Mirati Therapeutics, Inc.

Good afternoon and welcome to the Mirati Therapeutics third quarter 2022 earnings call. My name is Jenny 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. We ask that you please limit yourself to one question and one related follow-up. If you'd like to withdraw your question, please press star followed by the number two key. It is my pleasure to introduce Ryan Assi, Vice President of Corporate Affairs at Merati. Ryan, you may begin the call.

Thank you, Jenny. Welcome, everyone, to this afternoon's call. Joining me on the call today are David Meek, our Chief Executive Officer, Dr. Chuck Baum, our President, Founder, and Head of Research and Development, Dr. Jamie Christensen, our Chief Scientific Officer, Ben Hickey, our Chief Commercial Officer, and Laurie Stelzer, our Chief Financial Officer. We're also joined by our recently appointed Chief Medical Officer, Dr. Alan Sandler. Before we begin, I'd like to inform you that certain statements we make during this call will be forward-looking. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ maturely 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 30th, 2022, and recent corporate updates. This press release is available on the investor section of our website at marati.com. With that, David, I'll turn the call over to you.

Thanks, Ryan, and thank you for joining us on the call today. The third quarter was another productive one for Marati. as a team made important progress advancing our strategic initiatives. As a result, we are on the brink of realizing what could be transformative catalysts over the next several months. First, our PDUFA date for Adagracib is December 14th, and we're excited by the prospect that people living with non-small cell lung cancer could soon have the opportunity to receive Adagracib. We believe we've made a thorough and compelling application for U.S. approval and our interactions with the agency continue to be very constructive. Second, in first-line non-small-cell lung cancer, we expect to share updates and direction across our multi-pronged development approach this quarter. This will include more data on the concurrent dosing of adagracib at 400 milligrams twice daily with full-dose pembrolizumab, which is our most advanced adagracib combination approach in the first-line setting. Third, We're on track to top-line the interim readout of the Citruvacidib Phase III Sapphire Study by the end of the year. Fourth, we've made significant progress advancing MRTX1133, our KRAS G12D inhibitor, and plan to file an IND later this quarter. Jamie will say more about the 1133 program in his commentary. With that, I'll turn the call over to Ben to provide an update on our launch readiness and commercial organization.

Thank you, David, and good afternoon, everyone. I'm pleased to report that we are now launch ready. We have a greater than 100-person customer-facing U.S. field force, and our commercialization teams are fully trained. I'll take a few minutes to explain why we are highly confident that we've assembled an effective commercialization organization which can successfully deliver on our commercial goals. First, our U.S. commercialization team has specific and extensive experience in lung cancer, supporting multiple launches, and includes a fully integrated team of market access, sales, and medical affairs supported by a unique digital platform. Second, our commercialization team has a singular and unrelenting focus, delivering Adagracib to the oncologists, HCPs, and people living with cancer that we serve. Third, from a payer perspective, our team has interacted with nearly all of the top plans across the country, receiving positive feedback on the unique profile of Adagracib. We expect to generate broad coverage within the first few months of launch. Fourth, our teams continue to work on market development opportunities, such as increasing both testing and identification of KRAS G12C eligible patients, particularly in the community setting where over 40% of our pivotal study was enrolled. We have also designed a distribution and patient assistance program in partnership with community oncologists, and we believe this program is best in class. Importantly, we are also coming to market from a position of strength due to Adagracib's compelling clinical profile. We believe the key attributes of Adagracib will drive prescribers to utilize it in their treatment decisions. These attributes include Adagracib's strong activity, including a 44% response rate and a 14.1 months of median overall survival, as demonstrated in the pooled analysis we presented at ASCO. and low treatment-related discontinuation rates. Additionally, the data we presented at ASCO demonstrated that adagracib had significant activity in patients with central nervous system metastases, including those with active and untreated CNS metastases, which is estimated to occur in approximately 40% of KRES G12C patients. We are also seeing compelling clinical data in people with multiple non-long tumor types, which we believe is important in the mind of physicians. In summary, we believe that these important, differentiating characteristics, combined with an experienced and focused commercialization organization, position as well for market leadership within the KRAS G12 space over the long term, including future opportunities beyond the initial second line setting. David, I'll turn it back to you.

Thanks, Ben. Before we provide an update on our pipeline, I'd like to take a few moments to discuss the leadership transition we announced today. Dr. Chuck Baum has made the decision to retire next year after nearly 30 years of service to the biopharmaceutical industry and more than 10 years at Mirati. Mirati owes a great debt of gratitude to Chuck, who founded and then led the organization as CEO for nine years. We would not be in position today to receive approval for Adagracid and have a broad and innovative pipeline without Chuck. He has been a very generous partner and colleague to us all. We thank him for his leadership, which has established Merati at the forefront of targeted oncology. I'm pleased that we will continue to benefit from Chuck's guidance as he transitions in the second quarter of 2023 and will provide ongoing strategic leadership as a member of the board of directors. Chuck will continue to operate as president and head of R&D into the second quarter of 2023. This will enable Chuck to oversee several important milestones in the fourth quarter and support a smooth transition of the development organization to Dr. Alan Sandler, who is Joy Marotti, is our chief medical officer. We're very delighted to bring Dr. Sandler to the company. With 30 years of oncology and drug development experience, including as the global head of oncology product development at Zylab and late-stage oncology development at Genentech, Alan is extremely qualified to continue the progress we have made in our pipeline and explore additional opportunities for Adagracid, including our first-line combination strategy. Alan's depth of medical knowledge, including approximately 18 years as a practicing academic medical oncologist, a key opinion leader, and an investigator during his academic career, paired with his experience and proven track record as a clinical leader, makes him an ideal successor to Chuck. Alan has extensive experience managing complex R&D programs, and I fully expect that his leadership and industry knowledge will benefit patients, employees, and our shareholders. I'll turn the call over to Alan to share his initial thoughts.

