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Good afternoon, and welcome to the Mirati Therapeutics First Quarter 2022 Earnings Call. My name is Kevin, and I will be the operator for today's call. [Operator Instructions]
It is my pleasure to introduce Ryan Asay, Vice President of Corporate Affairs at Mirati. Ryan, you may begin the call.
Thank you, Kevin. Welcome, everyone, to this afternoon's call. Joining me on the call today from a couple of different locations are David Meek, Mirati's Chief Executive Officer; Dr. Chuck Baum, Mirati's President, Founder and Head of Research and Development; Dr. Jamie Christensen, Mirati's Chief Scientific Officer; and Vickie Reed, Mirati's Chief Accounting Officer. Ben Hickey, Mirati's Chief Commercial Officer, is 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. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31, 2022, and recent corporate updates. This press release is available on the Investors section of our website at mirati.com.
With that, Dave, I'll turn the call over to you.
Thank you, Ryan. Good afternoon, and thank you for joining us today. On this afternoon's call, I will provide initial remarks before turning to Chuck to share an update on our clinical development programs to Jamie to comment on our preclinical portfolio and Vickie to summarize our first quarter financial results. I will then provide a few concluding remarks before taking your questions.
2022 is a critical and transformational year for Mirati. And in the first quarter, we made significant progress on the ambitious goals we established for ourselves. We continue to execute well across our portfolio, and there continues to be significant enthusiasm across all areas of the company for the work we are doing.
The progress we are making and the life-changing impact we are having on patients living with cancer. We are pleased that our first new drug application is under review with the FDA. The FDA is reviewing our NDA for adagrasib as a treatment for patients with previously treated non-small cell lung cancer who harbor a KRAS G12C mutation for accelerated approval under the FDA's real-time oncology review pilot program. We remain confident in the approvability of the NDA and will be fully launch-ready in the third quarter.
Securing a U.S. approval and executing a commercial launch of adagrasib in the second-line non-small cell lung cancer setting is a key priority for the company, but it is also just the beginning of the full potential of where we believe this investigational product can help patients.
Without aggressive, we are advancing a broad development plan beyond previously treated non-small cell lung cancer is both a single agent and in combination with other therapies including in earlier lines of therapy and across a number of solid tumors. This includes the work we are doing in first-line non-small cell lung cancer in combination with pembrolizumab and in a broad range of other tumors such as colorectal and pancreatic cancers, where we have previously presented compelling early results.
In addition to adagrasib, we continue to advance and expand our broad target oncology pipeline. For sitravatinib, we recently completed enrollment in the Phase 3 SAPPHIRE registration trial and expect to reach a number of events needed to trigger an interim analysis for overall survival in the fourth quarter of 2022. If positive, sitravatinib would be a highly synergistic commercial opportunity with adagrasib.
As a reminder, in the U.S. and Europe, there are over 100,000 patients with second or third-line non-small cell lung cancer who derive prior clinical benefit following treatment with a checkpoint inhibitor and approximately 70,000 of these patients are of the non-squamous histology. MRTX1719, our NTA cooperative PRMT5 program is enrolling patients in an ongoing Phase 1/2 clinical trial with proof-of-concept clinical data expected next year.
Our earlier-stage target oncology pipeline, including MRTX1133, our KRAS G12 inhibitor and MRTX0902, our SOS1 inhibitor continue to advance toward investigational new drug applications in the second half of 2022. We have a tremendously productive in-house discovery capability that continues to discover and advance novel mechanisms and put us in a position to have as many as five unique yet synergistic programs in terms of the clinical execution and future commercial call points in clinical development in the next 12 months.
We continue to be in a strong financial position to execute on our strategy, which provides us with the flexibility to invest for success across our target oncology pipeline and in preparation for a successful and adagrasib launch pending potential FDA approval later this year. As we grow and advance our pipeline, we are continuing to strengthen our capabilities to better enable us to achieve our objectives.
With that, I'll turn the call over to Chuck.
Thank you, David. I'll begin with adagrasib update. We continue to work with the FDA as they review our new drug application based on our real-time oncology review and breakthrough therapy designation. We continue to work closely with the FDA to complete the review as quickly as possible. We are pleased with how the review is progressing and remain confident in an accelerated approval in the United States this year.
Outside the United States, we are making progress and expect to complete the submission and validation of our marketing authorization application to the European Medicines Agency in the second quarter of 2022.
In 2022, we will report a number of significant clinical updates for the adagrasib program, beginning with ASCO. We are pleased to have two abstracts accepted by ASCO for oral presentation. The first presentation is for the results of the registration-enabling Phase 2 cohort of the CRYSTAL I study evaluating adagrasib in patients with previously treated non-small cell lung cancer whose tumors harbor the KRAS G12D mutation.
