Mirati Therapeutics, Inc.

Good afternoon and welcome to the Mirati Therapeutics fourth quarter 2021 earnings call. My name is Sarah and I will be the operator for today's call. All lines have been placed on mute to prevent any background noise. After the conclusion of the speaker's prepared remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press the star key followed by the digit two. It is my pleasure to introduce Ryan Acy, Vice President of Corporate Affairs at Meradi. Ryan, you may begin the call.

Thank you, Sarah. Welcome everyone to this afternoon's call. With me today are David Meek, Meradi's Chief Executive Officer, Dr. Jamie Christensen, Meradi's Chief Scientific Officer, Ben Hickey, Miradi's Chief Commercial Officer, and Vicki Reed, Miradi's Chief Accounting Officer. Unfortunately, due to a last-minute acute stomach flu, Dr. Chuck Baum, Miradi's President, Founder, and Head of Research and Development, will not be able to participate in this afternoon's call. Please note that this conference call will include forward-looking statements. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K that is filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended December 31, 2021, and recent corporate updates. This press release is available on the Investors section of our website at verati.com. With that, I'll turn the call over to David.

Thank you, Ryan. Good afternoon, everyone, and thank you for joining us. On this afternoon's call, I will provide some initial remarks before asking Jamie to share an update on our clinical development programs, Ben to comment on our commercial preparedness, and Vicki to summarize our financial results. I will then provide a few concluding remarks before taking your questions. 2021 was an important year of growth, progress, and strong execution for Merati. There are many achievements our team accomplished, and I'll highlight just a few of them here. We received breakthrough therapy designation for adagracib for the treatment of previously treated KRAS G12C mutated non-small cell lung cancer. We announced positive top-line monotherapy data from the registrational Phase II cohort of adagracib's CRYSTAL-1 study and completed the submission of the adagracib new drug application in patients with previously treated non-small cell lung cancer under the FDA's real-time oncology review pilot program. We presented highly encouraging colorectal cancer data for adagracib, both as a single agent and in combination with cetuximab in late-line patients. We also shared preliminary results from the combination of adagracib and pembrolizumab in first-line non-small-cell lung cancer, which provided strong support for our continued prioritization of this combination. We initiated several additional potentially registrational studies with adagracib, including as a single agent in certain subpopulations of first-line non-small-cell lung cancer, as well as in combination with cetuximab and second-line colorectal cancer. Beyond that aggressive, we continue to advance and expand our increasingly broad targeted oncology pipeline, including completing the submission of an investigational new drug application for MRTX1719, our NTA cooperative PRMT5 inhibitor. In November, we bolstered our capital position with a secondary public offering, which gives us increased financial strength and flexibility to continue to appropriately invest for success across our pipeline and in preparation for a potential U.S. commercial launch later this year. We continue to build our corporate capabilities. We're a company with strong end-to-end expertise from early discovery through drug development and commercial with strong foundational enabling functions. We're incredibly excited about the transformational year ahead of us. We are well prepared and have the resources to achieve our bold agenda. Important potential milestones in 2022 include gaining FDA approval for Atagracid and rapidly launching our first commercial product to patients with lung cancer in the U.S., which remains our top priority. Adagracib's profile has the potential to make a meaningful difference for patients with lung, colorectal, pancreatic, and other cancers. We remain confident that Adagracib has blockbuster potential. We expect to complete the submission of our European regulatory package for Adagracib based on our Phase II results. With Adagracib's blockbuster potential, we are advancing the broad development plan we have for Adagracib. including exploring earlier lines of therapy and into additional tumors. We are aggressively moving forward the other important value drivers in our broader portfolio. We now have three meaningful programs in clinical development, each with a large commercial opportunity and areas of high unmet need. We're on track to reach the number of events needed to trigger the interim readout of CitraVaccine's Phase III Sapphire Study in the second half of 2022. We initiated a phase one clinical study for MRTX1719, our MTA cooperative PRNT5 program, and expect to submit INDs for MRTX1133, our KRAS G12D inhibitor, and MRTX0902, our SOS1 inhibitor, in the second half of 2022. We have established ambitious goals for ourselves this year. We see significant enthusiasm across all areas of the company, as we continue to execute on these priorities and drive results with a sense of urgency and passion to transform the lives of patients with cancer. I'm excited about our momentum and proud of the company we are building. With that, I'll turn it over to Jamie.

