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Intrinsic Value is all-important and is the only logical way to evaluate the relative attractiveness of investments and businesses.
Good today, ladies and gentlemen, and welcome to the Revolution Medicines Second Quarter Fiscal 2021 Financial Results Conference Call and Webcast. At this time, all participants are in a listen-only mode. Following management's prepared remarks we will have a question-and-answer session. [Operator Instructions]
I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer for opening remarks. Peg, you may begin.
Good afternoon everyone and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Company's President Research and Development; and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer.
As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the Company with respect to our business. These statements are subject to a number of assumptions, risks and uncertainties. Actual results may differ materially from these statements and except as required by law.
The Company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide we are presenting today, as well as all the Company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call.
With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?
Thank you, and good afternoon. Welcome to our Q2 earnings call. This is Revolution Medicines' first earnings call, and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session.
Treatment for RAS-addicted cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS-G12C mutation, Amgen’s Lumakras or sotorasib. Likewise, R&D at Revolution Medicines continued making exteprogress reinforcing our belief that the Company's innovative and cohesive asset portfolio can drive rational, mechanism-based and beneficial combination treatments for patients with RAS-addicted cancers.
Our ambition is to serve remaining and significant unmet needs for patients with KRAS-G12C positive tumors and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants as shown on Slide 4.
Today, we will highlight important progress we've made on our exciting tri-complex RAS Inhibitors and that extends the momentum we've described previously. We will also provide an update on several aspects of RMC-4630 and advanced an important asset in our RAS companion inhibitor portfolio.
We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study, the so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. And a second approach with RMC-4630, combined with the EGF receptor inhibitor osimertinib, aiming to enhance clinical benefit in EGF receptor mutant lung cancer.
We will also explain our continued commitment to treatment strategies, combining a direct RAS inhibitor with RMC-4630, and we'll announce an exciting high-priority combination study sponsored by Revolution Medicines evaluating RMC-4630 in combination with sotorasib in KRAS G12C positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the CodeBreaK 101 trial exploring this combination across multiple cancer types.
The RMC-4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHP2 inhibitor with the KRAS-G12C inhibitor through analysis of cohorts with and without certain co-mutations. Steve Kelsey, Revolution's President of R&D, will provide more information on the new 03 study and our other clinical programs after I provide an update on our RAS(ON) inhibitors.
For KRAS-G12C positive lung cancer and colorectal cancer, in particular, we continue to believe there's an opportunity to increase clinical response rates and/or durability as suggested by this table on Slide 5, summarizing some key outcomes reported with first-generation KRAS-G12C (ON) inhibitor so far that show both the clinical benefit of targeted drug and areas of ongoing opportunities. With these unmet needs in mind, we are pursuing development of several new RAS(ON) inhibitors.
A key element of the strategy for our KRAS-G12C (ON) inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations.
In Q1 of 2021, we had introduced the compelling profile of the development candidate, RMC-6291, our first-in-class potent oral and selective tri-complex inhibitor for KRAS-G12C as summarized on Slide 10. Standing from earlier examples shown previously, in Q2, we reported additional examples of deeper more uniform and/or more sustained antitumor effects in xenograft KRAS-G12C cancer models compared to a first-generation RAS(OFF) inhibitor. These experiments are part of a growing body of evidence that RMC-6291 has best-in-class potential among KRAS-G12C inhibitor.
Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with adagrasib and the described mutations provide a critical road map for treatment approaches to combat these mechanisms clinical failure.
As shown in this table on Slide 14, the Company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School, by demonstrating that RMC-6291 is active against all second sight resistance mutations reported thus far from patients treated with adagrasib.
As many of these mutations also confer resistance to sotorasib and other KRAS-G12C (OFF) inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND-enabling development program toward its expected IND filing in the first half of 2022.
We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we have described the compelling profile of our second development candidate, RMC-6236, a first-in-class potent oral and RAS selective tri-complex inhibitor for multiple variant RAS as summarized on Slide 17.
Expanding from earlier examples of KRAS-G12V and KRAS-G12D cancer model shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC-6236 as first-in-class and best-in-class potential for treating KRAS-G12V or KRAS-G12D tumors across multiple histotypes. Among the multiple resistance mechanism resistance mutations in adagrasib treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS-G12C (OFF) inhibitors and to RMC-6291.
