Mirati Therapeutics, Inc.

Good afternoon and welcome to the Merati Therapeutics second quarter 2022 earnings call. My name is Danielle and I'll 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 pound key. It is now my pleasure to introduce Ryan Acy, Vice President of Corporate Affairs at Merati. Ryan, please go ahead.

Thank you, Danielle, and welcome everyone to this afternoon's call. Joining me on the call today are David Meek, Merati's Chief Executive Officer, Dr. Chuck Baum, Merati's President, Founder, and Head of Research and Development, and Lori Stelzer, Merati's Chief Financial Officer. Dr. Jamie Christensen, Merati's Chief Scientific Officer, and Ben Hickey, Merati's Chief Commercial Officer, are also with us and will be available for the Q&A portion of the 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, factual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended June 30, 2022, and recent corporate updates. This press release is available on the Investors section of our website at Mirati.com. With that, David, I'll turn the call over to you.

Thank you, Ryan, and good afternoon, everyone. On this Saturday's call, I'll provide an update on key developments since our last earnings call, including steps we are taking to prepare for a potential commercial launch of Adagraphsit this year. Chuck will share an update on our R&D programs, and Lori, our recently appointed CFO, will summarize our financial results. I'll then provide closing remarks before we open the line for questions. So let's get started. The second quarter was a very productive and important one for Mirati, and we have a lot to be excited about. We made significant progress towards achieving a number of important milestones and strategic priorities in the second quarter, including presenting our latest data on Adagrasive at ASCO and building out our commercial capabilities in advance of its launch. At ASCO, we shared several significant Adagrasive updates, and Chuck will touch on the specifics. I'd like to point out a few key takeaways that are worth noting, as we believe there was a lot to be excited about with the data released. At a high level, these results highlight important points of potential differentiation, including CNS penetration and combinability of Atagracid with concurrent Pembrolizumab, and position us very well for both near and long-term commercial success. Our results give us confidence in our ability to secure a U.S. approval and execute a strong commercial launch of Adagraciv in second line and beyond non-small cell lung cancer, which is a key priority for the company. We are very comfortable competing in the KRES G12C inhibitor market, especially in the tablet formulation. Our ongoing interactions with FDA are productive, and we continue to collaborate closely and effectively through the review of the Adagraciv new drug application. We recently had our mid-cycle review, and have added clarity that there will be no advisory committee and no REMS program. The FDA has voiced no major safety issues to date or expectations for new studies prior to approval. As such, we are preparing for the approval of the FDA with a tablet formulation and are finalizing our commercial readiness plans. As a reminder, our PDUFA date is December 14th, but we will be ready to go if approval comes before then. We recently hired the remainder of greater than 100% customer-facing U.S. field force, and believe we have the talent needed to drive a successful commercial launch. In addition, we built out our marketing, market access, patient support, and medical affairs capabilities, and now have in place all the components of a successful commercial organization necessary to execute our commercial strategies. Our commercial team will be fully trained and launch ready in the U.S. by the end of the third quarter, Some of you know I have considerable commercial experience in pharma and biotech, and I can say without hesitation, I'm very impressed with the quality and caliber of the team we have been able to assemble at Mirati. Our commercial strategy is built on several pillars that we believe will enable us to be successful. First, Adagrasib's differentiating molecular profile and 24-hour half-life have enabled us to generate meaningful clinical data, includingly the recently presented greater than 30% overall response rates in non-small cell lung cancer patients with active brain metastases, and the longest-needing overall survival data to date of greater than 14 months in our pooled analysis. Second, we've been able to attract top talent across biotech, pharma, and healthcare provider organizations, giving us a team with extensive lung cancer experience and demonstrated success in launching top oncology products. There are opportunities to increase both testing and identification of KRAS G12C eligible patients. In response, our field teams are working to assist in market development activities to improve both patient access and outcomes. Third, we have purpose-built our commercialization team with a singular focus on adagracive. We have built this team with an optimized design and focus on integration, digitization, and speed of execution across functions. Fourth, we have the capital necessary to invest for success, both in terms of executing on the initial launch as well as investing in the long-term value optimization of this differentiated program. In summary, we're very excited about the potential launch and the opportunity to deliver Adagracib and make a positive impact on patients living with cancer. Beyond the U.S., we completed a submission of Adagracib's marketing authorization application for the treatment of patients with non-small cell lung cancer harboring the KRAS G12C mutation who have received at least one prior systemic therapy to the European Medicines Agency. This submission is an important step in bringing us closer to possibly expanding the availability of Adagracid to patients in the European Union. From a management team perspective, we made an important addition to our leadership team in the second quarter. Laurie Stelter joined Marotti as our CFO. bringing with her an invaluable skill set acquired over her 25-year career in the biopharmaceutical industry, including a wealth of finance expertise and strategic insight. Lori has considerable experience navigating the needs of a company, transitioning from a research and development stage to a commercial stage, which will be beneficial as we prepare for the commercial launch of Adagraphs in the U.S. and finalize our strategy outside of the U.S., We are very fortunate to bring Lori on at this pivotal time in our history. And finally, we continue to be in a strong financial position, which enables us to execute on our strategy and provides us with the flexibility to prudently invest for success across our target oncology pipeline and prepare for a successful adagraphid launch pending FDA approval later this year. With that, I'll turn the call over to Chuck for a clinical update.