Thanks, David. In Chuck's absence today, I will touch on our three programs in clinical development. Adagracid, Citrobatinib, and MRTX1719, our MTA cooperative PureMT5 inhibitor. We're pleased with the progress we're making in advancing Adagracib through clinical development, and we look forward to potentially delivering it to patients in the commercial setting this year. Earlier this month, we announced the FDA's acceptance of our NDA for Adagracib for accelerated approval under the subpart H regulatory path for the treatment of patients with non-small cell lung cancer who harbor the KRAS G12C mutation and have received at least one prior systemic therapy. The target action date is December 14, 2022. We have breakthrough therapy designation status and expect to continue to have positive and collaborative interactions with the FDA through the NDA review process. We look forward to presenting the full data set from the Phase II Registrational Cohort from the CRYSTAL-1 study, which was the primary basis of our NDA filing, as well as initial clinical activity in patients with non-small cell lung cancer brain metastases from a separate cohort of patients in the CRYSTAL-1 study who had active and untreated brain metastases. We expect to present both of these datasets at a medical meeting and are targeting ASCO as the potential venue this year. We continue to enroll patients in adagrassive clinical studies and are generating additional data in patients with a wide range of cancers. In first-line non-small cell lung cancer, we continue to explore adagrassive as a single agent in certain underserved subpopulations. These include patients harboring G12C and STK11 co-mutations, as well as KRAS-mutated patients with TPS scores of less than 1%. We expect to provide additional clarity on a potential pathway for accelerated approval of Adagracib as a monotherapy in these patients this year, as well as sharing initial data from these cohorts in 2023. systemic therapy naive non-small cell lung cancer, adagracib is being studied in combination trials. The most advanced and highest priority combination is with pembrolizumab, where we continue to enroll patients at the 400 milligram BID dose of adagracib in the CRYSTAL-7 study. We plan to share an update from the ongoing Phase II CRYSTAL-7 study in the second half of this year, including the analysis of patients stratified by TPS score. We are also actively planning to start a phase three trial evaluating the adagrasiv and pembrolizumab combination in treatment naive patients later this year. This is subject to results from the ongoing K7 study. We also continue to enroll patients with colorectal cancer, both in late line CRC as a single agent and in combination with cetuximab. We are also continuing to enroll the registration enabling phase three study in combination with cetuximab and second-line CRC patients. We're also pleased with the favorable results we recently presented at the ASCO GI Cancer Symposium in pancreatic cancer and other gastrointestinal cancers. We are continuing to enroll patients with KRAS mutations and other solid tumors, and we'll continue to explore potential accelerated regulatory approval pathways in these patient populations. We expect to provide additional clarity on a potential pathway for accelerated approval of adagracib in late-line CRC, as well as sharing next steps in other solid tumors, including pancreatic cancer, this year. We continue to pursue a broad combination development program for adagracib beyond the combinations with pembrolizumab and cetuximab. These include combinations with SHIP2, SOS1, or CDK4-6 inhibitors, as well as VS6766, a MECGRAPH pathway inhibitor with a unique mechanism of action. We expect to have initial data readouts for some of these proof-of-concept combination studies in 2023 after we've generated additional data. We will continue to explore the potential of additional novel combination options beyond those we are currently evaluating. Now moving on to Citruvatinib. We are enthusiastic about the program based on the 14.9-month overall survival demonstrated in the Phase II MRTX500 study of citramadonib in combination with nivolumab in non-small cell lung cancer patients previously treated with checkpoint inhibitor therapy. The Phase III SAFIRE study is on track to reach the number of events needed to trigger an interim analysis of overall survival in the second half of 2022. If positive, this trial could be the basis of regulatory submissions for full approval in the US and Europe. Now, moving on to MRTX1719. Again, this is the second generation or next generation MTA cooperative PRMT5 inhibitor. First, we're very pleased to have advanced another program into clinical development. 1719 is based on the principle of synthetic lethality through targeting of MTAB gene deletions, which are present in nearly 10% of all human cancers. In contrast to first generation PRMT5 inhibitors, 1719 is designed to selectively target the PRMT5 MTA complex. This leverages the abnormally elevated levels of MTA uniquely found in MTAP-deleted cancers. 1719 selectively targets MTAP-deleted cancer cells while sparing healthy non-tumor cells. 1719 is orally bioavailable, and its unique ability to bind to the PRMT5 MTA complex is predicted to spare patients from toxicities observed with first-generation PMT5 inhibitors. For this program, we recently initiated a Phase I clinical study and are actively enrolling patients. The clinical development plan includes moving through Phase I dose escalation, then into Phase IB dose expansion cohorts, followed by a number of Phase II cohorts across several tumor types. These include mesothelioma, pancreatic cancer, lung cancer, malignant peripheral nerve seed tumors, also known as MPNST, as well as a basket cohort of other MTAP deleted tumor types. We will explore 1719 as a single agent and have a number of rational combination strategies we're developing utilizing non-clinical translational studies that would also target next year. We expect to share initial clinical data in 2023 after we have a dose and have generated sufficient data to demonstrate clinical proof of concept. Finally, we continue to make significant progress with our preclinical programs. including MRTX1133, a KRAS G12D selective inhibitor, and MRTX0902, an in-house SOS1 inhibitor, which leverages SOS1's ability to enhance the activity of KRAS inhibitors such as adagracib. Both programs remain on track for INDs in the second half of 2022. With that, I will turn it over to Ben.