In addition, the presentation will include data across several important patient subgroups based on PD-L1 status, genomically defined patient populations, including co-occurring mutations like STK11 as well as patients with previously treated stable central nervous system, or CNS, metastases.
The second presentation will highlight the activity of adagrasib in patients with G12C mutated non-small cell lung cancer tumors with untreated CNS metastases. This presentation will be the first clinical data with a KRAS inhibitor showing activity in patients with active and untreated CNS metastasis. CNS activity is an important attribute because up to approximately 40% of KRAS G12C patients with non-small cell lung cancer present with CNS metastases and the frequency of these mutations increases over time with the current standard of care.
Together, these presentations reinforce adagrasib's unique molecular profile and underscore our commitment to advancing adagrasib full development program as a single agent and in combination, where we are pursuing a broad development approach including combinations with pembrolizumab, cetuximab, SHP2, SOS1, CDK4/6 and a MEK/RAF dual pathway inhibitor. We are actively enrolling patients worldwide in adagrasib clinical studies that are generating additional data in patients with a wide range of cancers.
Our Phase 3 confirmatory study in previously treated non-small cell lung cancer patients with a KRAS G12C mutation known as CRYSTAL 12 in which patients are randomized to adagrasib or docetaxel continues to enroll well worldwide. In first-line non-small cell lung cancer, we continue to explore adagrasib monotherapy in certain underserved subpopulations, including patients harboring KRAS G12C and STK11 COMI patients as well as KRAS G12C mutated patients with TPS scores of less than 1%. We expect to provide additional clarity on a potential regulatory pathway for accelerated approval in these subpopulations this year as well as sharing initial data from these cohorts in 2023.
Also in first-line non-small cell lung cancer patients, we are aggressively exploring adagrasib in combination trials with a focus on the combination with pembrolizumab. This adagrasib plus pembrolizumab combination, which is using 400-milligram BID dose of adagrasib with full dose pembrolizumab, in the Phase 2K Cristal VII study is enrolling well with strong interest from both patients and physicians. We plan to share an update from this combination study this year, which will include an analysis of patients stratified by TPS score.
Based on the results from Cristal VII, we plan to initiate a Phase 3 trial evaluating the combination of adagrasib and pembrolizumab in first-line non-small cell lung cancer patients later this year. Beyond lung cancer, we are advancing enrollment in patients with colorectal cancer, both in late line and in the second-line settings. The ongoing Phase 3 registration-enabling study in combination with cetuximab in second-line colorectal cancer continues to enroll well and potentially provides us with an opportunity to be the first to market in this patient population.
We continue to enroll patients with G12C mutations in other solid tumors including pancreatic, biliary cancer, gastrointestinal and others, and will continue to explore potential accelerated regulatory approval pathways in these patients subpopulations. We expect to provide additional clarity on the potential pathway for accelerated approval of adagrasib in late-line CRC as well as sharing next steps in other solid tumors later this year.
Now to move on to sitravatinib. As David mentioned, we recently completed enrollment in the Phase 3 SAPPHIRE trial, which is being conducted in patients with second- or third-line non-small cell lung cancer who have derived prior clinical benefit following treatment with a checkpoint inhibitor.
We are 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, the 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 next year.
For MRTX-1719, our MTA cooperative PRMT5 program, we are enrolling a Phase 1 dose escalation and dose expansion study in patients whose tumors harbor MTAP deletion, which make up to 10% of solid tumor patients. We will explore MRTX1719 as a single agent and through rational accommodation strategies identified in nonclinical translational studies across several tumor types, including mesothelioma, pancreatic, lung, malignant peripheral nerve sheath tumor and a basket cohort of other MTAP-deleted tumor types. We expect to share the initial clinical data for this program in 2023 after we have selected a dose and generated sufficient data to demonstrate clinical proof of concept.
And with that, let me hand it off to Jamie to discuss our preclinical programs.
Thanks, Chuck. I'll briefly touch on our pipeline of preclinical programs. including our SOS1 inhibitor MRTX-0902, our selective KRAS G12D inhibitor, MRTX1133 and our next-generation Spectrum selective platform to target additional KRAS mutations. We recently presented preclinical data for 0902 and 1133 at the American Association for Cancer Research Annual Meeting, also known as AACR. 0902 is a selective SOS1 inhibitor which shifts KRAS into its inactivated state and enhances inactivation of KRAS by adagrasib. This combination is anticipated to address feedback reactivation of KRAS and to address intrinsic and acquired resistance to KRAS inhibitors.