As shown on Slide 22, these mutations include new substitutions at KRAS-G12 in the upper panel, KRAS-G13 in the lower panel and NRAS-Q61and also in the lower right panel. Importantly, we've now shown in preclinical experiments that RMC-6236 is active against all of these clinically observed variants as well as a broader panel of KRAS-G12 mutants that to date haven't been described in patients. Hence, these findings indicate that RMC-6236 has important properties that may be useful for preventing or treating emergence of these RAS oncogene switch resistance mutations.
In Q2, we also reported information about the potential for additive benefit in combinations of either RMC-6291 or RMC-6236 with a checkpoint inhibitor. For example, as shown on the left of Slide 26, an immunocompetent mice and grafted with the syngeneic RAS mutant tumor, RMC-6236 induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CD8T cells and a decrease in immunosuppressive M2 macrophages.
As shown on the right, RMC-6236 alone was quite active against growth of these syngeneic tumor graphs, including inducing a number of complete responses. An anti-PD-1 antibody alone was active as well but the two together led to complete responses in all animals. These results are encouraging about the potential clinical benefit of combining our RAS(ON) inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors.
Like RMC-6291, RMC-6236 continues on track in IND-enabling development, and we continue making very good progress on advancing additional mutant selective RAS inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND-enabling development and others subsequently. Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we've disclosed in late lead optimization KRAS-G13C and KRAS-G12D.
Shown on the left of Slide 29, is a graphical surface representation of the SWITCH 12 region of the RAS(ON) protein, which shows that amino acids 12 highlighted in blue and 13 highlighted in red, by adjacent to each other in the protein and both are very close to the RAS(ON) inhibitor binding site highlighted in dark pink.
Our previous work enabled RMC-6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS-G12C on protein as indicated by the upward shift of the KRAS-G12C protein band and the cross-linking experiment on the left. We have now been able to engineer new RAS(ON) inhibitor compounds that covalently engaged the specific oncogenic cysteine at position 13 in the mutant KRAS-G13C on protein, as indicated by the upward shift of the KRAS-G13C protein in the middle panel.
Further, the exquisite molecular control we bring to the design of these remarkable compounds enable selective covalent binding to the cysteine 13 variant by 1 compound without detectable binding to the cysteine 12 variant or conversely, selective covalent binding to the cysteine 12 variant by another compound without covalent binding to the cysteine 13 variant, despite the similar positions of the cysteines acquisitions, 12 and 13 in these RAS variants.
Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the Free File group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging.
We also report today that we have extended covalent chemistry beyond cysteines to the oncogenic aspartic acid in the KRAS-G12D (ON) Variant, an exciting innovation and major achievements. Shown on the right of Slide 29 is a representative compound that binds and cross links to the KRAS-G12D (ON) variant as indicated by the upward shift of the KRAS-G12D protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS-G13D variant, despite the close proximity of aspartate 12 and aspartate 13 to 1 another.
We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition and the corresponding genetic context as anticipated by the specific cross-linking patterns shown above.
These laboratory-based feeds offer further insight into the groundbreaking drug design and execute capabilities deployed as we continue expanding our portfolio of RAS(ON) inhibitor assets, and we look forward to providing further updates as these programs reach further milestones.
We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHP2 inhibitor program, and we remain optimistic about this strategy. To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS-G12C colorectal tumor xenograft in Slide 32.
In contrast to another colorectal cancer model we showed previously that is highly sensitive to single-agent RMC-6291, this particular colorectal cancer model exhibits only a modest growth inhibition response to RMC-6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins and supporting growth of these tumors.
Notably, combining our SHP2 inhibitor RMC-4550, a tool compound we often use for preclinical research, with RMC-6291 induced deep and sustained regressions in the tumor xenografts as shown on Slide 32. Hence, while RMC-6291 itself has a superior preclinical profile to first-generation KRAS-G12C inhibitors as measured in a variety of models we've shown previously, additional antitumor impact can be obtained by the additive contribution of our ship to inhibitor. We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy.
And now I'll turn things over to Dr. Kelsey, our President of R&D, to bring you up to date on these efforts.
Thank you, Mark. In monotherapy clinical studies to date, RMC-4630, our clinical stage SHP2 inhibitor compares favorably with competitors and is well set up for continued evaluation of potential combination benefits of RAS inhibitors. Notable features of our RMC-4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose-limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response and the complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients.