Thank you, David. Good afternoon, everyone. I want to start by saying that it's an absolute privilege to work at a company with such a relentless focus on science and deep commitment to improving the lives of people in need. I share that same passion. Muradi is rapidly ascending to leadership in targeted oncology, and I'm thrilled to be joining the exceptionally talented team at Muradi at such a pivotal time. I have a long personal and professional relationship with Chuck, and I appreciate his support and encouragement as I join Muradi. It will be an honor to work alongside him over the next several months as we navigate through a number of important clinical events which could prove to be significant catalysts for Muradi. Looking ahead. I'm excited to assume the role of Chief Medical Officer at Miradi. From my prior experience, I am intimately familiar with Enneagrasib and believe it is a best-in-class drive with the potential to make a significant impact on people living with cancer. I look forward to applying my decades of experience towards advancing our robust pipeline of compelling clinical programs, which I believe show great promise. Chuck, I'll turn the call over to you for an update on our clinical activities.

Thank you, Alan. Let me begin by expressing my sincere gratitude to all my dedicated colleagues who have worked with me at Mirati over the last 10 years. The opportunity to lead Mirati and bring forward several potentially best-in-class treatment options for people with cancer has been the highlight of my career. I'm proud of the organization's accomplishments and extremely optimistic about our future. With David at the helm, Allen on board, and just a few quarters needed to complete the work I would like to finish. It's a perfect time for my transition. I will be moving on from my daily operational responsibilities during the second quarter of 2023, but I will continue to be a part of the company's strategic leadership as a member of the board of directors to support, influence, and celebrate our future success. I want to extend a warm welcome to Alan and express how thrilled I am that he has joined Maradi. My personal and professional interaction with Alan over the last 20 years lead me to believe that we are fortunate to have him leading our development organization through the next phase of growth. In fact, Alan and I have been working closely together for the last two years. He knows Adagrassive well and has worked extremely well with the Maradi team. I look forward to working with Alan as we advance the pipeline together. With that, I'll switch gears and begin with discussing adagracib. Let's begin with ESMO, where we shared positive results from CRYSTAL-1, evaluating adagracib as a monotherapy and in combination with cetuximab in people with previously treated KRES-G12C mutated metastatic colorectal cancer CRC in the third or later lines of therapy. Feedback from KOLs, investigators, and oncologists on our CRC data have been overwhelmingly positive. As we expected, the combination with cetuximab showed a particularly compelling and differentiated efficacy profile and will be our primary approach in CRC moving forward. The combination demonstrated a response rate of 46% and median progression-free survival of 6.9 months. Notably, these results suggest that potential of substantial improvement compared with the current standard of care and are part of the differentiation story for Adagrasis. The combination data strengthen our confidence in the potential for accelerated approval in late-line CRC, and we expect to finalize discussions with the FDA about the viability of utilizing this pathway soon. We are actively enrolling additional late-line CRC patients in the combination of adagracid plus cetuximab in a Phase II cohort of the CRYSTAL-1 study, which we expect to be part of our supplementary MDA filings seeking approval for this indication. We also have a Phase III registrational study ongoing in second-line colorectal cancer patients called CRYSTAL-10, which is comparing the efficacy of adagracid in combination with cetuximab versus standard-of-care chemotherapy. The study continues to enroll well with strong interest from patients and physicians, and we expect CRYSTAL-10 to be the basis for full approval in second-line and beyond colorectal cancer patients. As we see from these CRC data, Adagracib has the potential to treat people living with multiple tumor types, and we believe this is an important differentiating characteristic for our program. Moving to lung cancer, we have several important upcoming catalysts. We have an active and ongoing dialogue with the FDA as we approach our December 14th benefit date. As David mentioned, our interactions with the agency continue to be constructive. Beyond the U.S., we are continuing to advance discussions with the European Medicines Agency on their review of Adagrasib's marketing authorization application. We continue to make progress toward our goal to expand the availability of Adagrasib to patients in the European Union. In first line non-small cell lung cancer, we expect to share key updates across our multi-pronged development approach. As a reminder, our initial and most advanced adagressive combination approach in first-line non-small-cell lung cancer is the concurrent dosing of adagressive at 400 milligrams twice daily with full-dose pembrolizumab. The initial data we shared at ASCO give us confidence in the path forward or the combination in the first-line setting. Our Phase II CRYSTAL 7 study evaluating this combination is enrolling well, and we are targeting ESMO immuno-oncology conference in December to share more mature data with a larger number of patients. With these data, we expect to have enough follow-up on a sufficient number of patients to have a better understanding of the safety and tolerability of the combination. These data, along with feedback from scientific advisors and from the FDA, will help inform our registrational plans in the first-line non-small-cell lung cancer setting. We are finalizing our first-line strategy, and we will provide an update on our next steps at ESMO-IO. I'll now discuss CRYSTAL-12, a randomized Phase III confirmatory study in previously treated non-small-cell lung cancer patients rolling well worldwide. As a reminder, Adagrasib's Phase II Registrational Study, Cohort A, was conducted in a heavily pretreated patient population, with 98% of patients having received both prior chemotherapy and checkpoint inhibitor therapy. This is the same patient population being evaluated in CRYSTAL-12, and we would therefore expect our performance results. Additionally, it's possible that with the introduction of the tablet formulation, we may see improved tolerability. Based on the clinical data we've shared to date and our expectation for CRYSTAL-12, we believe Atagrassive will have a strongly differentiated profile in lung cancer with best-in-class objective response rates, overall survival, and penetration of the central nervous system, or CNS. activity in people with active, untreated CNS metastases, which is a large and poorly served patient population. Let's shift to citrobatinib, which is being studied in a registrational phase 3 study called SAFIRE. This study enrolled patients with second or third line non-squamous, non-small cell lung cancer who derived prior clinical benefit following treatment with a checkpoint inhibitor and chemotherapy. The SAFIRE study is on track to top line the interim results for overall survival this quarter. We believe this study was well designed and sufficiently powered to demonstrate a positive outcome. We intend to share the top line results in the form of a press release by the end of the year. Depending on the outcome, we expect to disclose the data at a medical meeting in 2023. If positive, this interim analysis could be the basis for full approval in the U.S. and Europe, with regulatory filings in both markets being submitted by the middle of 2023. Tetravantinib has the potential to treat a large number of people with approximately 70,000 patients with second or third line non-squamous, non-small cell lung cancer in the U.S. and Europe. With that, I'll turn the call over to Jamie for an update on our earlier stage development pipeline.