At AACR, we disclosed the chemical structure and profile of 0902 along with its broad antitumor activity in KRAS G12C preclinical models in combination with adagrasib. 0902 is also anticipated to complement additional agents in the Mirati pipeline and exert an impact on KRAS mutated cancers, irrespective of the KRAS mutation type. 0902 also has the potential to target additional mutations within the MAP kinase pathway. These include the opportunities combined with other MAP kinase pathway inhibitors. This agent is currently in IND-enabling studies, and we are on track to complete the IND filing in 2022.
1133 is a potent and selective noncovalent KRAS G12D inhibitor that binds to switch to pocket with high affinity in either the active or inactive state of KRAS G12D. At AACR, we shared additional preclinical data, reinforcing the broad antitumor activity of 1133 and putting market regression in the majority of pancreatic cancer models.
This presentation also provided insight towards combinatorial strategies to augment the activity of 1133. We continue to pursue IND track development of 1133 with focus on long-acting injectable formulation strategies, including Stealth Liposomal strategies and continue to focus on filing the IND in 2022. Additionally, we continue to pursue targeting of additional meat and variance of KRAS to our spectrum-selective KRAS inhibitor program.
This is a potential platform approach, which could yield multiple development candidates, targeting various KRAS mutations with different mutation selectivity profiles and ratios of potency for targeting KRAS wild type versus these selected mutations. We have a goal of identifying potential development candidates for this program in 2022.
With that, I will turn it over to Vickie.
Thank you, Jamie. We ended the first quarter with approximately $1.3 billion in cash, cash equivalents and short-term investments. Research and development expenses for the first quarter of 2022 were $131 million compared to $104.1 million for the same period in 2021. The increase in research and development expenses was primarily due to costs associated with the ongoing advancement of our adagrasib and sitravatinib clinical programs, preclinical and early discovery activities, employee-related expenses, including an increase in salaries and share-based compensation as well as professional services, facilities and IT expense.
General and administrative expenses for the first quarter of 2022 were $54 million compared to $28.4 million for the same period in '21. The increase is due to growth in employee-related expenses, including salaries and share-based compensation and costs related to the growth of our business as we continue to prepare for commercialization.
Net loss for the first quarter of 2022 was $188.4 million or $3.40 per share basic and diluted compared to a net loss of $135.7 million or $2.67 per share basic and diluted for the same period in 2021. Please see our press release sent earlier this afternoon for additional details about our first quarter '22 financial results.
David, I'll hand back over to you.
Thank you, Vickie. As you can hear from the team, there is a lot happening in Mirati. We're excited about the progress we've made in about both the short and long-term potential of the opportunity to lie before us. We have the products capabilities, people and capital, we need to not only execute in the short term but also to drive long-term sustainable growth.
Our targeted oncology pipeline is broad, spanning multiple targets and tumors and gives us a strong platform to support tremendous value creation and significant operational and commercial synergies across the portfolio.
As Vickie indicated, we have the financial resources to enable us to continue to appropriately and prudently invest in the advancement and expansion of our clinical and preclinical portfolio and also in preparing to become a commercial stage company. We have continued to advance our commercial preparations and execute on our commercial strategy as we prepare for a successful adagrasib launch subject to FDA approval.
Our objective to launch and further develop a market-leading KRAS G12C inhibitor, optimizing the full and tremendous potential of this important product remains the critical priority while we also invest to drive sustainable growth with the other exciting and innovative target oncology assets in our portfolio. I continue to be grateful and impressed by the talented, committed and passionate team we have at Mirati, asking a lot at every member of our team, they continue to not only meet but exceed expectations as we strive to improve the lives of patients.
With that, we're ready to take questions.
[Operator Instructions] And the first question comes from Salveen Richter of Goldman Sachs.
This is Tommy on for Salveen. And our question is about how - Andrew has talked about how many KRAS patients are being diagnosed with that the KRAS status isn't necessarily showing up in the patient files like as they progress to later in line. So what steps or actions can you take to facilitate patient identification and ensure that patients are being treated with a KRAS inhibitor. Thanks so much.
Great question, Tommy. Thanks, Bob. We've got Dan here, our Chief Commercial Officer. So he's been looking at as closely with his team. So I'll turn it over to Dan.
Yes. Thanks for the question. I would say, first of all, it is a real issue in regards to the patient identification and a number of these lung cancer patients are being treated in the community. So we've spent a lot of time, first of all, ensuring that our study actually included lung cancer patients from the community as one.
And then secondarily ensuring that as we get commercially ready, we're spending a lot of time, particularly with community networks and understand that patients flow other recording patients within the EMR had a flagging that patient as a G12C patient. And we really believe that the market will mature over time. And over time, as they become tested in frontline, more of those patients will become available in second line. But I would say the market is still immature and it's taking some time to fully present itself.
Our next question comes from Tyler Van Buren of Cowen.