In Q2 of the annual ASCO meeting, another prominent SHP2 inhibitor program, TNO155 by Novartis presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and thereby, a class-leading RAS companion inhibitor.
The earliest combination studies we were able to begin the for RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway. MEK and EGFR. And today, we provide an update on both. In the absence of direct inhibitors for most RAS mutants, our first approach was to try to Clamp the RAS Pathway by combining our inhibitor of ship to RMC-4630, which suppresses the top of the signaling cascade or upstream of RAS, with cobimetinib, a MEK inhibitor, which suppresses the bottom of the signal and cascade will downstream to RAS.
Preclinical work from several groups, including ourselves, have suggested modest but undoubtedly combinatorial antitumor potential for this approach, which we felt merited clinical evaluation in the context of serious unmet needs. In the RMC-4630-02 study, a group of patients with RASP non-small cell lung cancer were treated with the RMC-4630 plus cobimetinib combination, using the recommended Phase II dosing schedule that we had described last fall.
11 subjects were evaluable for efficacy. We observed acceptable tolerability and one patient with a KRAS-G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction.
In a group of patients with RAS mutant colorectal cancer, we have 25 efficacy evaluable subjects. Here, too, we observed acceptable tolerability, but the best clinical response is stable disease.
Together, these results are encouraging in that they further support the antitumor activity of RMC-4630 in a way that can deliver clinical benefit in RAS-driven cancers and can be combined tolerably with other drugs. However, the combination also showed insufficient clinical benefit to justify advancing this approach. To us, it strongly points us back to the primary hypothesis for RAS-addicted cancers, which is to focus our efforts on using RMC-4630 with a companion for direct RAS inhibitors.
Our second and quite different approach was to try to enhance the clinical benefit of a best-in-class receptotizing kinase inhibitor, osimertinib by including RMC-4630 to suppress resistance mechanisms that may eventually reduce the efficacy of the EGFR inhibitor upon long-term treatment.
Preclinical work has supported the antitumor potential for this approach, which we felt merited clinical evaluation. We had previously communicated that we were not confident these two agents with well-recognized on pathway side effects could be combined clinically, a precedent set by the combination of osimertinib with the MEK inhibitors. And indeed, last quarter, we reported intolerability at the early dose levels in the RMC-4630-02 study.
In fact, we did not identify a combination dose and schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC-4630, indicating that the combined on-target toxicity caused by suppression of RAS signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach.
Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC-4630 or other RAS companion inhibitors with direct RAS inhibitors and that strategy will be our highest priority going forward.
In view of the response rates, emerging drug resistance profiles and resistance mechanisms for the leading KRAS-G12C (OFF) inhibitors, we continue to have conviction about combining RMC-4630 with direct RAS inhibitors. Since to our understanding, all clinical toxicity driving our selection of the recommended Phase II dose of RMC-4630 have been attributable to RAS pathway effects in normal tissues. We have no reason to believe that combining RMC-4630 with a RAS selective inhibitor would be compromised by additive dose-limiting toxicities.
Amgen continues to enroll the CodeBreaK 101 subpart C study of sotorasib with RMC-4630 in advanced non-small cell lung cancer, colorectal cancer and other solid tumors. As noted earlier in the quarter, the dose escalation work continues, evaluating RMC-4630 at the target dose of 200 milligrams daily on a day 1, day 2 weekly schedule. The full dose used by RMC monotherapy in combination with sotorasib at 960 milligrams daily.
A combination dose for expansion is expected to be achieved by Amgen in the second half of this year. We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy.
RevMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC-4630-03 study. I will provide a more detailed update on this study momentarily. In addition, we plan to combine RMC-4620 with RMC-6291, our KRAS-G12C (ON) inhibitor and potentially other compounds from our RAS(ON) inhibitor collection as these become available.
Finally, the TCD-16210 study sponsored by Sanofi continues, evaluating INC4630plus pembrolizumab. We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1 positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet to the RAS inhibitor, RMC-4630 and a PD-1 inhibitor.