Thanks, Chuck. I'll begin by briefly touching on MRTX1133, which is a potent and selective KRAS G12T inhibitor that targets both the active and inactive states of the KRAS protein. In the past, we've highlighted our research emphasizing the importance of maintaining maximal KRAS C12D target inhibition for the full duration of the human dose administration cycles, which has historically been a challenge. In response to these observations, we have emphasized the development of formulation strategies designed to enhance oral absorption and increase durable systemic drug exposure. We've made progress and significantly increased our confidence in the ability to achieve sufficient drug concentrations and maximal target coverage in human clinical trials with oral administration. As a result, we're prioritizing the IND for the oral formulation of 1133, which we expect to submit by the end of this year. We remain very excited about 1133 and the transformational potential that this compound could have in a large and underserved patient population with G12D mutated cancers. As a reminder, the KRS G12D mutated cancer patient population is approximately three times larger than the G12C patient population. In addition, G12D mutations are highly prevalent in people with pancreatic cancer and colorectal cancer. Now, moving on to MRTX1719, our MTA-cooperative PRMT5 inhibitor. 1719 is enrolling an ongoing Phase I-II clinical trial in patients whose tumors harbor an MTAP gene deletion. This gene deletion represents up to 10% of cancer patients with cell tumors. We're encouraged by our early clinical experience, which shows that the pharmacokinetics and systemic exposure are consistent with expectations to achieve therapeutically meaningful drug concentrations based on our preclinically defined targets. We're also pleased to report that we were granted fast-track designation for 1719 in the third quarter, which reflects the strength of our preclinical data and the potential for 1719 to address unmet medical needs. Looking ahead, we expect to share initial clinical data for this program in 2023 after we've selected a dose and generated sufficient data to demonstrate clinical proof of concept. In addition, our investigational new drug application for MRTX0902, a SOS1 inhibitor, was accepted by the FDA, and we've recently initiated Phase I clinical trial. We believe that 0902 has the potential to be used in combination to enhance the activity of adagracib and is another example of our strategy to maximize the value of antagrassib by pursuing a broad range of KRAS targeting strategies and indications. We also recognize the potential value of SOS1 inhibition independent of KRAS mutations, including EGFR-mutated non-small cell lung cancer, as well as malignancies harboring other non-G12C RAS family mutations. Also, we have recently announced two clinical collaborations which continue to be an important part of our adagrassive strategy. First, we entered into a clinical collaboration with Adi Bioscience to evaluate the combination of adagrassive with NAB serolimus in people with advanced non-small cell lung cancer and other solid tumors harboring a KRAS T12C mutation. Preclinical models have shown compelling evidence supporting the combination of KRAS nematode inhibitors and KRAS mutated cancers. The combination is directed at achieving a deeper and more durable inhibition of the KRAS-dependent signaling pathway and also addressing resistance pathways that may bypass KRAS-dependent and selected tumors. We anticipate that this will result in improved patient outcomes compared to either single agent. Secondly, we entered into a clinical supply agreement with NSAID to evaluate the combination of adagracib with their oral small molecule PD-L1 inhibitor. Both clinical collaborations demonstrate Miradi's focus on pursuing anti-aggressive and combination therapies to benefit people living with difficult-to-treat cancers. Overall, we're pleased with the significant progress we're making across the portfolio. MRTX1133 will be our third IND in the last 12 months. This illustrates the productivity and efficiency of Miradi's internal discovery engine. We look forward to providing additional updates in the near future. With that, I will hand it off to Lori.