Congrats on the progress. And thanks for taking the questions. I want to ask about the Phase 2 presentation on Friday at ASCO. Should the bar for median duration of response be the prior sotorasib world lung dataset or the more recent AACR data set - and do you think adagrasib could improve upon it? Or how should we think about the potential to treat CNS mets and its ability to impact DOR and PFS when comparing to sitravatinib.
Yes, Tyler, first of all, regarding the data that's going to be released at ASCO, I think it's best that we reserve that conversation until we see the data. We're certainly excited to share all the data were being - that's going to be presented at ASCO. So I think we can have that conversation on ASCO.
Our next question comes from Ben Burnett of Stifel.
This is Neil Carnahan on for Ben. On the pembrolizumab combo, are you now able to characterize the safety profile for the 600-milligram BID dose - and then could you also say if you evaluated any doses, any adagrasib doses below the 400-milligram BID that you're pulling forward? Thank you.
Sure. Yes, we'll have Chuck answer that question for the team.
Okay. So yes, we're going to have - in the second half of the year, we were planning to present the data fully for those patients with an emphasis on the 400 milligrams because that's our - as we've indicated, that's our go-forward dose. But the doses that we've looked at were - the study started with 600 milligrams in full dose, pembrolizumab. And then we - as we had talked about previously, that the tolerability there was not as good. we switched to the 400-milligram BID and that's the patient population we're enrolling now.
So we'll have a substantial number of patients treated at 400 milligrams BID in full dose pembro in the second half of this year. And that will put us in a position to make the go/no-go decision on the Phase 3, which we intend to make by the end of the year. So, so far, things are looking good at the 400 milligrams. So we talked about 7 of those patients last year. and we continue to follow those as well as all the new patients, and we're pleased with the results thus far. But as I said, in the second half, we'll present the data in a more fulsome way.
Our next question comes from Gena Wang from Barclays.
I just follow up regarding also the pembro combo first-line data, safety data. So Chuck, based on the data you've seen so far, do you think the 400-milligram BID plus Pembro dosing is the path forward? Or do you think the live to do you agree that live tox is a drug class effect? Or you think it's a specific unique to specific compound. And then another question is regarding the ASCO update for CRYSTAL 1 full data do you expect to show definitive differentiation versus Lumacrost, i.e., one to two months better PFS or DOR.
So for the first question, we are going forward with the 400-milligram BID dose. We're happy with that dose at this time. We're accruing a lot of patients and we'll have patients at all the entire GPS range, which will give us a good sense of what the next step should be and what the design of the Phase 3 trial should be. So all of that continues as planned and is growing quite well. So we're encouraged by that.
In terms of liver toxicity, I think that, that can be sort of compound specific, not necessarily class specific. But part of the challenge is that we really haven't seen the full data from competitors. So it's - we've heard about it, but we haven't really seen it. So I'm hoping that as we present more data and they present more data this year, that we'll have more clarity around what the nature of those results is. But I would say at this point, we're not - for our program that is not a high level of concern in terms of liver tox.
Yes. Mike, just to add a few comments to Chuck here. I think, first of all, from the new chemical entity perspective that adagrasib and there asset are distinct small molecules with different physiochemical properties, different tissue penetration, different peak to trough ratios at steady state with regard to the PK properties.
So although they share the mechanism being able to irreversibly modifying KRAS G12C, they are distinct small molecules. I think it's also fair to note that in the field to date, looking at TKIs, for example, the split kinase or [indiscernible] GTK, when you kind of look at their ability to combine with immune checkpoint inhibitors, for whatever reason, these molecules have the same set of shared targets - but pembrolizumab and sunitinib, for example, were deemed to be noncombinable as was rest with immune checkpoint inhibitors and then contrast our own sitravatinib, other drugs like tavazetabbot quite combinable and effective in combination.
So there's, I think, a couple of examples historically of different drugs within a target class that differentiate with regard to their tolerability. I think the last point to make is just what we've seen so far with regard to liver function and anything that might be deemed as a penotoxicity.
So as a monotherapy, we have seen Grade 1 and Grade 2 liver function test elevations. We've seen a small fraction of those being Grade 3. We have not seen patients discontinue due to liver function test abnormalities or hepatotoxicity. We've seen no highs law cases with respect to adagrasib to seek monotherapy.
In combination, as Chuck mentioned, we're fairly happy with what we've seen so path 400 mg BID dose level. But I think 1 thing to add to that is that we do not see a signal with respect to 1 underlying toxicity, including appetite toxicity to be dose-limiting with respect to dose intensity or patient discontinuation. So I think all of our signals to date look fairly positive with respect to the pembrolizumab combination.
Jonathan Miller from Evercore.