Thanks, Jamie. I'll touch briefly on our financial strategy for a successful launch subject to FDA approval of Adagracid. We initiated our launch preparations two years ago and we continue to execute on a staged approach to our launch readiness efforts in anticipation of a launch as early as the third quarter of this year. There are several pillars that we believe will enable us to be highly competitive. Adagracib's unique molecular profile and 24-hour half-life have enabled us to generate meaningful clinical data across multiple lines of therapy and tumor types, and includes the potential for CNS penetration, which is a particularly important characteristic in lung cancer, where up to 30% of patients will develop brain metastases. Second, over the past two years, we've attracted top talent across biotech, pharma, and healthcare provider organizations. We've seen incredible interest in our commercialization roles, both because of Adagrasive's profile and because of Merati's unique culture and targeted oncology pipeline. This has enabled us to recruit a team with extensive experience and demonstrated success in launching some of the industry's top oncology products. Beginning in 2020, we have built an outstanding medical affairs capability, including a significant investment in customer-facing field medical. This has resulted in ongoing engagement across top academic centers and community oncology networks and the initiation of an expanded access program. We've established an experienced value and access team who continue to engage U.S. payers managing the majority of covered lives. We've also developed marketing, analytics, and insights capabilities as well as all of the foundational capabilities required for a deep understanding of customer needs and ultimately a successful launch. Because we've built our team from scratch, we've been able to optimize how the team is designed with a focus on integration and speed of execution across key functions at the account level. COVID has changed the way our industry engages with oncology providers, moving from a focus on repetition of live engagements to relevance and customization based on customer preference by digital or live channels. We view this as a fundamental shift that really levels the playing field among larger pharmaceutical and biotech companies like ourselves. and positions as well for long-term commercial success. Fourth, we have the capital necessary to invest for success, both in terms of preparing for and successfully executing on the initial launch, and to invest in the long-term growth and expansion of Adagracib across tumors, lines of therapy, and combination approaches. We are very enthusiastic and excited about this potential launch and being able to deliver this important treatment option to patients who are living with this type of cancer. The physicians who treat patients with lung cancer are also waiting for new options to treat their patients. With that, I'll turn it over to Vicki.

Thank you, Ben. We ended the fourth quarter with approximately $1.5 billion in cash, cash equivalents, and short-term investments, which includes net proceeds of approximately $475 million from a secondary capital raise we completed in November 2021. Research and development expenses for the fourth quarter of 2021 were $153.8 million, compared to $82.7 million for the same period in 2020. The increase in research and development expenses is primarily due to increases in expenses associated with the development of adagracib and citrobatinib, preclinical and early discovery activities, salaries and other related costs, which includes an increase in share-based compensation expense, as well as other research and development costs, including one-time costs associated with registrational manufacturing batches. General and administrative expenses for the fourth quarter of 2021 were $43.5 million, compared to $25.3 million for the same period in 2020. The increases due to growth in salaries and other employee-related costs which includes share-based compensation expense, professional services expense, which is primarily associated with commercial scale-up, and other costs related to the growth of our business. Net loss for the fourth quarter of 2021 was $199.6 million, or 3.72 per share, basic and diluted, compared to a net loss of $101.1 million, or $2.08 per share basic and diluted for the same period in 2020. Please see our press release from earlier this afternoon for additional details about our fourth quarter and full year 2021 financial results. David, I'll hand it back to you.

Thanks, Vicki. I'll conclude by reinforcing what an exciting time it is for Merati. We have a broad and sustainable targeted oncology pipeline across multiple targets and tumors and see significant long-term value in the operational and commercial synergies across our portfolio. We have the financial resources to continue to invest for long-term success. We are continuing to invest in aggressive U.S. launch readiness as well as in a broad development plan to enable us to optimize the blockbuster potential of this important product. Our objective is to launch and further develop a market-leading KRAS G12C inhibitor. We are investing to drive sustainable growth and ensure rapid progression across the breadth of our innovative targeted oncology pipeline beyond Adagracid. In addition to the internal capabilities we have built, we are enhancing and accelerating our progress through selective partnerships. In the fourth quarter, we announced two non-exclusive clinical collaboration agreements. The first is with Sanofi to evaluate the combination of Adagracid with Sanipi's investigational SHP2 inhibitor. The second is with Baristem Oncology to evaluate the combination of Adagrasib with Baristem's investigational RAF MEK inhibitor. We expect to continue to be active in pursuing opportunities to accelerate and expand our pipeline through partnerships. We are incredibly pleased with the progress we have made and look forward to the many important milestones we are approaching. I continue to be impressed by the team we have at Mirati. They have an incredible energy and passion for improving the lives of patients. I thank them for their continued efforts and focus as we work to transform the lives of patients with cancer. With that, we're ready to take questions.

Thank you. If you would like to ask a question, once again, please take note by pressing star 1 on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, that is star one to ask a question. And we'll pause for just a moment. And we'll take our first question from Tyler Van Buren with Cohen and Company.

Hey, guys. Great to see all the progress, and thank you for taking the questions. I had two. First, could you elaborate on the recent site audits or site visits that have been conducted by the FDA as part of the RTOR process, and if this is occurring earlier than expected based on your conversations with regulatory consultants? And the second question is related to the full Phase II data release at ASCO. We'll obviously look to confirm positive results that have been disclosed previously, but other than response data, is there anything else that might be disclosed that could be differentiating, or should we primarily look to the CMS MET data for that?

Hi, it's David. A couple things regarding the, you know, some of the site audits that are already occurring with Adagraphs. I think it's standard business. We certainly take it as a good sign that the FDA is engaged. You know, being part of the pilot program for the real-time oncology review, it certainly gives the agency a head start on the review. So the site audits that are happening right now, They have happened, some more will happen, but I think we're not going to discuss the ongoing interactions with the FDA, but we take it as a positive sign with that. Regarding having the data published at ASCO, so we're announcing for the first time that we expect the data to be released at ASCO, we'd say stay tuned for the data. We're going to announce a full data set for the cohort A of the registrational trial, and that will be presented at ASCO We're presenting that data set as well as, you know, we intend to present BrainMeds data at the same time. Thank you. Does that help, Todd? Yes. Thank you.