Thank you, David. I'll begin with adagraphic. It's an exciting time for the company as we approach our first potential regulatory approval this year. Our breakthrough therapy designation and real-time oncology review status enable our ongoing engagement with the FDA during the review process, and we remain confident in the approval of the NDA this year. We had a significant presence at ASCO where we shared positive adagraphic data in patients with KRAS G12C mutations living with non-small-cell lung cancer across lines of therapy. These ASCO updates included positive results from the registration-enabling Phase II cohort of the CRYSTAL-1 study, evaluating adegraxib 600 milligrams administered twice daily in patients with non-small-cell lung cancer harboring the KRES-G12C mutation who have received at least one prior systemic therapy. These positive results were also reported concurrently in the New England Journal of Medicine publication. We also presented compelling results from a prospective analysis of the Phase 1B cohort of the CRYSTAL-1 study, demonstrating intracranial responses to adagracib in patients with KRES-G12 seen mutated non-small cell lung cancer with active and untreated central nervous system Metastasis. Adagracib is the first KRAS G12C inhibitor to demonstrate substantial clinical activity in this large and poorly served patient population. In addition, we showed encouraging early results demonstrating the feasibility of combining Adagracib with Tumbrilizumab in first-line non-small cell lung cancer patients. These first-line results provide meaningful context and clarity as we aggressively advance our first-line non-small cell lung cancer strategy. Finally, the results presented at ASCO were based on the capsule formulation. In agreement with the FDA, all of our trials have now switched to the tablet formulation, and feedback from investigators has been positive regarding the tolerability. We expect the tablet to be our approved formulation for lung. We plan to present data from patients treated with tablet formulation at a future medical meeting. Feedback from key opinion leaders, investigators, and oncologists on the profile of Adagracib has been overwhelmingly positive. CRYSTAL-12, a randomized Phase III confirmatory study in previously treated non-small cell lung cancer patients with a KRAS-GTLC mutation, continues to enroll well worldwide, and is on track to complete enrollment in the first half of 2023. Maradi expects to provide key updates in the second half of 2022 in the following areas. In first line, non-small cell lung cancer, we expect to share updates across our multi-pronged development approach. This includes providing additional clarity on a possible regulatory pathway for accelerated approval as a single agent in patients harboring KRS-G12C and STK11 commutations, as well as KRS-G12C mutated patients with TPS score of less than 1%. We expect to share initial data from these subpopulations in 2023. Our initial and most advanced adagrassive combination approach in first line non-small cell lung cancer is the concurrent dosing of adagracid tablets at 400 mg twice daily with full-dose pembrolizumab. Our Phase II CRYSTAL-7 study evaluating this combination is enrolling well, particularly following our initial update from this study at ASCO. We plan to share more mature data with a larger number of patients in the fourth quarter of 2022. We continue to evaluate or have plans to evaluate Adagracib in various other first-line combinations, including targeted and chemotherapy-based approaches. We are finalizing our first-line non-small-cell lung cancer strategy with our scientific advisors, which we will align with the FDA and provide an update later this year. Beyond lung cancer, we are advancing enrollment of patients with a variety of cancers driven by KRAS G12C mutations. We expect to provide more mature data in late-line colorectal cancer at the ESMO conference in September. We also expect to provide additional clarity on a possible pathway for accelerated approval of Atagrasiv in late-line colorectal cancer later this year. Full approval will be based on our ongoing crystal 10 randomized phase 3 registration study in second-line colorectal cancer patients. In addition, we are continuing to enroll patients with other solid tumors that carry the KRS-G12C mutation, including pancreatic, cholangiocarcinoma, non-colorectal cancer, gastrointestinal, and other solid tumors. based on our positive data presented earlier this year at the ESCO GI Conference. Adagracin has the potential to treat multiple tumor types across a range of cancers, and we believe this could be another important differentiated characteristic of our program. Shifting to citrovapamin, which is being studied in a registrational phase three study called SAFIRE. This study enrolled patients with second or third line non-small cell lung cancer who derived prior clinical benefit following treatment with a checkpoint inhibitor. The SAFIRE study is fully enrolled and is on track to reach the number of events needed to trigger an interim analysis for overall survival in the fourth quarter of 2022. If positive, this interim analysis could be the basis of full approval in the US and Europe with regulatory filings in both markets being submitted by the middle of next year. Citratinib has the potential to treat a large number of patients, since there are approximately 70,000 patients with second- or third-line non-squamous, non-small-cell lung cancer in the U.S. and Europe. Finally, I'm pleased to announce that we've completed the submission of the investigational new drug application for MRTX-0902. 0902 is a selective SOS1 inhibitor that shifts KRAS into its inactive state, potentially enhancing the activity of adagracib by addressing KRAS feedback reactivation and intrinsic and acquired resistance to KRAS inhibitors. This agent has the potential to complement other agents in the Mirati pipeline and exert an impact on KRAS mutant cancers across KRAS mutation types. We expect to initiate clinical development with our SAS 1 program before year end. We're pleased with the significant progress we are making across the breadth of our R&D portfolio, and look forward to a number of significant updates later this year. With that, I'll hand it off to Lori.