Thank you, Janie. Let me begin by saying that from a financial management perspective, we continue to utilize our capital in a disciplined manner to ensure we advance our pipeline, invest in innovation, and effectively launch products to drive sustainable long-term growth. Now I will walk through our income statement and touch on a few other key financial metrics. Revenue for the third quarter of 2022 was $5.4 million, which was driven by the recognition of a $5 million milestone payment from ZyLab that was contingent on starting a pivotal clinical study for Atagracib and a second indication in the ZyLab designated territories. This compares to revenue of $71.8 million in third quarter of 2021, where we recognize $66.6 million of revenue associated with the transfer of the license and know-how of Adagrasiv as part of our agreement with XyLab, and a $5 million milestone payment from Beijing associated with the start of the first pivotal Sidervatinib clinical study in the Beijing-designated territories. Research and development expenses for the third quarter of 2022 were $131.1 million compared to $116.1 million for the same period in 2021. The increase is primarily due to an increase in salaries and other employee-related expenses, including share-based compensation expense associated with an increase in headcount to support our growing pipeline. General and administrative expenses for the third quarter of 2022 were $60.8 million compared to $35.2 million in the same period in 2021. The increase is primarily due to an increase in commercial readiness costs in preparation for a potential product launch, an increase in salaries and other employee-related expenses, including share-based compensation expense, as we grow our sales, marketing, and G&A staff, and an increase in facilities and IT costs to support the organization. Net loss for the third quarter of 2022 was $173.6 million, or $3.09 per share, basic and diluted, compared to a net loss of $80.1 million, or $1.55 per share basic and diluted for the same period in 2021. The net loss for the third quarter of 2022 included $9.5 million gain recorded upon the dissolution of Methylgene, which was Merati's Canadian subsidiary. We ended the third quarter with approximately $1.2 billion in cash, cash equivalents, and short-term investments, which gives us a cash runway well into 2024. During the third quarter, we sold approximately 1.9 million shares of common stock under our ATM facility, which generated net proceeds of $155 million. Please see our press release from earlier this afternoon for additional details about our third quarter 2022 financial results. David, I'll hand it back over to you.

Thank you, Lori. Before opening the call for questions, let me conclude by saying how pleased I am with the considerable progress our team has made this quarter. We continue to advance our diversified clinical pipeline and prepare for the potential launch of Adagrasive in the U.S. As we close out the remainder of this year and look to 2023, we're very excited about the prospect of Mirati helping people with cancer and creating value for the stakeholders who enabled that to happen. And thanks to those stakeholders, further investigate a host of promising clinical opportunities. We remain optimistic that we will be granted approval to launch Adagrassive in the coming weeks, and I can assure you that we will do so with vigor. Fortunately, we benefited from watching and analyzing the KRES G12C market evolve in the last 18 months as it has been built from the ground up. We have engaged extensively with key accounts and community oncologists which helped us to formulate what we believe will be a very effective launch strategy. As you have heard today, we are making solid progress on our key pipeline initiatives, and we are very optimistic and excited about our future. I'll close by thanking the Mirati team for their individual and collective efforts this quarter. I'm truly proud and grateful to lead such a dedicated and accomplished organization. On behalf of all of us at Mirati, We thank you for your support and interest in the company. With that, Jenny, we're ready to open the call for questions.

Thank you. I would like to remind everyone that if you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. We ask that you please limit yourself to one question and one related follow-up. If you'd like to withdraw your question, please press star followed by the number two key. Please hold for a moment while we poll for questions. And your first question comes from Salveen Richter with Goldman Sachs.

Good afternoon. Thanks for taking my question. Just with regard to the partnership with Insight on their oral PD-L1, could you just share what led you to this collaboration and what aspects of the early data gives you confidence here and your thoughts about where this may fit in longer term?

Absolutely. But Jamie will take that. Sure. Yeah, I think, you know, first of all, we remain very confident in our strategy to combine with pembrolizumab in the frontline setting. And as Chuck mentioned, we'll be talking about that at ESMO-IO. You know, essentially with the NSITE collaboration, you know, they approached us. They're very interested in augmenting their PD-L1 oral inhibitor program with a variety of combination strategies. And, you know, I think it was easy for us to have a very robust discussion with them about clinical trial design. And essentially, it's, you know, an opportunity for the further development of Add Aggressive in that setting, but essentially driven by insight.

Thank you.

And we'll go next to Tyler Van Buren with Cowan.

Hey, guys. Thanks very much. Chuck, I'd just like to say a heartfelt congratulations on the many impressive accomplishments you've achieved during your tenure at Mirati in your career. You've truly made your mark on the KRAS and the broader targeted oncology space, and I've enjoyed working with you, and you'll be missed. Thank you. With that, I'd just like to ask about the impending CRYSTAL-7 adagressive PEMBRO combo data at ESMO-IO. What do you guys believe is the upper bound of the acceptable limit of grade 3 plus LFTs? And on the efficacy side, what response rate do you think would be compelling as we think about the potential to beat PEMBRO chemo in a pivotal trial.