Thank you. And next we'll move on to Gina Wing with Berkley's.

Hi, good evening. This is Rashida on for Gina. Can you hear me okay?

Yes.

Thank you. First, I just had a quick clarification, and then I have a follow-up question. Did I hear correctly that for the monotherapy 1L first-line data set, both STK11 and TPS low, these data sets will be presented sometime in 2023?

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

Okay, great. Thank you. Then the other follow-up I had is for the PD-1 combo dataset in the second half, for the 400 milligram cohort, Is it fair to assume that the number of patients can be at least in the 20 to 30 patient range, given that, you know, at that time point, you'll have at least three quarters minimum to enroll patients?

So, it's David. I'll jump on that and ask Jamie to elaborate. So, what we're going to do is we're enrolling that trial right now, as we announced in the fall, when we switch the protocol to 400 milligrams BID plus full-dose pembrolizumab The trial is actively enrolling. We're encouraged with the ongoing recruitment. So what we're going to do is we're going to get to a data set. We think it'll be a meaningful number of patients. We can look at the safety and tolerability of the combination. Maybe I'll have a couple scans behind us, but it'll be a meaningful number of patients and well into the double-digit range for that patient population. That will inform us going into the Phase III program. And as you know, we're already actively preparing for that Phase 3 start, and we'll use that data to make that decision to jump into Phase 3. Jamie, anything else? Okay. Is that all? I appreciate it.

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

Sure.

Thank you. Next, we'll move on to Gavin Scott with JPMorgan.

Hi. Thanks for taking my question. Just a follow-up on the PD-1 combo. I guess, are there any molecular underpinnings that would suggest a better response in patients previously treated with PD-1 or PD-1 chemo? I guess I'm just asking in the context that you've highlighted that your registrational trial has 98% of patients there, while Lumicrafts had around 80%. So just curious on your thoughts.

Yeah, this is Jamie again. You know, I think it's hard to, you know, fully answer that question today based on the information we have in hand, especially as it relates to prior therapies. Would just say as a reminder that, you know, there is data out there suggesting the STK11 and KEEP1 commutations as unmet medical need for chemo-immunotherapy. The response rates, PFS and OS, are fairly low there. That's partially the premise of us going after the STK11 commutated subpopulation. If we continue to see strong activity there, we would suspect that the unmet medical need with standard of therapy would be a logical discussion point with the agency around making sure that we're developing the drug in a setting with enhanced unmet medical need. We're also looking at the TPS less than 1% population. would say that, you know, we follow both Amgen's data and of course ours. There's no reason to believe to date that the response rate wouldn't be at least as good as the rest of the population and the TPS less than 1% kind of subset of patients. So that remains as an effort for us as a model therapy. And would just say that, you know, we do believe based on preclinical data that the KRAS inhibitor can reawaken the immune response in tumors that may be somewhat immune cold. Again, citing those patient populations that I mentioned earlier. So do believe that these populations, like the STK11, KEEP1, and TPS less than 1, would be subject to treatment with both combination therapies as well as monotherapies. And in fact, we'll be pursuing both angles there. And if that didn't answer your question, please let me know. That was very helpful. Thank you.

Thank you. And next we'll move on to Umar Rafat with Evercore ISI.

Hi, this is Eric on for Umar. Just two quick questions. The first on the PRM T5, with the IMD submitted, what sort of details can you share on the trial design? And what's the expected safety or PD profile versus competitive agents?

Sure. Yeah. First, regarding the trial design, we are utilizing the agency's guidance around 2019 on multi-cohort studies. And these studies are essentially designed to allow rapid development in multiple settings for targeted therapies that are essentially targeting subsets of patients. So in a way, this study will be the first study and also a Swiss Army knife of studies with different objectives. Number one is we will be pursuing dose escalation for the first part of this study. We're pleased with the outcome of our toxicology studies, which allow us to start with a reasonably high dose in patients that would be approaching therapeutic concentrations. Once we establish a recommended phase two dose, or perhaps multiple doses, we would be breaking into phase one B studies, where we would be evaluating the monotherapy activity in any patient with an MTAP gene deletion to get an enhanced understanding of dose dependence, tolerability, as well as anti-tumor activity. As soon as we're confident in moving forward with a recommended phase two dose, then we would be opening phase two expansion cohorts. And they're, you know, essentially the four cohorts that I had mentioned, the pancreatic ductal adenocarcinoma, non-small cell lung cancer, including both adeno and squamous cell cancer, as well as the two kind of more niche indications, mesothelioma and malignant peripheral nerve seed tumors. And finally, one additional cohort, which would be a catch-all, you know, anybody who doesn't have one of those first four primary malignancies. And we'll be looking at expanded activity in all of these different patient sets as a monotherapy. So I would say that's part one. Part two is, you know, we are interested in combinations. I'm not going to go into much detail today, but I will say that the ongoing studies in the preclinical setting have pointed to a couple of interesting co-dependencies with PRMP5 inhibition that would be the substrate to start rational combinations as soon as we identify a recommended phase two dose. So that would also potentially be part of the first in human study, or depending on how regressively pursued could be also a separate study. Then I think your last question was related to the molecular aspects and the PK-PD relationship relative to first generation inhibitors. And, you know, one thing that has come out as interesting in our preclinical studies is suggesting that the maximally effective dose of a PRMT5 inhibitor, you know, with this particular mechanism of action, is really associated with near completely inhibiting symmetrical dimethyl arginine, the primary pharmacodynamic marker or molecular marker which PRMT5 works through to regulate histones and gene expression. So we do believe that near-complete or complete inhibition of SDMA for the full dose interval is going to be critical and do view the key differentiated factor with first- versus second-generation inhibitors is essentially the ability to achieve that near-complete inhibition. First-generation inhibitors are somewhat limited by neutropenia, thrombocytopenia, anemia, and although they're able to achieve pretty good SDMA inhibition, You know, in our measure, it's, you know, the full inhibition is going to be critical to drive monotherapy activity. Therein lies, I think, the value proposition and premise for development of this class of drugs. I think I hit all the key points. Did I miss anything?