Thank you, Chuck. First, let me begin by saying that I've now had more time to learn about the company, our technology, our team, and our pipeline, and it's very clear why there is so much internal excitement about the future of Merati. From a financial management perspective, we will be vigilant in utilizing our capital in a disciplined manner to ensure we remain able to advance our pipeline, invest in innovation, and effectively launch products to drive sustainable long-term growth. Research and development expenses for the second quarter of 2022 were $128.3 million compared to $134.6 million for the same period in 2021. The decrease is primarily due to adagraphs of manufacturing costs incurred in Q2 2021 ahead of our MDA, which is partially offset by an increase in salaries and other employee-related expense, including share-based compensation expense associated with an increase in headcount to support our growing pipelines. General and administrative expenses for the second quarter of 2022 were $54.2 million compared to $29.6 million for 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 second quarter of 2022 was $176.4 million, or $3.18 per share, basic and diluted, compared to a net loss of $166.4 million, or $3.23 per share, basic and diluted, for the same period in 2021. We've ended the second quarter with approximately $1.2 billion in cash, cash equivalents, and short-term investments, which gives us a cash runway into 2024. Please see our press release from earlier this afternoon for additional details about our second quarter 2022 financial results. And with that, David, I'll hand it back over to you.

Thank you, Maureen and Chuck, for your updates. As you have heard today, we've made considerable progress in the second quarter, advancing our clinical pipeline and advancing our commercial efforts to be fully launch ready in the U.S. by the end of the third quarter. I'll close our prepared remarks with a brief comment about the depth and breadth of the company and portfolio we are building. We have the products, capabilities, people, and capital needed to compete and succeed. Our pipeline spans numerous targets and tumor types and positions as well, for tremendous value creation and meaningful operational and commercial synergies. We expect target oncology to play an important role in the fight against cancer. We have generated compelling clinical data showing KRES inhibition has potential well beyond second line setting in non-small cell lung cancer. If that proves out, we will be able to help many people in need and create considerable value for the patients, physicians, and other stakeholders that have supported Mirati in that endeavor. It is a privilege to lead a company whose team never loses sight of why we come to work each day. And, Danielle, I'll turn it over to you. We're ready to take questions.