I guess following up on that PD-1 combo question. Obviously, just looking forward to data later this year. But I also want to ask how rapidly you could move to larger Phase 3s. It does seem like you're getting a little bit more comfortable with the strategy here and the safety profile in combination here. So what are the gating factors at this point on pivotal trial starts and what should we expect that to happen?
Yes. Chuck, I was going to say move start and then jump over to you. Yes, folks, just a couple of implications as a team. I think we're getting – we're advancing the program we haven't discussed – what advancing those points are. I think as the year evolves, as we share the data, we'll certainly discuss with some of those gains are. But as we did say, we're preparing for a Phase 3 start later this year.
Next question from Evan Seigerman of BMO Capital Markets.
Looking ahead to the Ataata, can you just talk about - I know you discussed the van brain penetrability of the drug. But what are your thoughts on whether or not the drug actually tick around in the Reneuron reports where we're seeing or I've heard theoretically that the drug may be excelled and not actually kind of giving the target engagement. You want - any thoughts on that would be so helpful. And any color on the enrollment of the Phase 3 confirmatory.
Sure. Yes, I would say with regard to the CNS penetrants of hetograsib, we've looked at this both preclinically and clinically. And with satiategrassiv actually has a unique at enter the CNS relative to other drugs. Point number 1 is it has favorable physiochemical properties with regard to tissue distribution appropriate log, lipophilicity and polar surface area to get into tissue. And that is, I think, the first principle of any drug that would have brain penetrants.
The second is that you bought it up related to [indiscernible] it's true that adagrasib is a PGP people like a protein or eFlex substrate. But what's unique is that at concentrations that we achieved clinically, we also are a PGP inhibitor, and thus, the drug actually inhibits its own ePlex out of the CNS. And when we've looked preclinically at dose levels that are associated with achieving the clinical dose levels, let's say, transaction of mouse to human, we see a KPU or a partition coefficient and CNS tissue relative to the free fraction plasma that is between 0.4 and 1.0. So meaning we get in extensively into the CNS at the dose levels we achieved clinically - when we've measured that in patients with the 600 mg BID dose level, we see a KPU of 0.47, again, meaning we're getting extensive tissue distribution.
Osimertinib is an example of a drug that has CNS activity. It's measured KPU is generally lower than adagrasib, around 0.3 to 0.4 depending on which study is cited. Alectinib and [indiscernible] are additional examples of ALK inhibitors with CNS penetrants and would just say that their intercranial response rates and their intracranial response rates are comparable our evidence of seeing uptake into the CSF are consistent with what we've seen there. So I think that's point one.
Point two, you mentioned the ebb and flow and elite of the just to remind you here that our drug has about a 24-hour half-life of administering BID. The effective half-life at study state is around 60 hours in the pizza trough variation of adagrasib at steady state is only around 10% to 20%. And we never dropped below concentrations that are associated with being able to inhibit the target. We believe that that's relevant both for peripheral disease as well as well as the metastases. So, so far, so good there. And of course, we'll be talking about the actual intracranial response here upcoming at ASCO.
The second question, I believe, was the pivotal study, and I think David is going to take.
So quickly regarding our Phase 3 confirmatory, that's the CRYSTAL 12 study. We're pleased with the enrollment. As you know, we're rolling in the U.S. and Europe. Also said, our partner in China will also help drive enrollment. So we're pleased with the rate of enrollment we're seeing at this time, and the study should be fully enrolled in the first half of 2023.
The next question comes from Michael Schmidt of Guggenheim.
This is Paul on for Michael. Just another quick 1 on the upcoming adagrasib data at ASCO in patients with brain met sort of based on your conversations with physicians, is there a CNS response rate that you expect positions to find clinically meaningful? And then secondly, just any color on how many patients we could see in the adagrasib plus pembro combo data later this year.
So let's talk first about CNS, what the physicians expect. We think it's in that 20% to 25% range. the activity would be well accepted. That's the research and the conversations we've had with physicians in the community as well as academic centers.
Yes. I would say we'll continue to build on the program. I think that, that is what we anticipate with respect to monotherapy. We know a lot of our combination strategy evolves around combining adagrasib with additional targeted therapies the ability to enhance response rate in combination should apply to our drug being able to get into the CNS as well. So I would expect our ability to augment the internal response rate as we advance in the program.
The next question comes from Michael Ulz of Morgan Stanley.
Maybe just another 1 on some of the ASCO updates we'll get in a month or so here. You mentioned some subgroup analysis in the K1 study and in particular, based on PD-1 status. Can you maybe clarify that - and is it specifically in TPS less than 1 patient?
Sure. We will be presenting data at ASCO on Cohort A that goes into molecular subtypes. So that includes both PD-L1 status and would say that this data set that we will present will have a significant number of patients to be able to draw conclusions about whether a different TPS strata categorically or continuously related to response to adagrasib.