Regarding the new RMC-4630-03 study, informed by preclinical data, the CodeBreaK 101C work to date, and important learnings in the field over the last few years since the CodeBreaK was written. The RMC-4630-03 study was designed as a global Phase II study of the combination of sotorasib plus RMC-4630 in advanced KRAS-G12C non-small cell lung cancer that have not previously received a KRAS-G12C inhibitor. It is intended to establish the extent and nature of additional clinical benefit from combining these two agents and to inform the design of a possible registrational trial.
While the 03 study is complementary to CodeBreaK 101C it has several important differences. The RMC-4630-03 study will enroll approximately 46 non-small cancer subjects with two cohorts that are defined by co-mutations that may affect the outcome to either KRAS inhibitor or SHP2 inhibition. First cohort will have KRAS-G12C positive tumors without co-mutations and the second cohort will have KRAS-G12C positive tumors with co-mutations such as KEAP1 or STK11 mutations.
This will allow us to better define who may most benefit from this promising combination strategy. Unlike CodeBreaK 101, the study will restrict eligibility to second and third line therapy and it will enroll outside the United States as well as within the United States.
RevMed is sponsoring and executing the study under its global partnership with Sanofi, with clinical supplier sotorasib provided by Amgen for the ex U.S. sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotorasib has been approved in the United States.
For data analysis and full interpretation, we will have the ability to draw from both CodeBreaK 101C results and the 03 study results. We review RMC-4630-03 as an important and exciting clinical study. We are preparing to launch the study, and we expect the first patient to be enrolled in the second half of this year and to have preliminary findings by the end of 2022.
Back to you, Mark.
Thank you, Steve. Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our RAS(ON) inhibitor program that will help power advancing additional research stage assets into development.
In addition, our mTORC1-selective inhibitor, RMC-5552 continues advancing in monotherapy dose escalation and our SOS1-selective inhibitor, RMC-5845, is on track to be IND-ready by the end of this year.
Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS(ON) inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in the first half of 2022 and selection of a third RAS(ON) inhibitor development candidate later this year. For RMC-4630, later this year, we anticipate selection by Amgen of a dose for further study with sotorasib in CodeBreaK 101 and to begin dosing patients in our new 03 study with soda acid.
I'll now turn things over to Jack Anders to review our financial results. Jack?
Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash, cash equivalents and investments. Revenue for the second quarter of 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sanofi.
Total operating expenses for the second quarter of 2021 increased to $53.2 million largely driven by R&D expenses, which were $45.9 million during the quarter. Net loss for the second quarter of 2021 was $44.3 million or $0.60 per share.
Turning to financial guidance. We continue to expect full year GAAP net loss to be between $170 million and $190 million, which includes estimated noncash stock-based compensation expense of approximately $20 million. Our GAAP net loss for the first half of 2021 was $81 million, and we expect net loss to increase during the second half of the year, primarily driven by increases in operating expenses as we advance our preclinical and clinical programs.
And with that, I'll now turn the call back over to Mark.
Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future.
This concludes our prepared remarks for today. And I'll now turn the call over to the operator for the Q&A session. Operator?
[Operator Instructions] Our first question comes from the line of Chris Shibutani with Goldman Sachs.
I want to get a sense for time lines for clinical data, a lot of progress and updates with your clinical planning here. Obviously, with the study that you have with sotorasib, this 03 study, it looks as if we're going to get the preliminary findings in the second half of next year, 2022. Can you help time line in context with your confidence in starting the Phase II now? And also, will we be able to get a sense for what Phase I data looks like?
Thanks, Chris. This is Mark Goldsmith. Thanks for asking your questions, good to hear from you. I think I'll ask Steve Kelsey to comment. There were several pieces built into that question.
Maybe Steve can tackle them for you.
Yes. Thanks, Chris. I'll try to -- I'll try to answer your questions in a logical sequence by [indiscernible]. Firstly, the 03 studies, which we referred complementary to the Amgen CodeBreaK 101C study. And so the data -- the totality of the data will be evaluated together.
And we expect as we said, first [indiscernible] towards the end of next year. The Phase I data, which you're that there is going to be a very brief safety run into the 03 study, we are compelled to do that, because a recommended Phase II dose schedule has not yet been defined that we can reduce at assets to start the study with. And obviously, we will be able to use that for the expansion of the 03 study.
What we can do is comment on when already data from the Phase I component of the CodeBreaK 101C study other than we are guiding to the fact that they will select the dose in the second half of this year. What we can tell you when they will disclose that.