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

Sure. Hi, it's David. Regarding the commercial launch preparedness, I tell you, we're real excited about where we've come so far. You know, we plan on being launch ready by Q3 this year. And that did, you know, we've got a medical affairs organization already in the field. We have a value and access team in the field. We have sales management in the field. This timeline gives us even more time to prepare for a highly successful and rapid launch. So that's the approach we're taking right there for the launch planning, and we'll be really, really ready to go and look forward to a rapid launch and building a blockbuster. Ben, anything you want to add to that?

No, I think you've framed it pretty well. No big changes. We get to sharpen things a little more. We get a a few more interactions with our customers and really understand some of the dynamics going on. And we feel, you know, very confident. So I think that a little bit more time hopefully means that we can sharpen things even further.

Great. Thank you.

Thank you. And next we'll move on to Salveen Richer with Goldman Sachs.

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

Sure. Yeah, you know, we've looked closely at, of course, the properties of our drug, and we are aware of formerly presented Lumicross data. So I think a few key points about antagrassib. You know, both preclinically and clinically, we've studied the ability of the drug to get into the CNS. And we previously commented on what's called a KPU value, which is essentially the level of drug in the cerebral spinal fluid relative to the free fraction-adjusted plasma concentrations at a comparable time point. And we've seen KPU values approaching 0.5, which is meaningful. Just a couple of, you know, kind of bars that have been set. Asimertinib is an example of a drug that has a KPU value of about 0.3 and very robust activity against brain metastases. The two drugs in the ELK inhibitor space, electinib and oralatinib, are agents with KPU values of greater than five and have very strong CNS penetrants. And again, have demonstrated activity in patients with brain metastases that is pretty different or differentiated relative to first-generation inhibitors So in the EGFR space, let's note that erlotinib and confitinib are agents with response rates of around 10% in intracranial metastases in lung cancer patients. And then, no, crizotinib is an agent with about a 27% response rate in the ALK inhibitor space, again, a non-brain penetrant inhibitor. You may be aware that our submertinib, erlotinib, electinib are all agents that have demonstrated intracranial response rates fairly consistent with their activity in peripheral disease. So suggesting that if the drug can get into the CNS, it can be differentiated and demonstrate essentially robust activity there. As mentioned in the call, we believe we will have a substantial number of patients to talk about at the ASCO meeting or wherever we land. And essentially there would note that we've had the open cohort with active brain metastases or untreated brain metastases We will be talking about that. We'll also be talking about subset analysis from our cohort A patients, which essentially have treated or controlled brain metastases. And again, you know, think that the number of patients that we'll have to talk about will be meaningful to at least appraise the preliminary activity of the drug in this setting.

Got it. And then for a second question, maybe for Ben, just, you know, with the fourth quarter of luma cross bales being lighter than some had expected, had expected despite diagnosis and patient identification being pretty robust. Just curious what your sense is for what is slowing physician uptake here and is there anything you can do to drive additional utilization when Adagraphis is on the market? Thanks so much.

Sure, thanks for the question. I think just as a reminder with a novel class coming to bear, the people have to be reminded that most of the testing, almost 80% of it, does occur in front line. So those patients now, with the benefit of the 189 regimen, it's still taking 18 to 24 months for these patients to actually come into second line or be on therapy. So that does take some time. And secondarily, we've done a lot of work about understanding the local dynamics and understanding that it does also take a while for the patients to be identified in the EMR. So physicians to see that it's an actual mutation and to be able to take action on it. We expect that the market will take a little while to mature. We see it continuing to mature and those patients becoming available in second line and beyond. And I think that as we come to market, hopefully later this year, physicians will be looking for the preferred KRAS G12C inhibitor. So sometimes being second to market is not always the best, but sometimes it has its advantages and advantages. In this case, having some of the testing already, the foundational work completed, that's been something that we have not been or have not focused on so much to date.

Yeah, I would add to that that certainly we're going to benefit by, you know, Lumicrafts doing those market shaping, you know, building the market shaping of KRES G12C testing. And by the time we're approved, you know, we think a lot of this will be behind us and we can then focus our efforts on, communicating and educating the physicians on the clinical profile of Atagrassive as a G12C inhibitor for their patients.

Thanks so much.

Thank you. Next, we'll take our next question from Evan Seigerman with BMO Capital Markets.