Secondly, we'll be looking by mutation subtype. That includes things we've talked about before like SDK, but also common mutations like TP53 and CDKN2A. So we will be able to provide perspective on all those. I think as you also know, we are pursuing strategies in the first-line non-small cell lung cancer related to molecular subtype less than, for example, an STK11 for example.
Just to remind you all of that, those are 2 particular subtypes when they're seen with KRAS mutation. They are particularly nonresponsive to chemoimmunotherapy thus creating an opportunity for potential accelerated path development in that setting. And I would just say, in general, that we continue to be pleased by what we see in those particular subpopulations and are continuing the enrollment of those first-line studies. But bottom line is we will be presenting that data as part of the ASCO presentation.
Got you. That's helpful. Maybe just a follow-up there. What do you think - what's the bar for adagrasib monotherapy based on TPS stratification, less than 1 and greater than 1.
I would just say growing what's out there. We do not anticipate that TPS less than 1 would have a - TPS score would have a major impact on the response to KRAS inhibitors. But we do know, based on the subset analysis of KEYNOTE-189, work out of major medical institutions or otherwise that those same patients have a poor response to chemo immunotherapy.
Notably here with PD-L1 lesson 1, if you look at the KEYNOTE-189 subset analysis, the response rate was around 30% for that particular subset. If you look at the STK11, again, either in KEYNOTE-189 or at major medical institutions, the response rate is 25%. Note here that these are treatment-naïve patients.
So they have never seen chemoimmunotherapy, and this is their response to chemoimmunotherapy. So in a way, that creates a bar for us to shoot for. And if our data continues to hold up for KRAS inhibitor or adagrasib even as a monotherapy, reason to believe that we should be able to exceed the response rates seen in those unmet medical need populations.
We can go to Yigal Nochomovitz of Citi.
This is Carly on for Yigal. Just to follow up on some of the prior questions on the combo with pembro. Can you share any preliminary thoughts on how you're thinking of designing a potential Phase 3. I know it will depend on the data from CRYSTAL 7 later this year, but any early thoughts on the different options on the table would be helpful. And then you did notice on clinicaltrials.gov, the adagrasib combo study with boring [indiscernible] ALS1 inhibitor stop recruiting. So if you could give any more color on the reason for that, that would be helpful as well.
Yes. Sure. I'll start, and I'll turn it over to Chuck regarding the combination study, CRYSTAL 7. And then what could evolve into a - will evolve into a Phase 3 trial. Just a reminder, we'll share more data in the second half of this year. but we'll give you maybe some really high level at this point, where we're thinking of for a registration trial, but it's preliminary, Chuck?
Yes. Yes. It's still early, obviously, but I think we might have had a conversation previously where we're thinking that the optimal opportunity for us initially would be in those patients with TPS score of less than 50% versus the 189 regimen. So that's the thoughts right now. It's not solidified yet, but we're working on that. We're also - we're not ignoring the greater than 50% population. We continue to study that, and we'll have more data there. but that would be a larger and longer trial. So in terms of sort of first priority, doing the trial that's more doable and could get us to a first-line approval faster, we think would be in the less than 50% TPS score.
And then you mentioned the BI study. Yes, we did discontinue, as you probably also noted, we have a [indiscernible] 1 of our own that's going to enter the clinic in the second half of this year. And we think that it has potentially favorable properties. And so that's where we're going to focus our efforts going forward.
I think there's one thing to add to Chuck's comment as well is the basis for stopping that study was not related to any adagrasib related toxicities or adverse events. And as Chuck mentioned, we remain quite enthusiastic about our own program, which we hope to start enrolling patients by the end of this year after we file the IND.
The next question comes from Andrew Berens of SVB Securities.
I assume you had some additional dialogue with FDA and since there's still some concern about the reason you didn't get a priority review despite having breakthrough designation. I was wondering if you can give us some more color on what you think happened? I know you may be reluctant, but I do think it would help investors feel more comfortable with the outcome of the review process since it does seem to be a lingering concern that I continue to get questions about.
So I'll as we - Chuck and I both mentioned in our opening comments, we remain very confident in the approvability of the new drug application of adagrasib. We're working with the FDA, leveraging our breakthrough therapy designation in the real-time oncology review pilot program we have. There's a good active dialogue productive, and we think it's progressing well. And while we do have a standard review, there's many examples where drugs have been approved before the PDUFA date and we're going to be fully launch-ready in Q3. So that's where we are with the NDA review. It's progressing, and we remain optimistic.
The next question comes from Jay Olson of Oppenheimer.