Thank you. I'd like to remind everyone that if you'd like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you'd like to withdraw your question, press the pound key. We do ask that you limit yourself to one question along with a related follow-up. And we'll take our first question from the line of Michael Smith with Guggenheim. Please go ahead. Your line is now open.

Hey, guys. Thanks for taking my questions. I had a question on your Keytruda combination study about aggressive where we've seen some very interesting early data at ASCO. And I think the median follow-up at the time was only two months. You know, there are some general questions about the safety profile of ASCO. PD-1 inhibitor combinations with more follow-up, and I guess now that it's been some more time since then, I was wondering, you know, where your confidence level is with respect to the tolerability profile as more time has passed now since the ASCO data presentation.

So, Michael, it's David, and I'll turn it over to Chuck. The data we presented at ASCO, yes, it was early data, and the median time was 2.1 months of time on the combination therapy, so we realized that at the time. We're continuing on with the trial, and we feel based on that trial as well as the earlier seven patients we have that were on drug for more than a year at that point at ASCO, that we're building a nice database here of patients being on drug for a good amount of time, and we'll give an update later this year. on where we are with the CRYSTAL 7 trial. We're encouraged by what we saw, and we're anxious to give an update later.

Yeah, I just reinforced that by saying that, you know, honestly, in our previous experience with combinations of targeted agents and IO, that oftentimes the adverse events occur in the early cycle, so that does give you some initial read, at least, on tolerability of the combination. Also, as David said, we did have the seven patients that were treated for over a year, which gives you an idea of the tolerability of the combination as well over time. And there were patients up to six months on treatment, even in the data. We presented the data updated for a K7, even though the median was two months. So, you know, so far we're feeling confident, and we're Looking forward to presenting more data later this year.

We'll take our next question from Tyler Van Buren with Cohen. Please go ahead. Your line is open.

Hey, guys. Good afternoon. Congrats on the progress, and thanks very much for taking the question. Regarding the ongoing aggressive regulatory review, I appreciate the update. Can you confirm that the final Phase II data, the CNS met data, and the tablet data have all been submitted and when they were submitted? And as a related follow-up, have label discussions started yet, or what are the outstanding items in the review?

So, Tyler, yes, we can confirm, you know, the brain meds data that was shared at ASCO, that information, all the clinical data has been shared with the agency. You know, that's important we do that so that data was shared with the agency. They have everything that we have regarding the tablet formulation as well. And that's why we've talked about we're preparing for an approval and our approval with a tablet formulation. Regarding anything else with the ongoing and productive conversation with the agency, I think it's premature to get into some of the details of the conversations. But as Chuck and I both said during the prepared remarks, it's constructive, it's active and ongoing with the agency as we move along in the MDA process. Good.

We'll take our next question from the line of Gina Wang with Barclays. Please go ahead. Your line is now open.

This is Rashida on for Gina. Thank you for taking our questions. Our first question was on the K12 2L Plus confirmatory trial for lung. If you remember correctly, the initial plan was to enroll 450 patients, and I think the powering assumptions disclosed at ASCO last year, the trial was sufficiently powered to detect the treatment effect of PFS and OS at an alpha of 0.05. But now that the enrollment has been decreased to 340 patients, can you remind us the rationale for decreasing the patient size and also comment on how this changes the powering assumptions. And then I have a follow-up, if I may.

So, yeah, the design of the trial was changed, which is the reason for the change in numbers. So that if the primary endpoint is now PFS, and so with PFS as the primary endpoint, then it was possible to decrease the overall patient number. That was the rationale, and partly that was based on the fact that we were allowing crossover since that significantly enhances enrollment, and when you do that, that could potentially compromise the overall survival. So that's the rationale for the design, but in terms of the patient numbers, we're still having a similar power to detect the difference, but that's going to be on PFS.

Okay, great, thank you so much. And the second question we had quickly was on the tablet versus capsule formulation. We know you previously noted improvement with the tablet formulation, but was wondering, can you comment on how much improvement you saw for the GI tox?

Yeah, we haven't gone into the specifics. We will when we have more experience and have more patients. I can say that the difference clinically and it was related from the ongoing trials by our investigators, is in the gastrointestinal, so things like the nausea, vomiting, those are the primary differences, but we don't have the exact quantitation at this time, but we will present it later when we have more data.

