify both 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 as noted in the earlier comments. If you look at KEYNOTE-189 broken down by TPS score, I think it's notable there that the response rate is about 30% and TPS less than 1 patients. And then 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 would just say that we're working with academic investigators and internally to determine if there may be an increased signal for adagrasib in certain patient subsets, also is recognized STK11 is enriched in the TPS less than 1 population.

So together, when we look at our own data and if you dig through the supplemental figures for sotorasib's New England Journal article, you can see that there appears to be a trend towards potentially increased response rate in that TPS less than 1 population. So together, those 2 suggest that there may be a path forward as a monotherapy perhaps with a single arm accelerated opportunity.

We'll take our next question from Umer Raffat with Evercore.

I think 2 broad themes here today, if I may. First, it will be helpful on 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 an increasing base case expectation on the Street that PD-L1 lows is where we should expect some synergy or better synergy in combination for Keytruda with adagrasib, but perhaps not so much in PD-L1 highs. Would you agree or disagree with that?

And then finally, 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 pharmas reporting their Phase Is next year.

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 the Mirati to where it is today. And what I would say that the changes that were made that 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 for financials.

So I just wanted to say that upfront. These overlaps are really based on myself joining and Chuck taking on a new role as Head of R&D. With 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 as President and Head of R&D, he'll have more direct line of sight into the R&D organization with the day-to-day activities within R&D.

And then finally, I'd say is Mirati has grown, become more complex, and we're rapidly approaching commercialization that 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 where we have an active search ongoing.

I'll turn the second question over to Chuck.

Okay. Great. So Umer, I think that -- the way I would phrase it is that the -- as you know well, that the less than 1%, the 1 to 49 and the greater than 50% TPS score populations have different outcomes currently. That the outcomes to 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 ones 49 or the greater than 50. 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 a superiority over to less than 1% than the 1 to 49 and then 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 the Phase II what the performance of the combination is in the greater than 1% patients. And then we can design the Phase III accordingly. 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 competition.

Sure. Yes. Before I do that, Chuck, just to build on your last comment. From a scientific or biologic 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 immunosuppressed microenvironment and maybe more poorly responsive to checkpoint inhibitor therapy. Same story with PD-L1 scores of TPS less than 1%.

And what that data illustrated is that we were seeing a tumor response, but also a molecular response in tumors harboring these co-mutations or having PD-L1 scores. 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 adagrasib 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 a clarification on the last question. If that refers particularly to KRAS inhibitors from other large pharma companies, is that what was meant here?

Yes. Basically, the competition for all the readouts next year, which includes BRAF 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. Yes. 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 keep a pulse on this. And as the data emerges, we will learn from 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 referring to our own KRAS program, which targets multiple spectrum mutations. Those are our programs that are directed at the -- at least partially at the active state.

And what may be of benefit here is that there are maybe less of a subject to feedback reactivation of KRAS upstream. So 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 adagrasib, that's both the monotherapy on combination and believe that there's a path forward for both classes of these inhibitors.

We'll take our next question from Salveen Richter with Goldman Sachs.

With regard to adagrasib and the combo with pembro, do you think more dose optimization work is needed? Or are you really comfortable here with the 400 milligram BID? And then if you could give us an update on the 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, just would love your initial thoughts on Amgen's launch here and how you see yourselves prepared to launch and fitting in into the landscape just given it could be approved pretty quickly?

Yes. So why don't we start with the pembro combination. So yes, just to say that we are -- the 400 milligram BID dose looks to be well tolerated. The results thus far, right, with the partial responses, a patient who couldn't be classified as a partial response but did have a good tumor reduction and then surgical resection is encouraging. So we're -- we believe that there is a path forward, but we're doing further investigation in Phase I.

So the KRYSTAL-7 trial is a Phase II trial where we're looking at that dose. And that will be the Phase II to establish the activity and the parameters that we would investigate in Phase III. So we don't have the final answer yet, but we think we're on the right track and that the data from KRYSTAL-7 ultimately will be used to decide exactly the design of the next set of trials in the Phase III to come.

And then in terms of CRC, so we believe there's 2 options here, and we're going to -- we're discussing both with the agency. So 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 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 KRAS-mutated patients. So in essence, the combination is almost like the equivalent of a single agent. 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 accelerated approval strategy. And then, of course, as we mentioned, we already started the second-line study of the combination with cetuximab 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 our ongoing discussions we expect to go well forward with regulatory agencies, in particular, the FDA. And then for the launch question...