I appreciate it. Can you talk about what is required for a tumor agnostic path forward for adagrasib and non-lung and noncolorectal tumor types? And then maybe just a big picture question. What are some of the lessons learned from adagrasib that you can apply to the development of 1133 and do you plan to have the first FDA-approved KRAS G12D inhibitor.
Sure, we'll start with Jamie on that.
Sure. Yes. I mean regarding the adagrasib [indiscernible], I think you are familiar with what we've shown in pancreatic cancers and then also other GI solid tumors, and we've seen what I would call as response rates that were compelling with early signs of the type of durability that would be associated with that tumor-agnostic approval. We know the regulatory precedent here with immune checkpoint inhibitors looking at patients with MSI-high. We also know of this with respect to NTRK inhibitors as well as BRAF inhibitors.
So we do believe that there's a path there, both based on the activity that we've seen with the drug so far as well as having a regulatory precedent due to the infrequency of the KRS C2C mutation and tumors other than lung and colon. We wouldn't anticipate that it would take a large number of patients to get a tumor-agnostic approval, but we do anticipate that it would be valuable for us to have as many different tumor types enrolled on the trial so that we can show the diversity of tumors that would respond to the drug. So I think we remain optimistic that, that's going to be a path for us.
Regarding the G12D read-through from G12C. So we have been evaluating our G12D inhibitor in models of colon and pancreatic cancer. And the read-through from adagrasib is that we have been able to see activity, particularly in combination with cetuximab in patients with third line plus heavily pretreated colon cancer and the response rates and durability hold up with response rates over 40%. And then we will be talking about the duration of response and activity in the colon cancer setting later this year, but just suffice to say that we are encouraged by what we see there so far.
On the pancreatic side, the response rate of around 50%, but the durability that we've seen so far seems supportive of monotherapy in KRAS being a driver in the pancreatic cancer setting. What we've seen preclinically with the 1133 compound is very consistent with that. With a monotherapy 1133, we see about a 20% response rate in the colon cancer models.
When we combine with cetuximab, that response rate starts to go up in the models to around 40% to 50%, just like what we're seeing clinically with G12C. And then regarding pancreatic cancer models, we've seen 8 out of 11 responses. So response rates over 50%, probably consistent with what we've seen with an adagrasib model therapy.
We also know that combining with EGFR inhibitors or monoclonal antibodies in the pancreatic setting seems to be a promising approach based on our preclinical data. So we do believe that if we are able to advance 1133 into the clinic, at a dose level that really covers the target that we would be confident that KRAS is a driver and that we can come up with therapeutic strategies to advance the molecule forward. I'm blanking on your last question.
I think you pretty much hit it. I would add just late more is the lessons learned from adagrasib into 1133 was very comforting for us. The team that transitioned the program from discovery through development. That team is here in Mirati and certainly, there's lessons learned from the adagrasib program that we can apply to the G12D program. So we think that will help some of the synergies we talked about earlier. There are significant synergies we have in the development organization as well as the portfolio expands the tumor types and academic center study sites and so on. So we're excited about that.
Yes. I guess just to hit on your last question, competitive state. So probably can't answer that question directly on whether we would be the first Growth1 inhibitor approved. We shouldn't hope and aspire to that. But just to say, we've been following the patent literature and publications. And we haven't really seen much out there that would indicate that at the entry of another Growth12D inhibitor into the clinic is imminent. And of course, we'll continue to keep a pulse on that as we advance our program.
The next question comes from Silvan Tuerkcan of JMP Securities.
Congrats on the progress in the quarter. In my opinion, I seem that ACR were obviously much earlier stage KRAS [indiscernible] inhibitors and also the potential emergence of Pan KRAS inhibitors. Could you just tell us about how they would compare or contrast to direct KRAS neighbors such as yours that are already in the clinic.
Sure. I think first to note that we remain interested in that space as well. We have our own spectrum-selective KRAS inhibitor program. We've learned in that program as well as our G12D program that there are legitimate ways to target the active state.
So we continue to look at that with respect to our programs. With regard to the kind of read-through for G12C. So G12C is among the most rapidly cycling mutations for KRAS, meaning that it's shifts significantly between its GDP and GDP balance state. And as you know, adagrasib does bind in the inactive confirmation of KRAS G12C.
One advantage we think adagrasib has with that respect is that although it binds irreversibly in an inactive state, we remain above target plasma concentrations for the full dose interval. So even though active state inhibitors may be able to buy it effectively to the active state due to the kinetics by which that G12C cycles, we still believe that we are at least with G12C able to achieve the level of inhibition regardless of whether the active state or an inactive state is present.
Also to note that with regard to targeting the active state. There are other mutations like G12 or some of the Q61 mutations that actually predominate them and the active state. And to go after those mutations it's probably is desirable to target the active state. And we do believe that, that is something we're able to accomplish with our pipeline. And finally, you kind of asked about competition there, so for the pan-KRAS setting.