We'll take our next question from Jonathan Miller. With Evercore, please go ahead. Your line is now open.

Hi, guys. Thanks for taking the question. I'd love to ask, now that we've seen a little bit more data on the first-line combo and you're feeling confident about the tolerability profile, what are the remaining gating factors on beginning a potentially registrational study at this point? And I know you said you'd give some clarity on what that path would be later this year, but what are we waiting for to get that clarity at this point?

I think as the trial matures, you know, we have more patient numbers, longer time on the combination therapy. That's important. And then, importantly, we want to have a conversation with the FDA as we craft together a registration trial. So that's all going to take a little bit of time. And as soon as we're ready for that, you know, we'll come. We'll let you guys know. But we expect that to be by the end of this year is expected. trial advances, have a conversation with our scientific advisors, and go with the agency before rolling out that trial. But we're encouraged by it. Chuck, anything you'd like to add on?

Just that, of course, the efficacy in terms of response rate and early reads on PFS will be part of the evaluation and triggering of Phase 3 randomized studies. So that takes a little bit longer, as you know. The tolerability profile is really the first thing that you start to see, and then looking at the efficacy is what we're doing as we get closer later this year to getting ready to start a phase three program.

Yeah, this is Jamie. I think one thing I'd like to add is that the ADAP plus PEMBRO combination will be our first foot forward. Just to note that we have additional activities ongoing. We believe chemoimmunotherapy may be an important combination. In some first-line settings, we'll be evaluating that. Secondly, I think we have an increasing understanding of how KRESH signals and what some of the feedback pathways are and what might ultimately cause resistance. So a number of the targeted combination strategies are ongoing, starting in the second line lung cancer space. But should they look compelling there, there's an option to bring those up to earlier lines of therapy, either as doublets or even in combination with immunotherapy. So, you know, this is really a first foot forward with additional work ongoing.

We'll take our next question from Salveen Richter with Goldman Sachs. Please go ahead. Your line is now open.

Good afternoon. Thanks for taking the question. This is Andrea. I'm for Salveen. Maybe a question on the competitive landscape with Amgen having their first contributed combo data this weekend at World 1. Just curious what you'll be focused on to understand differentiation in your approaches, and then as a follow-up to that, can you just remind us on your thinking of sequential versus concurrent common tutorial approaches And mechanistically, is there a reason to believe that one approach might be more efficacious than the other?

So, yes, David. We're going to wait to see the data this weekend like everybody else. So, you know, we'll see what is released by Amgen and World Lung, and we'll take it from there. But I would say, you know, what we're looking for is, you know, for us to release that data. As Chuck just mentioned, you want to see, you know, immediate tolerability, tolerability over time. with any combination regimen. So, that's what we're looking for. Then, ultimately, you want efficacy in that. So, that's what we'd be looking for. I think relative to the other combinations and so on, I think Jamie just answered that a moment ago, other strategies we'd have. So, Chuck?

I think the only other thing I'd add is that we believe pretty strongly that the co-administration of Adagressive with Dumbrolizumab is going to be the most appealing to investigators, and we think will be the most successful way to combine the two. So that's what we want. That's why we're focusing on that approach. But we'll see what, as David said, what Amgen presents, and that will give us a better idea of where they're going as we explore additional approaches as well.

I'd say that's why we're really careful to say and deliver to say it's 400 milligrams twice a day of adegressive plus full-dose Pembroke concurrently. That is where we think the greatest opportunity for activity is for the patients.

We'll take our next question from Ben Burnett with Stifle. Please go ahead. Your line is now open.

Hey, thank you very much. I also wanted to ask a question about the competitive landscape. I guess, does the outcome of Amgen's Lumicraft confirmatory study have any impact in how you guys are thinking about the regulatory path for Adagrasa, whether that's a successful study or not?

For us, with our CRYSTAL-12 trial, when we look at our registration trial that was presented at ASCO cohort A, as well as our confirmatory trial, it's the same patient population. Remember, 98.3% of our patient population in the registration trial were patients that had followed the Keynote 189 regimen, if you will. And that's also our confirmatory trial. We look at that. We think of the pool analysis. We've also shared at ASCO. So we're pretty confident with our CRYSTAL 12 trial design and the outcomes. And, you know, the trial will finish enrollment next year, and we'll see what happens.