I'll add one more thing on the CRC. I think it's also just important to note, historical precedents in a targeted patient population in late-line colon cancer. So some of you may recall that the biomarker of MSI high where PD-L1 inhibitors are active as historical precedent as an accelerated approval in colon cancer. So nivolumab with a 27% overall response rate did receive that approval path. And then we would recognize as a monotherapy at 22% response rate, we're essentially in range. I would say with the cetuximab combination, we're certainly well in the range of historical precedent, thus really the focus on that path forward.

Great. 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 RTOR pilot program, we expect an approval by midyear next year. So we are aggressively planning and in launch mode already with our team. 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're aggressively planning for this.

Our medical affairs team has been in place already for a year, fully deployed medical affairs team, educating the physicians, answering questions from the physicians. It's a highly capable team across the board. Many folks want to join Mirati based on not just adagrasib but the pipeline that we've talked about today. So we have folks that are joining in our team with 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. Without adagrasib -- 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 adagrasib. So we're investing behind that best-in-class asset. And we're also thinking about not just the launch but beyond the launch. 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're 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 the team will be ready when we're ready to -- for the approval and launch up against any competition that's out there.

(Operator Instructions) We'll take our next question from Anupam Rama with JPMorgan.

On the G12C pancreatic cancer for adagrasib. I think in the opening comments, you said warrants further study. Maybe you could expand on that on what the next steps are for that indication and how we should think about it?

Yes. 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 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.

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.

And maybe just to add to that as well. One reason to study pancreatic cancer in more detail, in addition to being -- seeing an interesting signal is we recognize 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.

We'll take our next question from Yaron Werber with Cowen.

This is Gab on for Yaron. 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 adagrasib with pembro data. So first, what were the Grade 3 adverse events at the 400 milligram BID dose? And how common were they? And also if you can share any of the most relevant toxicities seen with the 600 milligram BID combo cohort that led you to evaluate the lower dose adagrasib as we try to better understand the most relevant potential overlapping toxicities between the 2 drugs.

And then secondly, if you could just share quickly, what's the historical response rates that you look at for the KRAS mutant first-line patients compared to the unselected populations treated with KEYTRUDA?

Right. So in terms of the overall picture, 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 the single agent and the same kind of adverse events. So the most common were GI-related events, like nausea, vomiting, diarrhea, there's some overlap there with some of the pembrolizumab adverse events as well. And so I think in the overall picture that the combination of effects meant that, that was less well tolerated. And that's why we investigated at the 400 milligram.

As we said, there were not any treatment-related discontinuations at the 400 milligram dose and no Grade 4 or Grade 5 events. So other than that, the types of events were similar to what we've described previously for single agent adagrasib. So nothing new has come up. Obviously, we need to continue to study. We're early in the process. There's 7 patients. So we are enrolling patients now, as I said, into the Phase II 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 2 doses and decide on the next steps forward as we get closer to triggering a Phase III study next year.

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

I was just wondering if you already had some preliminary FDA interactions regarding your plans for potential accelerated approval in different subsets and first-line non-small cell lung cancer. And if the 30% ORR, if that is a reasonable hurdle, as you mentioned, for the PD-L1 negatives, just in the context of some data that was published that indicates that KEYTRUDA may potentially perform better in KRAS non-small cell lung cancer patients as opposed to all comers.

Yes. So there's limited data on the KRAS 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 KRAS subset of patients. But I think in our thinking that bar would be lowest for the less -- the TPS less than 1%, which is in that 30% range, STK11 may be even lower than that. And that's 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 adagrasib 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 that is -- those are ongoing discussions now and then we should have more information coming soon.

And I think just to add discussions with the agency, they freely acknowledge the unmet need for KRAS-mutated patients that have either a TPS score less than 1 or an STK11 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 STK11 co-occurring mutations with KRAS where response rates are probably closer to 20%, and PFS are just insidiously low, really around 2 to 3 months.

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, it doubles in the details and depends on what the data looks like.

We'll take our next question from Yigal Nochomovitz with Citi.

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?