Sure, Ty, I'll take that. First of all, thanks for your kind words about Chuck. Just to let you know, he's not going anywhere tomorrow, as I mentioned. So you'll see him again, trust me. Regarding... you know, K7 and what we expect to see, upper bounds and so on. Let's have that conversation about four weeks. You know, we're going to be at ESMO IO in four weeks, as Chuck mentioned, and we'll lay out everything to you, our overall strategy for the frontline setting with that, and we'll get in all those details at ESMO IO.

Fair enough. Thank you.

And we'll move to our next question from Gina Wang with Barclays.

I also wanted to add, Chuck, you will be missed. It has been a great working with you in the past many years. Also, Alan, welcome on board. We look forward to working with you. So I also have just one question regarding CRYSTAL 7. At the asthma aisle, will you be aiming for regular abstra or late-break abstra? And also, you know, since last update in June, All the patients were from the cohort that are taking capsules. What percentage of patients from this update will be on tablet?

Sure, I'll jump into that, and I'll throw it over to Chuck to talk about some of the specifics of that. We're shooting for late-break or abstracted ESMO IL, and as soon as that's, you know, when we know more details, we'll share that with you, Gina. But stay tuned over the next couple weeks. Chuck will answer the question about tabs and caps.

Yeah, so Gina, all of the recently enrolled patients since our last discussion were on the tablet, and I don't have the exact percentage for you, but it's the vast majority of the patients that we'll report at ESMO-IO will have been dosed on the tablet.

Okay, great. Thank you.

And moving on, we will go to a question from Jonathan Miller with Evercore ISI.

Thanks for taking my question, and congrats from me as well, Chuck. Why don't I ask about second-line launch, actually, since we've had a bunch of questions on the Crystal 7 data. I'd love to get your sense on testing adoption in the second line and what proportion of patients you expect in the second line know their KRAS status. Is that still going to be a major limitation on the rate of a launch in the second-line setting? Yeah.

Yeah, Jonathan, we've looked at this very closely. We continue to look at it closely, and then I'll share some of the details with you.

Sure. So, as you know, testing predominantly occurs at diagnosis. So, we think that testing rate today is just over two-thirds or so of the market. So, still some room to grow there. And to your point, as they transition, unfortunately, some of these patients progress in second line. We're seeing over 50% of those patients being identified, so we do think that over half of the market is available today, and we expect it to continue to grow almost on a linear basis as both the testing rate has room to grow as well as that patient identification issue in second line. So, again, we think it will continue to grow, and I think we'll be launching into a market with momentum, but it will take a little while to fully mature.

Thanks very much. And how about reimbursement in that setting? Do you expect that to be relatively easy to accomplish given KRAS is already active in the space?

We spent the last six to 12 months engaging with all of the top payers across the country, and they understand our profile very well and understand our efficacy profile in particular. We do expect to get broad coverage. The rate of adoption, you know, it will take a couple of months, but we'll be there very quickly and have pretty broad coverage. We don't see significant issues on that front.

Thank you very much.

And we'll go next to Michael Schmidt with Guggenheim.

Hey, guys. Thanks for taking my question. Yeah, maybe another commercial question, you know, with the PDUFA data approaching here in December, how should we think about the potential launch trajectory of Adagracib next year, perhaps relative to the Amgen experience, considering the clinically differentiated profile of the drug? You know, is there perhaps, you know, an opportunity to switch patients from other KRAS inhibitors? thinking more about initially addressing newly diagnosed patients. Thanks so much.

I'll start and then I'll add a couple things. Let's not forget we're 18 months after the launch of Lumicrafts. We are the second to market. Being the first to market, you do have a bolus of patients that are quickly available to you, patients that were on an early access program. before the launch of Lumicrafts, you know, immediately moved to commercial drug. So, that certainly helps the first mover. That patient population will not be available to us. Some of the second, third line patients that, you know, were available at launch would not be available to us. Rapid reimbursement will happen, as Ben mentioned. So, we expect reimbursement in the first, in the early months of approval, but that's going to take a few months. So, the market, but over time, you know, we certainly see, you know, uptake of that aggressive, and then over time, we clearly see market leadership over time, but the launch trajectory will be a little bit different than one does see with Lumicrest.

Yeah, I'll just add in that, no, we wouldn't expect to see a great deal of switching from existing, so we're really playing in that new to second-line patient population, which is where we'll As David mentioned, we don't expect to see the significant bolus that first-to-market assets have, but more of this linear, incremental approach over time with the benefits being realized by the patients and physicians over time.

We'll go next to Michael with Morgan Stanley.

Hey, guys. Thanks for taking the question. maybe just a follow-up on the K7 data that we're expecting at ESMO-IO here in a couple weeks or months here. I know you mentioned having sort of sufficient data to get a good read on efficacy and safety, but wondering if you could maybe give us a rough idea of the patient numbers and maybe also the level of follow-up we should expect.

Thanks. You know, what we're going to share, and it is four weeks from now, we'll certainly share all the details there. It will be more patients than we shared at ASCO. It will be longer durations of therapy than will be shared at ASCO. We're definitely going to have an – it will be early data. Let's not forget that. But it's a look at safety and tolerability, the combination, an early look at efficacy. In this case, it will be more response rates. But over time, we're looking at PFS and OS. in this patient population, and we'll have all those details in four weeks. Thanks.

And we'll go next to Jason Gerberry with Bank of America.