Okay. That's helpful. With the studies that have been discontinued with the Amgen program, can you provide us with a preliminary sense for what impact you feel the design of the studies may have factored into this outcome in the decision?
Just to clarify, you're talking about the cobimetinib and some studies, the two studies?
That's correct. Yes.
I'm not sure -- Steve, if you want to comment on that? I'm not sure what design in the studies, what aspect of design you were referring to, it's really the choice of drugs that we're combining with there, but maybe Steve can clarify.
Yes. I think there's two components to the question. One is what at -- why are the, that decision we're making and why are we making it. And then the second is how the design of the -- both the cobimetinib combination or the osimertinib combination culture to the fact that we didn't see as encouraging efficacies we won't see more it forward.
So let's be clear about the reasons why we're not moving forward with those two combinations. The first and now compelling one is that the efficacy profile wasn't especially compelling justify moving forward, but there's also a large component of prioritization here itself. We have been very publicly moving towards combining the companion inhibitors that we have, which include RMC-4630 with RAS inhibitor therapies that we and others make.
And that's an important part of our consideration here. It's really about what do we -- where do we think the best place to go RAS-addicted to cancers and patients with respected cancers is as much as it is the data presentations.
I don't think there is any design fault with the studies. We think we have comprehensively tested the hypothesis at least as far as we can with a mechanism of cobimetinib. And the data is fairly in our opinion, is conclusive in that respect. As you are aware of, we are still supporting the Netherlands Cancer Institute to do a study in combination with [indiscernible] in pancreatic and cell cancer.
And in as much as that represents a slight variation on the hypothesis, then we'll be interested to see the outcome from that experiment. But I think we designed the best experiment we could. And we are making the decision a for compelling reasons, both strategically and confidently.
And if I could just add to that, Chris, just to see if I can get to the question that you're raising here. I think it goes back to the indirect strategy, planting approach, which is one that we now disfavor. And that is trying -- not actually inhibiting the cancer driver by inhibiting the pathway upstream and downstream. And that appears to deliver some benefit. There's a modest benefit.
We did see a PR, KRAS-G12B positive patients, but it's just not sufficient in our view to justify pursuing. And furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. And so that makes much more sense to us is to combine them -- to combine a direct RAS inhibitor with the RAS inhibitor. And after all, we call RAS companion inhibitors -- RAS companion inhibitors to indicate that it will be combined with RAS inhibitors. So I think that all makes sense, but maybe that's the design feature you're asking about.
The hypothesis is seemed reasonable. There was clinical data to support it. and there's a serious unmet need that couldn't be satisfied by any existing compounds. So we tested it. But we don't think it will be -- those results are a bit positive or read through to a strategy that involves a direct inhibitor plus a RAS companion inhibitors.
I think that's really the key point maybe that you're getting to.
Next question comes from the line of Marc Frahm with Cowen.
Maybe just start on the 03 trial, but the brief safety running that you discussed, is that -- is all that going to be run at 200 milligrams day 1, day 2? Or are you going to have some dose exploration built into that run in? And then related on that trial, just why is the right structure to move now with a RevMed-sponsored trial rather than waiting for the formal selection of a recommended Phase II dose within code break and kind of keeping everything contained within that first collaboration with Amgen?
Yes. Thanks, Marc. I appreciate those questions. I think I'm going to comment on the second question, and then Steve, we can take a crack at the first one and you can answer the second one if he wants, which is why, why do it now. I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing CodeBreaK 101C study. And we feel there's sufficient information now to really go after that.
There is some overlap with CodeBreaK 101C, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the CodeBreaK study was designed. And we think it's also an urgent to get to the answers to the questions. And the question that we're posing here has to do in part with the co-mutations that Steve alluded to.
So we think it makes sense to move forward and there will be just a little bit of overlap in time there, but it will give us the advantage of getting to the answer as repos as possible and as quickly as possible with regard to lung cancer. Steve, do you want to -- you can comment on that, you can comment on the first question, whatever you like.
I think you answered the second part of the question, we'll happily address it. But with regards to the dose exploration at the beginning, it's not really a dose exploration. I mean, we basically have two choices, 140 milligrams day 1, day 2 or 200 milligrams day 1, day 2. We know -- as we said, we know and I think we publicly disclosed our Amgen CodeBreaK 101C with regard to dose RMC-4630 in combination with that full base.