And I think obviously we'll be watching to see what their results are change our plan.

We'll take our next question from Andrew Behrens with SBB Securities. Please go ahead. Your line is now open.

Hi. Thanks for taking my questions. A couple on the ongoing 400 milligram BID monotherapy cohort from Crystal One. Can you give us an idea when that cohort started enrolling, how far along it is at this point? Are the patients getting tablets or capsules, and is this a cohort that the FDA specifically needs to run?

So the trial started earlier this year. Regarding that, to get into details, I don't think we'll get into the details. The trial was actively enrolling, and it is in the tablet formulation at this time. The patients run the 400 milligram twice a day of the tablet formulation. And the trial is up, and the FDA is, of course, aware of the trial. They are of all of our ongoing clinical trials in the second line, plus non-small cell lung cancer patient population, patients with a KRAS G12C mutation. So they're aware of that trial. We will not have data for that trial until next year.

We'll take our next question from the line of Evan Sigerman with BMO Capital Market. Please go ahead. Your line is open.

Hi, guys. Thank you so much for taking my question. You know, just thinking ahead to the launch, you know, now that you are second to market, I guess, you know, what feedback have you gotten from physicians and K-Wealth that you're interacting with as you build up the commercial force regarding differentiation and And then also, you know, you seem to be pretty optimistic that you'll be able to secure approval ahead of your December PDUFA. You know, what indications have you gotten from regulators that that may be the case? Thank you.

So I will start and then I'll jump in too. So we're preparing and we're preparing for a launch as early as the end of Q3. There's no guarantee that the FDA will approve us early. We want to certainly be prepared if we are fortunate enough to be approved early, so I just want to be clear on that part of the conversation. The feedback, especially at ASCO, and all of us were there, we spent a significant amount of time with the community-based oncologist, the investigators went over all the data that was shared at ASCO, and the enthusiasm level is very high regarding the totality of the clinical data that's been published for Atagrassive. In the second-line setting, The COVID-8 data was, you know, we reviewed that. The response rates, the overall survival data was very compelling to physicians. The CNS brain mets data for active and untreated, this is a real differentiator in the minds of the physicians. Anything they can do to treat those patients and, you know, even control brain mets is a good thing for patients. So the feedback was great. The feedback on the lifecycle management programs that we have in place, such as a combination regimen with PEMBRO in the frontline setting. colorectal cancer, the response rates across the board were very appealing, especially to the community-based oncologists where most of these patients are treated. So overall, the feedback's been good. It's given us confidence for us to go to the market, and we're ready to compete in the marketplace. Ben's got a few more points to add.

Sure. As you know, we've been out there for a while, so had a number of interactions with physicians. We've actually... But our field force today has been able to actually interact with 90% of the top 100 plants across the country and have just very positive feedback. And it really is around some of the differentiation. Obviously, the molecule has been designed for a 24-hour half-life, and that's enabled some of the response rates and up to 14 months of overall survival with our pooled data set. So coupled with the CNS data in the active and untreated CNS mets, we think we have a compelling story to bring to physicians. We're working very hard out there and also ensuring that we'll have unrestricted access. So we've also engaged on the payer front and ensured that we've actually been able to reach out to almost 90% of covered lives and had great deal of engagement with the payers to ensure that we can bring Adagressive and gain access to it in an affordable fashion as soon as possible and as soon as we're approved. So yeah, very positive today.

And I would... You know, to add on to that, you know, Ben has done an outstanding job of bringing on board a commercial organization. As I mentioned, we're north of 100 people out there, customer-facing right now with sales, market access, medical affairs, and so on. And all of us around the table have been doing this a long time, and it's a very impressive organization that we have that's out there interacting with customers. And they know lung cancer. They know targeted oncology. They know these physicians well. They know the clinics at the local level well. So the people, I would say, are going to be the real secret sauce in addition to the profile that we have of that aggressive.

We'll take our next question from the line of Igor Nikomovic with Citi. Please go ahead. Your line is now open.

Hi, thank you very much for taking the question. I'm curious regarding your thoughts on differentiating properties for adagracid at the MEG-10 level versus how it would behave differently from cetaracid from a tox perspective when combined with Tembro. Obviously, the molecules have a lot of structural overlap, but there are also some important differences when you compare the two. Thank you.

