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. 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…

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…

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?

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 . 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 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 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 .

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…

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 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 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 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 mechanisms by which 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 , 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.