So we fully expect to move forward with the Phase II component of the study at the -- what we call the target dose of RMC-4630 200 milligrams day 1, day 2 with the current timing and the just the way that CodeBreaK 101C study is at the moment. We are obliged to build short safety run into our study. So it's more of an operational detail, but it is a real sort of dose exploration. And we don't do then we'll go back and revisit it, but I would be surprised if we don't end up reason target dose in combination with [indiscernible].
Okay. That's very helpful. And then maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of wild-type RAS inhibition that's acceptable and kind of how that makes you think about designing your multi-RAS inhibitor on kind of how much spillover effect either the multi-RAS or the targeted ones are allowed or kind of allowed to have before their acceptable profile to move in when you ultimately want to use them in combination?
Thanks, Marc. Let me just add something to that previous discussion about timing. It just also occurs to me that is important to mention. Amgen is collaborating with us on this 03 study. They view it as an extension of expansion of complement to the current CodeBreaK 101C study, just as we do, as does Sanofi.
So we have three companies all getting together a green on that concept. And based on that, there's no reason not to proceed with it. And as Steve said, we're so close to finalization of those that there's no reason to wait.
Now with regard to what have we learned again, maybe I'll just take a crack at this, which is we already do that SHP2 inhibition has a tolerability constraint because of its effect on normal tissues. There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in as a way to take advantage of tumor cells being able to tip into apitosis if they're covered deeply enough and long enough, but they don't require continuous coverage.
And so we're trying to create a pharmacologic way manipulating tumor cells versus normal cells. But there's a limit to that. And to limit that is probably 200 milligrams day 1, day 2 or thereabouts in a dosing regimen. And we have seen objective responses with that sort of regimen.
So it's clearly a very active agent with our compound at that kind of regimen. But we're also having to take into account the landscape and when there are G12C specific -- specific inhibitors that are in play as when grafts are now approved and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit not so what you can achieve with those targeted selective agents.
And so I think we're still -- net of all that is we're so quite confident that SHP2 inhibitor antitumor activity. There's just no doubt about that now. And when dosed in the ways that we dose it, and we fully expect that it will show activity, but that's why we have to do the clinical studies when we combine the RAS inhibitors.
With regard to read through, to RMC-6291, which is the G12C selective inhibitor, I don't think there's any read sort of whatsoever that we're aware of to be selective inhibitor G12C selective inhibitor that we're aware of. With regard to RMC-6236, which is a multi-RAS inhibitor, I think you're right in principle to raise that question. I think we had already learned what we needed to learn before.
I don't think this changes that if anything was changed by the results that we just described. That is that there is a limit to how much you can dose stack, how continuously you can pivot all RAS targets. That's for sure. But we also know that rate the tumors are particularly sensitive to inhibition of the RAS driver and that it is possible to achieve a quite deep antitumor effects.
And we show this, as you know, across multiple preclinical models that we never achieved with a SHP2 inhibitor alone or a SHP2 inhibitor even when combined with the MEK inhibitor. So I think the tolerability limits are there but in the right context. And when combined specifically with inhibiting the mutant driver even if it's not a be a selective inhibitor, one can achieve quite profound effects. And as you know, there's precedent for that with Tarceva and EGF receptor antagonists and so on that have had profound impacts in tumors at tolerable levels.
So I think we feel very good about RMC-6236. We continue to evaluate it, but everything continues going in the same direction. We feel terrific about RMC-6291 and then the combination strategy of combining a companion inhibitor with a RAS inhibitor is on the forefront of our thinking. And so the 03 study I think is the first example where we really get to deploy that fully as we prepare going forward the rest of the RAS inhibitor.
Our next question comes from the line of Michael Schmidt with Guggenheim.
I had one regarding the KEYTRUDA combination with RMC-4630. I guess, nice to see that you're moving forward here with the Phase II. First question is, what's been driven predominantly by safety and mechanistic rationale or also by clinical efficacy data? And then perhaps if you could speak to a decision to move into PD-L1 positive patients in this initial Phase II study and how we should think about a potential longer-term registration path for this combination?