Hi, guys. Thank you so much for taking my questions. Just a few for you guys with the update. So, Can you expand on the bar for monotherapy in the frontline setting in patients with both the TPS less than 1 and the STK11 commutation? And if you had conversations with the regulators as to kind of what they're looking for here, then I have two follow-up questions.

Sure. Regarding your first question, you know, noting, first of all, Keynote 189 as it relates to TPS score. So, Keynote 189, as you may recall, the overall patient set had a response rate of around 48%. And then when they did the subset analysis, the response rate was 32%. And essentially, that represents our bogey or null hypothesis to improve upon for the TPS scores of less than 1% with KRAS commutations. Secondly, you know, the STK11 KRAS subset The bogey there has mostly been defined by academic analyses at major cancer centers. And I think the numbers that are coming out for STK11 patients that have also a KRAS commutation is that the response rate there is going to be about 20% to 25%. So, again, that's essentially what we need to improve upon. Now, I think when you look at prior drug approvals in the first-line setting, that also sets a bit of a precedent or a bar for us to shoot for. And so there have been drug approvals with response rates in the first line setting of over 55%, perhaps over 60% in some cases. And so if you take those two parts of the equation together, you would expect to be able to hit a 55 to 60% response rate or higher would give a clear differentiation from how standard of care performs in those particular patient populations. We have had ongoing discussions with the agency They will, of course, never quote a particular number that we need to exceed. They call that a review issue. But I think, you know, they've encouraged us if should we present or provide compelling data in the target response rate ranges with reasonable duration responses that we would generally be in range to submit for those particular patient sets. So that's really where we stand today. All of our discussions with the agency are considered preliminary, and now the rest of our program is data-driven.

That's quite helpful. And then when you kind of talk about planning for a phase three PD-L1 combo, can you expand like what that actually means and also touch on when the study may start and what you're waiting for here?

So let me start, David. And that is, first of all, regarding the preparation for the phase three protocol. We want to be aggressive and we want to move fast. We realize that the opportunity in the frontline setting is significant for that patient population. And we want to be the first G12C inhibitor to be studied in combination and ultimately approved and launched and available to patients over time. So that's why we're planning for success with 400 milligrams BID plus PEMPRO. So we don't like to do things sequentially here. We like to do things in parallel and move as fast as we can. So that's the first part of that question. I'll turn it over to Jamie to answer.

Yeah, I certainly agree. I mean, you know, we need to be poised for success here. And, you know, let's note that, you know, planning a Phase III study and it's opening globally is an equation of greater than nine months. So essentially we are actively planning to be able to open that study. With regard to the statistical hypotheses, you know, I think we know what part of that equation is, and that is how Keynote 189 as a control regimen would perform NK-RAS mutated patients. So we're essentially basing some of our clinical trial design assumptions on that. And then, as you know, we have the ongoing CRYSTAL-7 study to help inform how adagrassib and pembrolizumab will perform initially with respect to tolerability, dose intensity, and otherwise, but also at least with regard to initial response rate. And with that data, we would be able to make some additional assumptions around the clinical trial design. So, you know, that's really where we stand at this point. We've been encouraged with what we've seen from the small number of 400 BID patients and are looking to better understand that as the year comes along.

All right. Thanks so much, guys. Appreciate it.

Thank you. And next we'll move on to Michael Schmidt with Guggenheim.

Thanks for taking my questions. Just a follow-up on the first-line lung cancer model therapy, you know, the two cohorts. I guess in your preliminary discussions with the FDA, have you had any conversations about the sample size in those cohorts? How many patients are targeted to be enrolled in either of these two cohorts? And then the other question was really about your potential plans in pancreatic cancer. Should we consider a third-line accelerated approval strategy potentially, or are there opportunities to perhaps move into an earlier setting in PDAC? Thank you.

Sure. Yeah, regarding the two cohorts, so, you know, we essentially know what the null hypotheses are. For PD-L1 less than 1, it would be de facto around 32% response rate with a meaningful duration of response for the SDK-11 subpopulation. it would be somewhere in the 20 to 25% range, again, with a meaningful duration of response. As noted, the discussions with the agency, they will not give us a number, what we need to accomplish with regard to response rate or duration of response, but we do have prior experience with the approval of other targeted therapies as monotherapies in these settings. And essentially, if we use those as targets, the number of patients necessary to get approval wouldn't be unreasonable. We also recognize that we have a significant safety database as a monotherapy from all the other additional work we're doing. So I can't really give you a number today, but we essentially believe that the enrollment of a kind of approvable data set could be in the range of other accelerated approvals or monotherapies for targeted therapies in the non-small cell lung cancer setting. For your question on pancreatic cancer, I think you're aware of the data we presented at ASCO GI earlier this year. So just to note, when you look at standard of care, maintaining a 50% response rate and a progression-free survival or duration of response north of six to seven months is actually meaningful even for first-line. Now, it would be challenging for us to start a development program in treatment-naive patients, so we'll continue to focus on second- and third-line patients. As we get more and more data, we'll wait for that to mature, along with a better understanding of the durability of response. And otherwise, we think if that data holds up, again, along with the safety database that we've generated and other types of cancer, that an accelerated approval would be a possibility in either one of those settings. And really, the ongoing generation of data will help further inform that path.

Okay.