Hi, this is Jamie. So I think when you look at adagrassive and sotiracib, you know, there are a few key differences. Although they share part of the same core chemotype, the log D polar surface area and other characteristics are a bit different. And the other difference is really in the reactivity of the molecules when you look at KI and KNF. So one difference for adagrassive relative to sotiracib is its reactivity. You know, we've kind of tuned down the electrophilicity of adagracib, which results in decreased binding to other cysteine-containing proteins and reduced propensity for off-target effect. With regards to other physiochemical properties, one might notice some of the differences in pharmacokinetics. For example, sudracib has a high peak-to-trough ratio when administered once a day, and essentially it clears out of the system once a day, so the Cmax to Cmin is quite different. And aggressive only changes 7% within the interval. And that's really related to the high tissue distribution and, you know, kind of the physiochemical properties of the drug. And this reduced C-max to C-min ratio may also allow us to avoid certain off-targets that may be achieved at very high concentrations. So the drug really never hits a high C-max relative to the C-min. You know, what might be different in terms of the toxicity from a target perspective I think is an unknown. But at least those two kind of theoreticals on the physiochemical property side could be a key difference.

We'll take our next question from the line of Mike Oz with Morgan Stanley. Please go ahead. Your line is now open.

Yep. Hey, guys. Thanks for taking the question. Maybe a follow-up just on the adagracid formulation. So you're planning to launch with the tablet, but just curious how that might look in the label. Do you expect to have any tablet data in the label, like, for example, on safety, or is that something that might get adjusted at a later point in time?

Thanks. Mike, I think it's more early to be having that conversation about what would be in the label, the tablet formulation. So I think we'll punt on that one as we get a little bit closer to the PDUVA date.

We'll take our next question from the line of Jason Gerberry at Bank of America. Please go ahead. Your line is now open.

Hi. Good afternoon. Good evening, everyone. This is Keon for Jason. Thanks for taking the question. I'm curious, you know, when you said you'd share the, you know, other clinical data, including the brain mass data with the FDA, I'm curious in what context do you think the brain metastasis data might play a role in the NDA or the label. And, you know, in terms of, you know, what might ultimately make it to the label, if I recall correctly, you know, Rhesus 1.1 was sort of the standard for sort of all these intracranial oral arteries, including some of the oncology drugs. So I'm curious, you know, do you have sort of the data, the similar DNS data in Rhesus 1.1? How does that look compared to the data you presented previously at Haskell? Thank you.

So I'll start regarding the labeling. I go back to my previous reply to Mike. It's a little bit early to talk about what's going to be in the label or not. The brain metastasis data has been shared with the agency, so they have all of that information. We think in totality, when we look at the risk-benefit profile, it's certainly a benefit for the patients to have that information. you know, that impact on the brain mass patients. So that's a good thing. So they have it. We'll see what happens over time as we move forward, move closer to the approvability. I would say it's not just having it in a label. Ultimately, we'll get it in a label at some point in time for sure. So let's see what happens with the approvals. but also it's important for guidelines. So we'll work on NCCN guidelines, compendia listing, and so on. That's also very important, along with the publications of the data.

Yeah, this is Jamie. I had just two quick things to add. So just following up on David's comment on risk-benefit profile, this is part of a package that we've submitted that I think it should be recognized that with a drug on the market, a first-time presented drug Activity in CNS mets is unique to the class, so would be part of a favorable overall risk-benefit picture, especially in consideration that this would be the second drug to the market. I also caught a question in there about resist, 1.1 or intracranial resist. And just to say, we've looked at multiple ways of looking at the activity of antagrassive on brain metastases, and the IC resist is very similar to the mRNA outcome, so we wouldn't expect a difference be a methodology for determining response.

We'll take our next question from Maury Raycross with Jefferies. Please go ahead. Your line is now open.

Hi. Thanks for taking my question. You saw a similar overall response rate for patients in the registrational trial stratified by TPS score. Are you commenting on what the differences in duration of response or PFS were based on TPS? And how are you currently thinking about combo versus monotherapy for TPS flow patients?