Thanks, Michael. Let me just give a quick preamble, and then Steve, I think you can really address the need of your question. Preamble is we can't disclose anything about the dose escalation work that Sanofi did, they're the sponsor of that study. So when they decide to dispose it they will. So we can't really address your carefully worded question about what the tolerability or efficacy that drove it.
But it was primarily intended as a safety and dose escalation study that was the purpose of it. But what's now going to be tested is, as you point out, in PD-L1 positive lung cancer and particularly first-line treatment, so previously untreated patients, which is an exciting move and maybe Steve can speak to that.
Sure. I think helps to explain when we think we may end at in the positive study because I think that will explain the rationale behind the study in the first place. But if it turns out that adding the SHP2 inhibitor to pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which, by the way, it does include Rasputin non-small cell lung cancer, then we really -- it leaves us with two large opportunities. One is, obviously, that there are a very limited number of drugs that improve outcomes over above checkpoint inhibitors alone without significantly the toxicity. And obviously [indiscernible] that represents a huge opportunity, not just in lung cancer, there are a lot of other tumors where ages have another PD-1 inhibitors are used.
The second -- probably from our perspective, the primary driver when we said about doing this is the fact that checkpoint inherits is a primary standard of care for absolute lung cancer. And we do foresee a future state where the [indiscernible] chemotherapy for mutant lung cancer is replaced by a combination of a RAS directed inhibitor, whether it's a GRC inhibitor or one of our other RAS inhibitors for other RAS mutations in combination with a companion inhibitor like RMC-4630 then plus pembrolizumab.
Now that requires us to demonstrate that each component -- each dominant component of that triplet is tolerable. And that's the primary intent of that study, which we have declared a recommended base to those schedule moving into a Phase II expansion of that study. Unfortunately, it is [indiscernible] eventually, you will learn. And then it will become clear what the tolerancy profile looks like.
All we can say at the moment is this profile is perfectly acceptable and encouraging enough for us to want move forward to efficacy testing. There is a very mechanistic basis as well. And again, going back right back to the very beginning, in fact, paper published by RM back in 2017, shown very clearly that one of the roles of SHP2 is to regulate checkpoint signaling. And so there's a huge rationale for SHP2 inhibitor augmenting the effects of checkpoint inhibition.
We have also subsequently demonstrated both in preclinical and in patients that ship to inhibition to both DNA and adaptimmune system, the way we should be beneficial in an antitumor effect should be, it should be helpful rather than a hindrance. And so when you compound the mechanistic basis of SHP2 inhibition as demonstrated in the PD studies from our clinical trials the fact that checkpoint inhibitor is our standard of care for rash new lung cancer and the opportunity the oral cancer, I think it proves a very compelling place for us to do a study.
Got it. Okay. And then on -- just wanted to get your thoughts on Amgen's recent decision to also study sotorasib with adagrasib, actually. Just curious to give any thoughts on that and perhaps conversely have plans to evaluate 4640 with KRAS inhibitor?
Yes. I think for us, the main thing it suggests is that Amgen continues to have a high interest in SHP2 as a target and using it as a co-target along with the mutant driver RAS driver. So I think that's a very positive signal as to why they chose specifically TNO-155 or something else, I couldn't speak to that at all. It obviously is a leading SHP2 inhibitor. So there's it may be as simple as that.
What they've indicated publicly, I'll just reiterate sort of my interpretation of data research comments, which are that they think it's an important target. They want to make sure that the Lumicast franchise, which is rapidly building has access to whatever makes it to the finish line, but that they have no particular concerns about RMC-4630 and continue to support CodeBreaK 101C and are excited about it. And -- but it couldn't say then, but now you can read into it is that they're also about the 03 study that, of course, they knew we were about to announce, but he couldn't speak to that then.
So I don't think it reads at all negatively on RMC-4630 if anything, increase positively on it. And we've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors until the music is over until we know all the answers, there's advance to be asked. And so people are going to switch around try different partners. And we've been doing that. We'll continue doing that, and I suspect everybody we'll do that.
That makes perfect sense in a rational approach to drug development.
Our next question comes from the line of Jonathan Chang with SVB Leerink. Your line is open.
This is Faisal Khurshid on for Jonathan Chang. For RMC-5845, the SOS-1 sort of clarification, is this an asset that would be considered for like a potential out-licensing or is this simply a delay in a potential IND filing? And then I guess a related question, are there any features of the molecule itself that kind of played into the decision? Or was it just the other priorities?