Sorry, let me just say something, Mike. Just on the frontline lung cancer, you know, with the STK11 commutation and the patients with a TPS score of less than 1%, you know, we're already moving very aggressively in that patient population as well because that represents about 40% of the first-line non-small cell lung cancer patients with the G12C mutation. So the unmet need is high and the opportunity is great in that patient population. Back to you, Michael. That makes sense.

Just to clarify, are we thinking, you know, 100 patients per cohort in first and non-cancer or something lower than that, just given that you already have a certain amount of data in other patients?

Right. Again, I mean, please take my response in the spirit that this is a review issue and it remains undefined. So in a way, we've developed our statistical hypotheses and are targeting those hypotheses. And ultimately, depending on how the data shakes out, that would determine the number of patients necessary probably to present a convincing argument to the agency. But we just say, if you looked at this as a purely statistical argument, the number would be under 100. Again, assuming response rates of 55% to 60% or higher and assuming that the null hypotheses of 20% to 25% in STK11 or 32% in, you know, essentially the TPS less than one were the assumptions beyond those statistical hypotheses.

Okay. Thank you. And next we'll move on to Ben Burnett with Stiefel.

Excellent. Thank you very much. I had just a quick question on the CNS data. Just given the timing potentially at ASCO, is this something that might be included in the adagrassive drug label if it's approved?

Yeah, great question, Ben. We're certainly going to, you know, have that dialogue with the agency as the data emerges. We'll have that with the agency. We'll try to have as much data as possible put in the label, both preclinical and clinical data. You know, no guarantees. You know, we're certainly moving to get adagraphs approved as fast as possible. So I'd say, as a minimum, the data will be published. If it's not available in the label, we certainly would like to go for a compendia listing, listing of the guidelines, clinical pathways, until we're able to catch up with the label.

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

Yeah, I think that's a really interesting question. We've been looking at that as well. And I think there are some commonalities between G12C mutations in PANG versus G12D. You know, I think one of those observations is that these appear to be the founding genetic event in this class of cancers, you know, going back, you know, kind of now 20 years looking at the sequence of genetic events that move, you know, kind of pancreatic ductal adenocarcinoma from, you know, kind of pancreatic inter-epithelial neoplasia, which is a very early lesion, Those are caused by KRAS mutations. So at the very least, we would expect the founder mutation to demonstrate that the vast majority of tumor cells, if not all of them, are going to have the KRAS mutation. It's not going to be a heterogeneous or late acquisition of a genetic event. Number two is when we look at disease modeling preclinically, we have tried to get our hands on every possible G12C pancreatic ductal adenocarcinoma model. looking both ectopically and orthotopically with regard to implantation. We've looked, you know, certainly at a number of G12D models. And the data stacks up pretty well. You know, the majority of those models are decreasing in tumor size at least 30% off and greater than 50%. So we have a paper that will likely be accepted here shortly, and it goes over the data in pancreatic ductal adenocarcinoma models for MRTX1133. And 11, eight out of 11 of those models responded by tumor regression of at least 30%, often again, higher than that. And then finally, if you look at, you know, kind of depth map project drive and a lot of these large kind of functional genomic studies that have looked across hundreds, if not over a thousand different tumor cell lines, looking at the systemic knockdown of genes, both, you know, certainly G12D pops up as one of the strongest DepMAP hits, including the enrichment for pancreatic ductal adenocarcinoma lines, is one of the strongest dependencies found in those studies, you know, if you look closely at DepMAP mining. So, you know, you take those kind of three pieces of information and triangulate. You know, we do believe that G12D is a very strong driver in PANC and that there is likely some read-through for adagracib.

And the patient population is significantly longer – significantly larger – the G12D patient population of pancreatics of prevalence is significantly greater than it is for G12C mutations. Right.

Yeah, just to build on David's comment, 36% of pancreatic ductal endocarcinoma patients are going to have a G12D mutation. I believe the overall U.S. prevalence is around 40,000. All of those are a strong medical need.

Okay. That's great, Kalar. I appreciate it. Thank you.

Sure. Thank you, and we'll move on to Maury Raycroft with Jefferies.

Hi, this is Kevin Strang on for Maury. Thanks for taking my questions. Just first on the Phase 3, could you give any color into how the enrollment's going and whether or not you plan to open on any more sites than the 115 you have listed right now, and then how confident you are that you'd be able to enroll this prior to the December PDUFA?

A couple things, it's David, and Jamie can jump in too. For the confirmatory trial for Adagracib and second line non-small cell lung cancer, for that we're really encouraged by the increase in enrollment. With that, we've expanded the trial. It's a global trial at this time. We've added a number of U.S. sites, excuse me, European sites. Our partner Zai is helping us in Asia, so the recruitment is going well. Just for clarity, that trial does not need to be fully enrolled prior to an approval. That's per FDA regulations. However, we'll be well underway, and we are well underway, and we'll be very well recruited by the time we think Adagraph-SIB should be approved later this year. Jamie?

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

Is that your question, Kevin? Yes, it does. Thank you. And then just a quick one on, you know, you've opened a couple new arms for your crystal study on ct.gov for cetuximab combinations in small cell and PDAC. You've spoken before about, and you've shown data for CRC. Can you just talk about your rationale for pursuing that combination in these indications?