Hey, guys. Thanks for taking my questions. My question is just curious on the Insight press release. There was some commentary about mitigating immune-related adverse events, and just curious sort of what you potentially see as sort of the unmet need of going to an oral PD-1 may solve for, or maybe that's just language that Insight chose to use and you don't agree with. And then also, just the rationale, it seems like you started a new Phase II study looking at KRAS monotherapy sequentially followed by KRAS PD-1 in the TPS greater than 1% patients. So just curious to what extent that may have been driven by anything that was seen with the Amgen study data at World Lung. Thanks.

Sure. Yeah, this is Jamie again. You know, so regarding your first question on the commentary and the Insight press release, you know, I would just say that this is a way that Insight is really positioning their molecule. They, you know, really believe that the flexibility around an oral and the shorter half-life is a way to, you know, kind of, you know, mitigate potential immune-related AEs. But I think if you look at all of Insight's press releases and positioning around this molecule, they've used consistent language throughout. And I don't think this especially applies to adagracib in any way. So I think that's the first answer. I think on the second question regarding sequential administration of KRAS inhibitors with pembrolizumab, you know, I think – or other immune checkpoint inhibitors – You know, our focus remains concurrent administration. You know, we do believe that there's a clear path forward with concurrent administration. We do believe that there's a mechanism-based interaction between KRAS and its ability to essentially affect some of the cells in the immune microenvironment and the ability to co-administer with a drug that affects immune checkpoints is, in our mind, a clear advantage, and this remains our strategy moving forward. And, you know, as mentioned a couple times on the call, you'll get a good picture of that at ESMO Iowa this year.

And we'll go to our next question from Maury Raycroft with Jefferies.

Hi. Thanks for taking my question. You talked about the potential to get the adagressive approval before December 14th. Can you provide more specifics on where you're at with discussions with FDA I guess particularly, do you have a draft label in place and does it include any specifics on CNS activity? And have you had a lifecycle review meeting?

Sure. You know, what I would say is we remained very confident in the approvability of the NDA. We don't think it's appropriate to get into the, you know, or disclose the details of the conversations of the recent interactions we're having with the agency. You know, the conversations are productive, they're constructive, and, you know, more details will come out as soon as we have them. But we remain optimistic about the approvability.

Got it. And as far as the label goes, is there anything – do you have the CNS data in the label? Can you comment on that?

Yeah, we're not going to get into the specifics of, you know, the FDA interactions at this time.

And we will move on to a question from Eric Joseph with JP Morgan.

Hi, good evening. Thanks for taking the questions. I'm just wondering whether, I guess, given the Codebreak 200 update with LumaCross at ESMO, where data sort of underperform the Phase II performance. I'm wondering if there are any read-throughs in your view to your Phase III CRYSTAL-12 study. I'm also curious to know whether you've had any feedback from physicians on sort of the evolving efficacy profile of Lumicras and whether that kind of represents an opportunity for differentiation with the launch of Adagrasib.

Thanks.

Yeah, so, you know, I think that, importantly, we pointed out during the call that our patient population from cohort A and K12, crystal 12, were identical. And just to point out that if you look at the patient population for COVID-100, if you just look at those patients that had IO plus chemotherapy, that the response rate there and the PFS looked very similar to what was seen in Code Break 200. So we do think, actually, that the data from 100 was predictive of what would happen in 200. It's just that the patient population was different. So we don't expect, in our case, for there to be any difference between studying all patients in our studies were administered both chemotherapy and IO checkpoint inhibitor therapy before coming on to our trial.

And regarding the physician reaction, you know, as to where Adagrasa will fit in the armamentarium of physicians when they do need a KRES-G12C inhibitor, it's been a really good third quarter for us as we've rolled out more data and actually began at ASCO And then the data that we've shared, the competitive landscape, the more of the profile the physicians have seen with that aggressive, as Ben had mentioned, with the response rates, CNS activity, median overall survival data that we shared at ASCO, colorectal cancer data that was shared at ESMO. The totality of this data has been very encouraging, the feedback. All of us have spent a lot of time with customers, and the feedback has been very positive for us. So physicians are anxious. present that to physicians.

And we'll go next to Ben Burnett with Stiefel.

Hey, thank you very much. I want to ask a question just on the ongoing NDA review. Regarding the change of adagrass, the formulation change from capsule to tablet, have you disclosed how many patients or what level of patient data with the tablet that you submitted to the FDA that's being reviewed as part of this NDA?

Ben, we have not disclosed that information regarding the tablet formulation. But what I can say is the tablet formulation is in the NDA, and that's the formulation we expect to have approved.

And we will move on to Andrew Behrens with SBB Securities.

Hi, thanks for the questions and my congrats too to Chuck for reaching the milestone. I guess another on the commercial LumaCrafts, you mentioned in the prepared comments that you learned a lot from the LumaCrafts launch, which I think most agree has been more sluggish than many had anticipated. Wondering if you could give us some color on what you think was going on and what you plan to do differently. And then I have a follow-up question too after that.

Andrew, then I'll take that first question.