Really, we're aware of right now is kind of the Boehringer-Ingelheim and Revolution Medicines program. And we know that Bongerheim has talked a lot about protect based strategies and that Rev Med has talked a lot about strategies to kind of engage the engage the cyclophilin machinery. What we're looking at is to stick from that. So bottom line is we think we can target the active state with a differentiated mechanism of action.
Next question comes from Maury Raycroft of Jefferies.
I was wondering for the docetaxel arm in your adagrasib Phase 3, what kind of PFS are you expecting in these patients? And is there anything to suggest that KRAS G12C patients could do better or worse than the general patient population on docetaxel. And then lastly, can you remind what proportion of patients in the confirmatory are coming from China?
Sure. I can take that. So we've done a meta-analysis or a metal like analysis of all the published data for docetaxel controlled studies where KRAS was looked at as a subset. And generally, our conclusions from those studies is that the falls around 2.8 months if you look at the conglomerate.
So a little bit worse than what you would expect from the overall population. When we look at overall survival generally, the numbers are landing at around 8% based again on historical data. So again, the data suggests a little bit less than the overall population. I think 1 caveat to note is that immunotherapy and chemo immunotherapy are present and those studies are older. But the preponderance of the evidence suggests that KRAS is a poor player and a KRAS-mutated subpopulation.
Regarding the China question, I think David is going to take that.
Regarding the CRYSTAL 12 trial iPERVATORE trial. The trial is currently enrolling in the U.S. and Europe. China has not yet come online. It will come on online later this year. So by the study finishing in the first half of next year, China will be a relatively small amount of patients that have contributed to the total enrollment, primarily Europe and U.S.
The next question comes from Jason Gerberry of Bank of America.
This is [indiscernible] on for Jason. Thanks for taking our questions. Two from me, one on monotherapy and one on SHP2 combination. So on monotherapy, I'm curious if you explore the 400-milligram BID dose with monotherapy and cyclin lung patients, specifically looking at sort of how the response rate and safety profile compared to the 600 milligram BID. It looks like from the combination with pembro, you're getting better therapeutic window with the PD with the 400 milligram combined with PD1. So, and then secondarily, on the same question based on your understanding of project optimists, do you think the body of work of an adagrasib monotherapy [indiscernible] requirement.
And then on shift to combination, I think there was initially quite a bit of excitement because of the mechanistic rationale and also for the preliminary clinical data a limited number of patients, but we haven't quite seen a lot of data since then, and there is some timeline push from players across the industry. So - but lately, Novartis indicated they are starting a Phase 3 with a ship to combination. Obviously, you cannot speak to what other companies rational but from Mirati perspective, where are you at right now regarding the opportunity with the SHP2 combination. Thank you.
So yes, I would say a few things. Number 1 is we're highly confident in the approvability of the 600-milligram BID dose as part of our submission package. And you had mentioned project Optimis. So the agency does continue to reinforce the importance of project optimists.
And as part of the collaboration with the agency, we're looking at the 400-milligram BID dose as a monotherapy. We do anticipate that this is kind of a post-approval commitment, and we're going to continue to work with the agency on that front. And then noting your question about 400 mg BID.
So several things to note. One is that it covers our target plasma concentration of 1.5 micrograms per ml. And that is a concentration derived both from preclinical models, successing we remain above that target for the full dose interval that we are near completely inhibiting KRAS and the 400 dose appears to accomplish that. That it is also derived from our ability to look at PK/PD and repeat biopsies in the clinic.
Again, at the 600-milligram dose, I think we have data suggesting that we are near completely inhibiting KRAS and modifying KRAS as a target. We, of course, continue to look at our own data clinically and we're confident that the 400 mg dose level is covering the target based on exposure response analysis.
In short, that is looking at the concentrations that would be anticipated at the 400 mg dose level and looking at the response rates and noting that those response rates are fairly consistent across the various kind of quartiles of exposure observed. So we're confident in the 400 dose in general, especially in combination as we see increased dose intensity in combination with pembrolizumab.
And then I think your last question was related to ship 2. We do have plans to continue and our exploration of adagrasib in combination with SHP2 inhibitors as part of our overall development program.
Ladies and gentlemen, that concludes the question-answer session for today's conference. I would now like to hand over to David Mike for any additional or closing remarks.
Well, thanks for joining us this afternoon. In closing, I'll reinforce the relentless focus we have on Mirati and translating novel science in innovative therapies that bring Ulta patients. We're excited about the path we're blazing and we're confident in our ability to successfully execute. And we look forward to speaking with many of you with sharing additional updates in the coming weeks and months and see you at ASCO. Take care, everybody.
That concludes today's call. You may now disconnect.