Sure. You know, EGFR and EGFR family have turned out to remain among the very top combinations that we've observed preclinically. There's a very strong link to EGFR biology and KRAS. Certainly, that's been demonstrated first in colorectal cancer. But we also believe it to be important in lung and pancreatic cancers as well. So essentially we want to double down and make sure that we are covering all of the options to be able to block both of those pathways. And due to the success of Cetuximab and CRC, it certainly opened up some interest for us to look at that and other malignancies as well. So that's really the basis of us looking at that.

Great. Thank you.

Thank you. And next we'll take Mike Old with Morgan Stanley.

Hey, guys. Thanks for taking the question. Just one quick one for me on adagracib in terms of your combination strategy beyond the PD-1 and cetuximab. You'd mentioned providing some of that data next year, but I'm just curious if you can remind us what dose of adagracib you're using there. Is it the 600 milligram dose or are you considering using 400 as well?

You know, generally when we start a dose escalation, we're starting with 400, and then if that looks promising, we can go up from 400. So I would say we have combination trials ongoing right now with the 400 dose, and we have some combination studies that have escalated up to 600. So we're essentially looking at both. And just to say that, you know, we've done some analysis of the 400 dose with regard to PK exposures. And as you can imagine, we constantly look at things like exposure response analysis in any of the clinical data sets that we've generated and are highly confident that 400 makes BID is covering the target quite well. So any combination that we move forward with at a 400 milligram dose level, whether it be pembrolizumab or otherwise, you know, the data exposure response, you know, PK overall look quite promising at that dose level.

Yeah, thanks, Mike. Sarah, it looks like we have time for one last question.

That was it for me. Thanks.

Thank you. We'll take one last question from Yagal Nokomotiv with Citi.

Great. Hi, this is Carly on for Yagal. Thanks so much for taking our questions. We have two questions. First, I think you mentioned that you've begun medical affairs activities in preparation for the launch. So we're just curious if there are certain aspects of adagrassips differentiation that you believe are resonating most with physicians, whether it's the PK properties, long half-lives, CNS penetrants, or something else. Any additional context you could provide there would be helpful. And then the second question is just on G12D. We were just hoping to get an update on where you stand with the formulation work for that program. Thank you.

David, Ben, and Jamie will answer this. Regarding the medical affairs, medical affairs has been in the field since 2020, so they're rapidly approaching two years in the marketplace of preparing the market for Adagracib as well as a KRAS G12C inhibitor. And part of the story that the physicians find very appealing is the unique molecular profile, the 24-hour half-life, the time on target, that Adegreasef has, you know, reading through to, you know, overall response rates. Physicians have been very appreciative and very excited about the 43% response rate that we have in our registration trial, so that's going over very well. Also, the unique molecular profile Jamie spoke about earlier regarding CNS and brain meds and the activity we have there is also very appealing to physicians. So there's a couple data points. regarding the medical affairs organization, the impact they're having. And Ben, other comments you'd add?

Yeah, I would just add one that they're doing a magnificent job, and we have folks in both the US and the EU focused on driving enrollment of the studies. From what we hear consistently back is that they are enthused by the molecular profile and 24-hour half-life, and they They do believe that that's part of the story and why we've seen some consistent results around response rates across tumors. And then on the brain mesh front, obviously from preclinical data, they're enthused and looking forward to seeing more of the clinical data. But they certainly ask us a lot about that data and are looking forward to the upcoming data presentation.

Ed, what do we have time? Okay. Yeah, on the G12D front, so I think as we've previously communicated, G12D, you know, 1133 checks a lot of the boxes with respect to potency, metabolic stability, solubility, and otherwise. But the, you know, intrinsic oral viability is fairly low. And we initially started developing this as a standard IV formulation, but just weren't really satisfied with the duration of target coverage necessary to drive monotherapy activity. So we shifted our gears into long-acting injectables. One example of a long-acting injectable is a liposome-based formulation. And we've been, I think, encouraged by the preclinical data we've seen thus far, where we see strongly differentiated PK properties, you know, essentially extending the half-life of the 1133 in preclinical species that we've evaluated to date. And that is associated with achieving longer duration of target coverage. And if we can set that up in a way where we can deliver the drug once a week or somewhere in that range. Clinically, I think it's going to be more clinically feasible for us to develop that as a formulation approach. We do have other long-acting injectables that we're looking at as well, and those are also in process. And then finally, we've discovered that there are some ways to enhance oral bioavailability or oral absorption of the drug. Those are ongoing, and I'd say exploratory at this point, but if we can make progress there, it's possible that in addition to the long-acting injectable IV that we're advancing towards the IND tract, that there may be a lifecycle strategy with other formulations that we could eventually move forward with this as well.

Great. Thank you, Jamie. Okay, perfect.

Thanks again.

And thank you, everyone. Yeah, thank you, everyone, for joining us today, and also thank you very much for your questions. As you can tell from the team, we're real excited about the future of Mirati. We're well on our way to creating a leading biotech company with one of the most exciting and tangible target oncology portfolios in biopharma. There is a relentless focus at Mirati on translating novel science into innovative therapies that bring hope to patients, and we look forward to speaking with many of you and sharing additional updates as we continue to progress toward a mission to discover, design, and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones.

Thank you. And that does conclude today's teleconference. We do appreciate your participation. You may now disconnect.