Sure. I'll just start with the we've very intentionally built an organization around our customers and the micro markets that we see. So that's coming across access, medical, and our sales representatives. So we really think that we've hired a best-in-class team and a differentiated team. Secondly, we really do believe we've got a differentiated product. And then specifically as it pertains to the account dynamics, We've been out there for a while and really spent a lot of time. Keep in mind that our study, over 40% of the patients were actually enrolled from the community. So we've spent a lot of time in the community centers and really understanding the patient flow and where the genetic marker occurs in the electronic health system or if it doesn't and who in the office is responsible for that role. So there really is some operational challenges that we've spent a lot of time with that we think that we can help try and affect. And keep in mind that with our, you know, over 100-person field team, we're really kind of doubling the noise and promotion in the space and bringing K-Res G12C even more to the top of mind. So we think with those additional efforts, we'll continue to see the market opportunity grow over time. And hopefully, you know, we really think that Adagrassive is a really competitive agent in that market.

Okay. And then just a question on the ongoing – 400 milligram second line cohort just wondering how far along that is an enrollment. And I just want to get confirmation. You still think that's going to be a phase 4 commitment at this point.

So, regarding the enrollment, we haven't disclosed where we are with enrollment with that specific trial. regarding, you know, post-approval commitments. You know, I don't think we're prepared to have that conversation at this time as well. I think, you know, upon approval, assuming any post-marketing requirements, we'll share those details.

And we will go next to you, Gal. Malcolm, that's with Citi Group.

Hi, great. Thank you very much for taking the question. I just had a question on CRYSTAL-12 and then an unrelated follow-up on TRMP5. So on CRYSTAL-12, I think Chuck said you said it's enrolling well worldwide. I'm wondering if you could say specifically what the percent enrollment was in CRYSTAL-12 at the time when you submitted the NDA for adegracid. And the reason I ask is I'm sure you guys saw that earlier today another company, ADC Therapeutics, indicated that for the FDA to consider accelerated approval pathways that they want to see that the confirmatory phase three is well underway and ideally fully enrolled at the time of the filing. Thank you.

Yeah, I'll take that question. That's a pretty clear one. What I can say is our trial, CRYSTAL 12, was underway prior to our NDA being submitted. It was well underway when our NDA was accepted. The FDA is very aware of where CRYSTAL 12 is in enrollment. And we have met the bar of substantially enrolled. So we do not see that as an issue for approvability for adagracin, crystal 12.

Okay, got it. And then this one's probably for Jamie. Jamie, so with respect to 1719, the PRM25 inhibitor, can you comment on how it's different potentially from the Amgen drug, AMG-193 inhibitor? from a biochemical perspective as well as how you're planning to develop the drug differently versus Amgen's strategy? Thank you. Sure.

Yeah, it's a little bit hard to read through to Amgen as they have not disclosed the chemical structure of their molecule. To my knowledge, you know, we have, you know, been following the patent literature and otherwise. You know, I would just say with regard to 1719, you know, we are very comfortable with the degree of selectivity for MTAP-deleted tumor cells versus non-MTAP-deleted cells. That includes normal cells, so we have a 70-fold-plus ratio of selectivity. And when we model that out with regard to the clinical pharmacokinetics and peak-to-trough ratio, we believe that it's very likely we would be sparing PRMT5 in normal cells. I think, as you know, one of the key issues for first-generation PRMT5 inhibitors is that don't discriminate for the MTA binding and PRMT5, that there are mechanism-based toxicities, a lot of myelosuppression, neutropenia, thrombocytopenia, anemia, and other issues that are encountered. And we do not anticipate to encounter those for that reason. And finally, you noted the development path for the drug versus Amgen. You know, I would just suffice to say that, you know, we're interested in a lot of key MTEP-deleted cancers where the deletion is common and where genomic testing is available. That includes non-small cell lung cancer, pancreatic cancer, and a number of smaller indications where we believe there might be a fast-to-market strategy if the response rate should hold up. Our preclinical data is suggestive that this can be a mechanism of action where you do see tumor response or cytoreductive activity in We would like to leverage that certainly during our development program.

And we will go next to Sylvan Torkin with JMP Securities.

Yeah, thank you very much for taking my question. I have a question regarding kind of comments made by Amgen. So far, the ZumaCrest has been prescribed to 3,700 patients, and they estimate there's roughly 7,000 in the second line, non-small cell line cancer available. So in my eye, I view the penetration fairly good. So how would you say going forward now you could influence or kind of tip the hand in the new patients that come in, you know, telling doctors to take ZumaCrest adegaseb versus lumicrizin in these new patients, given that that's already a fairly high penetration in the second-line non-sponsored cancer patients. Thank you. Sure. Ben has that question.

Sure. I think just on definition, it's important to get definitions correct here. So there are 7,000 patients who are new to second-line. When you look at the entire second-line plus market, that's 12,000 to 13,000 patients. So that's the market that Amgen launched into with the 12,000 to 13,000. Now, over time, that market gets closer to really the 7,000 as patients get treated, and they will likely only get treated once with a KRAS inhibitor. So while they had launched into that, and the 3,700 really comes from that larger pool, the majority of the opportunity moving forward will be in that 7,000 pool. But again, that 3,700 was being pulled from a much larger market.

We will go next to Evan Sigerman with BMO.

Hi, guys. This is Malcolm Hoffman on for Evan. Thanks for taking our question. So you had mentioned on the call a focus in Adagrassib on the opportunity in the community setting. How are you thinking about the community versus the academic setting? And we were just wondering, what you're seeing in the market or hearing from physicians and what this means for potential market segmentation?