Yes. Thanks for your question. I don't think that there are specific features of the molecule that are affecting that position. I think it's primarily a prioritization decision. We're moving two compounds into the clinic next year.
We already have two compounds in the clinic. We said that there's at least another one coming in several more behind that. So over the next 12 months, we've got our hands quite full. And at RMC-6291 is entering a crowd of space and RMC-6236 is entering a very large space. So those are pretty big programs. And we just announced the 03 program, which is going to be a significant commitment of resources.
So I think it's really more a timing question. And we will evaluate -- we'll continue evaluating what's the right timing for moving that forward and if and when, that's what we'll do. But I don't think I would anticipate any sort of out-licensing, I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors and having a good quality SOS-1 inhibitor is part of that approach. It's not on the point of the spear, but it's part of our overall integrated approach.
Our final question comes from the line of Eric Joseph with JPMorgan.
Just a follow-up on the 03 study, I'm curious to get a maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal given the sort of the relatively higher unmet need and the lack of objective responses there. I guess, was this decision based on anything that you've seen thus far in CodeBreaK 101? And is combination potential in colorectal cancer or something that might still be on the table?
Thanks for your question. I think, Steve, you've got some comments to make on that.
Yes. Let's start with the colorectal cancer a bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is really twofold. One is we were swayed to some extent, by the data that was presented at AACR and then published [indiscernible] mechanisms by which [indiscernible] escape from KRAS-G12C of inhibitors.
I think if you look at that data, the potential for a SHP2 inhibitor into meaningfully in the effects of KRAS-G12C (OFF) inhibitor or some the effect on the aggregate resistance is potentially great announces lung cancer. Secondly, we know the objective response rate to single-agent rather is a little bit higher, and that's actually oddly enough if you're comparing mix makes it easier to detect a difference maybe you're living in other.
So I think there's a very good reason Thirdly, we wanted to focus our attention on a single disease and make sure we've got the right answer. But absolutely, it absolutely doesn't say anything negative about the potential for 46 and case I think there's every expectation at some point in the future, we will be doing that combination as well.
Yes. And if I could add to that, Eric, the CodeBreaK 101C study continues and it is an exploratory suddenly looking at multiple histotypes so we're going to continue to get information out of that. I'd also highlight that in the formal part of the presentation, we did show an example of colorectal cancers tumor line that was relatively unresponsive or a low response to RMC-6291 alone. But when combined with the SHP2 inhibitor actually developed quite deep regressions.
And so I think we're still quite committed now with other things as well. But at this point, you sort of break off of the broad multi-tumor approach and start delving down one at a time, and the first approval for [indiscernible], of course, is in non-small cell lung cancer. So if we're looking for a place where we can make a difference. And build on an improved treatment regimen that would be the place to start. But by no means, as Steve said, are we excluding other opportunities.
Okay. Okay. Great. And with respect to the RAS(ON) portfolio, it looks like you're deciding between two targets in naming a third development candidate between RAS -- sorry, G12D and G13C. Just kind of curious to get a sense of your think that remains in deciding between sort of which you nominate here?
And I guess how far apart are these compounds, I guess, in their preclinical development, should we be thinking about multiple development candidates coming to the for being named over the next year or so?
Yes. I wouldn't read too much into that back to the question sort of the complex strategic decision about which one to move forward. We basically have a bunch of teams competing with each other to put forth the best package when they've got the package together. And when they've got a package, we'll look at it and consider whether to we're moving forward with it. So it's not as if we ask one team to slow down and other teams to speed up.
I mean everybody is moving as fast as they can. We also didn't explicitly say that we'll be choosing between G12C or G13B for this decision. We just said those are two that we've disclosed that are in late lead optimization and we expect to select a next development candidate coming up but principally, there could be other options on the table, too.
So I wouldn't read too much into the -- whatever comes out of that, and we're looking forward as swiftly as we can. If one gets named in the other one doesn't, at some point thereafter, not too far after the other one, I'm sure we'll get named. And these programs are moving along well as our unnamed target programs that are continuing to work their way through.
As there are no more questions in the queue, I will turn the call back over to Dr. Mark Goldsmith for his closing remarks.
Thank you, operator, and thank you to our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicines.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.