Sure. Yes. So we will be filing an IND this year. We are working out plans for the Phase I, 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 in Phase I, Phase Ib and Phase II 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, peripheral nerve sheath tumors. 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 will be our goal to focus there, 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 otherwise. Collectively, all tumors with MTAP deletions start approaching around 10%. So that is our initial focus, but certainly, our Phase II 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.

We'll take our next question from Maury Raycroft with Jefferies.

Just wondering if you could say where you're out with enrollment for STK11 adagrasib 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?

Yes. So it's enrolling currently in that arm of the study and going well. We will provide an update soon as we get more patients enrolled and then 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. I think based on previous accelerated approvals, we think that's something in 80 patients, maybe 80 to 100 patients is a reasonable 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%, obviously, we think that the results, even that 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 we're -- we should be in the ballpark where that could be acceptable result. But we need to verify that with the agency directly before we can be sure.

We'll take our next question from Ben Burnett with Stifel.

I was wondering if you could just talk about just with regards to the first-line data that you just read out or talked about pembro plus adagrasib. Can you just talk about the level of target engagement that you saw with the 400 mg dose? And I guess 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 that you can offer on how you're able to maintain good target engagement at the lower dose.

Sure. Let me answer that question in 2 parts. So first of all, our nonclinical 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 ml corrected for protein binding. At the dose of 600 mgs BID, we achieved around 2,200 nanograms per ml above for the full dose interval. At the 400 mg dose level BID, the longer half-life allows us to achieve at or around that 1.5 micrograms per ml for the entire dose interval. So we were above our preclinically defined 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 tumors.

I think the second point to make here is, 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 which way, but loose above or below median, by quartile or otherwise. And we particularly studied quartiles where the exposure would be around what we would predict at the 400 mg 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 mgs BID are essentially at 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 that dose level.

We'll take our next question from Jason Gerberry with Bank of America.

I wanted to just come back to the front-line pembro combo, the 7 evaluable patients. Can you comment where the PD-1 levels sort of broadly across the full range of different levels? And really, what I'm getting at here is, I know that in KEYNOTE-42, the exploratory subgroup analysis showed that pembro was closer to 60% in KRAS-mutated patients. So from an ORR perspective, just wanted to realize that we're dealing with really small numbers here. I just wanted to make sure how to evaluate these data. And then I think there was 1 patient that went on to surgery. So were there inclusion of Stage III patients? Or were these all advanced metastatic patients that got enrolled? Just wanted to clarify those 2 points.

I forgot the first question.

The level of -- I'm sorry, the PD-L1.

Yes, yes, yes. So -- sorry. With the Phase Ib study, which is where we investigated 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 KRYSTAL-7 study, that is -- the patients are typed up front, and they're put into different groups, less than 1% and 1 to -- or greater than 1%. And that's when we'll know what the correlation is between a TPS score and response rate. There's limited data available, as you know, and we have still limited data.

So I think we're -- although the responses look good that we need further study, as I said, to enroll more patients to define these parameters more carefully. 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. 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 -- their judgment about that particular patient.

And that (inaudible) is still on study and still on drug. So it's doing well.

Our last question is from Andrew Berens with SVB Leerink.

In terms of the responders, you said all 5 of them are on therapy. Are they all still maintaining a response? And then just -- I think in the press release, you said 37% was the lower boundary of shrinkage, what was the reason that all of them were not considered responders?

So yes, the all 4 plus the 1 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 in terms of...

(inaudible).

Yes. So we had a couple of patients who had tumor reductions and just part of it is around RECIST 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 RECIST. So -- but the other 5 that we discussed, they all continue in response at this point.

Okay. Is there any chance of going up on the dose might have kept them in a response?

I may have missed your question. The dose...

These were 400. Yes, these were 400 BID, I would concomitant KEYTRUDA, 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 than maybe they would have stayed in response?

Yes. That's a hard question to answer. I mean, certainly, we've seen in other trials where we've had patients that had an initial tumor reduction, some increase. The some stayed on study and others didn't. But it's small numbers at this point. So we are -- it's not part of the protocol to reescalate or to escalate from 400 to 600. So that's an outstanding question. We don't know the answer to that at this point.

Okay. Congrats on all the progress.

Thank you.

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 Vickie this afternoon. As you can tell, we're really excited about the future of Mirati as we continue to progress toward our mission to discover, design and deliver breakthrough therapy to transform the lives of patients with cancer and their loved lands.

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 the patients. So thank you very much. This concludes today's call, and thank you for joining.

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