Sure. Regarding the community academic setting, we're actually focused on both. So it's important, you know, the academic centers, that's where, you know, a lot of clinical trials are conducted. It's where a lot of the key opinion leaders are. In the community setting, you have that, plus you have a lot more of the patients that are in the community setting. And second, mentioned in his comments, you know, 40% of our patients in the cohort A trial, the registration trial, were from the community setting. So it's good that the community physicians, you know, a number of them already have clinical experience and we have other ongoing clinical trials. within the community setting as well because that's where the patients are. So we've got that surround sound approach, if you will. It's not just the academic setting. It's also the heavy reliance on the community setting because that's where the patients are. Ben, that's a comment to make too.

Yeah, I think the only thing I'd add to that is in the community, you're also treating across tumor types as well. As we think about the data that Chuck had mentioned now that we presented in CRC and in pancreatic and pan-tumor data, we continue to see differentiated efficacy there. So we think that is a really robust part of our differentiation story moving forward, both in monotherapy as well as combinations, so across tumors.

Yeah, good point, because the community setting physicians, they treat all tumor types. They're not as specialized as the academic centers are.

And we will go next to Jay Olson with Oppenheimer.

Oh, hi. Thanks for taking the question, and I'll add my congrats and well wishes to Chuck. I'm curious about any thoughts you could share on the combination of Lumicrast plus SHIP2 inhibitor and how that may impact your expectations for Adagracib plus SHIP2 and when we might expect to see data from that study. And I had one follow-up if I could

Sure, it's David here. I would say, you know, we've got an ongoing study with SHIP-2 with Novartis. That trial's underway. Novartis is leading the way with that program. And, you know, we'll look forward to sharing the data when it becomes available sometime. Yeah, it'd be sometime next year. I'm sorry, Sanofi. I said Novartis, not Sanofi.

Okay, great. I guess, can you also comment on the potential for adagressive plus chemotherapy in first-line non-small cell lung cancer and whether or not that could be a registrational approach?

We'll get to that next month at SMOIO. When we talk about the holistic frontline strategy, we'll talk about our multi-pronged approach to the frontline setting. So four weeks from now.

And we'll connect to Swapnil Malikar with Piper Sandler.

Hey, thank you for taking my question. Although alluded to in the past, like given the importance of the combination approach of Adagracil and PEMBRO in the frontline setting, I'm just wondering if there is any specific data that has been generated to see that the tox that was associated with Lumacras and PEMBRO is not a class effect of KRAS inhibition and that Adagracil is differentiated.

Oh, Jamie will take that. Yeah, this is Jamie. You know, first of all, you know, I think we do not believe this is a class effect. You know, again, you know, we're moving forward with the combination, and we'll be talking about that more in the future. And I'd say, you know, there are a few reasons to believe that this is not a class effect. One is if you look at historical combinations with immune checkpoint inhibitors and tyrosine kinase inhibitors, it's very clear that there are some agents that are readily combinable you know, our own citrubatinib and, you know, cabizatinib and others are readily combinable. Same drugs in class, pazopanib, sinitinib, drugs like crizotinib, unfortunately not. So I think it's hard to say that the TKIs are a class effect when you see that, you know, particular observation. I think point number two is, you know, we could point to the differentiated physiochemical properties of drugs like adagrassib and some of the competitors. And one thing to note about adagrassive is the, you know, kind of KI to K in act ratio is probably a best in class. That means adagrassive has low intrinsic reactivity and a lot of its binding affinity is through non-covalent means. That means we're likely to avoid off-target issues. The second physiochemical property to, I think, note is the peak to trough ratio in terms of pharmacokinetics. We don't see a large variation in Cmax exposure to Cmin exposure. So it's likely we don't see high levels of drug and tissue that are disproportional over the dose interval. We do think that that's another way we might be able to avoid any, you know, for example, hepatotoxicity. So, yeah, bottom line, don't think this is a class effect. I think there are several reasons to believe both based on historical development of drugs as well as the physiochemical properties of ADA.

Thank you, Jamie. We have time for one more question, Jenny.

And we'll go to Patel with B. Riley Securities.

Yeah, hey, good afternoon. Thanks for taking the question. Maybe first, just to be clear on one of the previous questions that was asked, can you confirm that based on any recent communication with the FDA that the agency is not requiring you to fully enroll in Crystal 7 before potentially granting approval by the PDUPA date?

Yeah, first let me say, I think you mean Crystal 12, which is our confirmatory trial. Crystal 12. So, yeah, we can confirm that. Okay. I think that's a different situation. I can't speak for that company. I can just speak for us.

Okay, fair enough. And then I think previously there was some talk about maybe a potentially accelerated approval path in certain subpopulations in the frontline setting, particularly the STK11 co-mutation patients. Maybe how is that plan shaping up? Is that still on the table or are you leaning towards a full complete phase three trial instead?

We really look forward to having that conversation in four weeks at ESMO-IO because it's all – that's certainly part of our multi-pronged approach to investigating the frontline setting where we see a tremendous opportunity and potential for autographs. So we'll get into those details at ESMO-IO, and hopefully you all can join us in Geneva for that conversation. So thanks for joining us this afternoon, everybody. We really appreciate your interest in Mirati, and we look forward to sharing additional updates with you here in the coming weeks.

And so this concludes today's call. Thank you for your participation. You may now disconnect.