Hi, this is Jamie. So, yes, I think you're referring to the data presented at ASCO in the journal where we've looked by the three TPS strata and response rate and would say that there's a minor difference in response rate. We've also looked at outcomes by other measures, PFSOS, duration of response, I would say we have not presented that data yet, but I wouldn't expect large differences there based on our experience thus far. We will be more replete in our characterization of outcomes by TPS strata in the future. With regard to how we might develop the drug in different settings, one thing we've talked about previously is the strong out of my medical need and the TPS less than one KRAS T12C population. I'm here to recognize that the outcomes on chemoimmunotherapy are fairly poor. Let's note in Keynote 189 that the overall response rate was 32% and the PFS and OS was a bit lower. We knew that lower bar is viewed distinctly by the regulatory agencies and that there's a chance that Adagracid would work as a monotherapy in that setting to demonstrate response rate and durability greater than what might be anticipated for chemoimmunotherapy. So we have a study ongoing in the TPS Lesson 1 as a model therapy. And then secondly, the STK11 subpopulation where we've seen signs of clinical activity. And again, poor outcomes on chemoimmunotherapy presented by Memorial Sloan Kettering, Dana Farber, MD Anderson, indicating the response rates are really in the low 20s there. And that's a place where we believe we can observe a higher response rate. And that study's ongoing, so we'll be talking about it when the data is mature. Just to say then, when we look across TPS strata, we're interested in all strata, and we believe we can devise a combination strategy. In addition to what I just mentioned for the monotherapy and the defined subset, the overall combination strategy would cover all the strata. And just to note here that slightly different study designs may be required for different strata. These are all part of our overall strategy for the program.

We'll take our next question from Jay Olson with Oppenheimer. Please go ahead. Your line is now open. Oh, hey, thank you for taking the question.

Is there any read-across or other observations you'll be looking for in the data for the combination of Lumicrafts with RevMed SHP2 at World Lung? And then as a related follow-up, you indicated that Atagracib will be administered concurrently in combination with Pembroke. So, can you comment on the pros and cons of parallel versus sequential administration in adegressive combinations such as PEMBRO or SHIP2 or any other combos? Thank you.

So, it's one of the things we're looking at. We've looked at preclinically as well in terms of the co-administration versus sequential. And so far, at least, there hasn't been any clear advantage for sequential approaches versus co-administration. I think You asked about SHIP2. We do have a study that's now unveiling, but it's at early stage, so we haven't reported the data of the same SHIP2 combination with Adagracib. So that data would come out sometime next year. But we are interested in the mechanism. We believe that the SHIP2 combination and certainly the preclinical data is supportive of doing that combination. So I think it's just a matter of seeing how that clinical data develops. And then in terms of the IO combinations, we think that the Pembrolizumab co-administration is the best way to go and is most consistent with standard of care and clinical practice so that that's the best approach. And we don't have any reason to think that sequential would be superior to that. So it just makes it more simple and beneficial. Any comment to that?

I would just say, yeah, the feedback has been unanimous around that. Our medical affairs team has held numerous advisory boards around that, and that's the way they treat today, and that's the way they'd like to treat in the future. So a concurrent PEMBRO is a good approach.

To have a chemo-sparing targeted agent would also be good. So having an Adegraxib plus PEMBRO concurrently, that's something that we'd be very keen on for patients with a KRAS G12C mutation.

And then maybe just to add one point from a scientific perspective. So concurrent administration with immunotherapy. You know, I think one thing we've been able to recognize through mechanistic studies, both in preclinical and clinical studies, is the impact of adagracin on antigen presentation. So the upregulation of MHC-dependent antigen presentation. The second is a fairly acute effect on some intratumoral cytokines that result in the uptake of T cells, expansion of T cells, reduction of immunosuppressive cells. And you can see there where having the KRAS inhibitor on board at a comparable time to the immunotherapy agent would be desirable. I think the same story with SHIP2. You know, SHIP2 functions at least in part by shifting KRAS into its inactive state, desirable to have those two drugs administered concurrently, and that's currently our focus for both of those areas.

This concludes today's question and answer session. David Meek, I'd like to turn the conference back over to you for any additional closing remarks.

Thank you, Danielle, and thank you, everybody, for joining us this afternoon. We appreciate your interest in Mirati, and we look forward to sharing additional updates with you in the very near future.

This concludes today's call. Thank you for your participation. You may now disconnect.