RMC-6291 (KRAS^G12C)—RMC-6291 is a first-in-class, potent, oral and selective tri-complex inhibitor of KRAS^G12C(ON) with a differentiated preclinical profile designed to address persistent unmet needs for patients with cancers caused by KRAS^G12C.

During the second quarter, the company reported additional data at the American Association for Cancer Research (AACR) annual meeting and in a subsequent presentation showing that RMC-6291 provides deeper and/or more sustained anti-tumor effects in xenograft KRAS^G12C cancer models compared to a first-generation RAS(OFF) inhibitor, expanding the evidence that RMC-6291 has the potential to be a best-in-class KRAS^G12C inhibitor.

The company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran’s team at the Massachusetts General Hospital/Harvard Medical School by demonstrating that RMC-6291 is active against all second-site 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.

The company remains on track to submit an Investigational New Drug (IND) application for RMC-6291 in the first half of 2022.

RMC-6236 (RAS^MULTI)—RMC-6236 is a first-in-class, potent, oral RAS-selective tri-complex, RAS^MULTI(ON) inhibitor that is designed to treat cancers caused by multiple RAS variants for which no targeted treatment is currently available.

During the second quarter, the company reported deep anti-tumor activity of RMC-6236 in preclinical lung, colorectal and pancreatic cancer models driven by various common mutations, including KRAS^G12V and KRAS^G12D, at the AACR annual meeting and in a subsequent presentation, supporting its potential as a first targeted therapy for treating KRAS^G12V and/or KRAS^G12D tumors.

A study published by the Dana-Farber Cancer Institute in the New England Journal of Medicine identified “RAS oncogene switch” resistance mutations in patients treated with adagrasib. The company subsequently presented preclinical data demonstrating that RMC-6236 is active against all of these clinically observed variants, revealing important properties of RMC-6236 that may be useful for preventing, or treating, emergence of such resistance mutations.

The company remains on track to submit an IND for RMC-6236 in the first half of 2022.

Continued expansion of other RAS(ON) inhibitor programs – Revolution Medicines continues to progress its expanding portfolio of RAS(ON) Inhibitors designed to target RAS variants driving the vast majority of RAS-addicted cancers and remains on track to nominate a third development candidate from its RAS(ON) inhibitor portfolio in the second half of 2021.

RMC-4630 (SHP2 Inhibitor) – RMC-4630 a potent, oral, selective inhibitor of the SHP2 protein, is being advanced in collaboration with, and is primarily funded by, Sanofi.

RMC-4630 and KRAS^G12C inhibitor sotorasib

Amgen’s CodeBreaK 101c study continues evaluating sotorasib in combination with RMC-4630 in patients receiving second line or later treatment for advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors. To date this combination has demonstrated acceptable tolerability and cleared early dose levels. The dose escalation work continues at the target dose for each compound: RMC-4630 200 mg on a Day 1 / Day 2 (D1D2) weekly schedule, in combination with sotorasib 960 mg daily. Amgen anticipates selecting a combination dose for this study in the second half of 2021.

Today, Revolution Medicines announces a global Phase 2 study that will evaluate further the combination of RMC-4630 and sotorasib in lung cancer. The protocol for the new study, RMC-4630-03, is informed by the CodeBreaK 101c work to date as well as the many important learnings in the field over the last few years. The study, sponsored by Revolution Medicines under its global partnership with Sanofi, will be conducted in collaboration with Amgen, including supply of drug by Amgen at ex-U.S sites. RMC-4630-03 will evaluate the combination in inhibitor-naïve patients with advanced NSCLC that builds on, and is complementary to, CodeBreaK 101c.    Study startup activities are ongoing, and the company expects to dose the first patient in the second half of 2021 and to have preliminary findings in the second half of 2022.

RMC-4630 and MEK inhibitor cobimetinib (Cotellic^®)

Previously reported findings from the Phase 1b/2 study of this combination in patients with relapsed/refractory solid tumors harboring specific genomic mutations demonstrated acceptable tolerability, also observed among patients enrolled in expansion cohorts. Among 11 efficacy evaluable patients with NSCLC, one patient with a KRAS^G12V tumor mutation and gene amplification exhibited a confirmed partial response (PR) with a 45% tumor volume reduction. Among 25 efficacy evaluable CRC subjects, the best clinical response was stable disease. These results support the anti-tumor activity of RMC-4630 and its potential for clinical benefit in RAS-driven cancers and to be combined tolerably with other drugs. However, insufficient clinical benefit was observed to justify advancing this approach, and no additional patients will be enrolled in this study. The findings reinforce the company’s belief that the optimal treatment for RAS-addicted cancers may come from combining RMC-4630 with direct RAS inhibitors.

RMC-4630 and EGFR inhibitor osimertinib (Tagrisso^®)

The company initiated a Phase 1b study of this combination with the intent of suppressing adaptive resistance mechanisms that may eventually reduce the efficacy of osimertinib upon long-term treatment. To date, the company has not identified a combination dose and schedule with acceptable tolerability, indicating that the combined suppression of RAS signaling in normal tissues caused by these two agents presents too significant a safety hurdle to justify advancing this approach, and no further patients will be enrolled in this study. No clinical toxicity was observed that has been attributed to off-target effects of RMC-4630. Rather the company believes that osimertinib and RMC-4630 are both effective, and additive, on-pathway inhibitors. The company intends to increase its focus on RAS-addicted cancers by combining direct RAS inhibitors with RAS Companion Inhibitors including RMC-4630.

RMC-4630 and PD-1 inhibitor pembrolizumab (Keytruda^®)

The TCD16210 study sponsored by Sanofi continues evaluating RMC-4630 in combination with pembrolizumab, a PD-1 inhibitor. Today, the company reports that preparation is underway for Phase 2 expansion focused on evaluating this combination as front-line treatment for patients with PD-L1+ NSCLC.

RMC-4630 monotherapy

The company presented a dose escalation activity data set from its ongoing Phase 1 study at the 2021 AACR annual meeting, showing anti-tumor activity and safety and tolerability that are consistent with on-pathway inhibition.

Additional data were presented at the AACR meeting showing reduction of variant allele frequency in circulating tumor DNA (ctDNA) samples from select patients treated with RMC-4630, further validating its expected clinical mechanism of action.

RMC-5552 (mTORC1/4EBP1 Inhibitor) – RMC-5552 is a potent, selective bi-steric inhibitor of mTORC1 that suppresses phosphorylation and inactivation of 4EBP1.

Enrollment and dosing are underway in a Phase 1 monotherapy dose-escalation study. The company continues to expect initial safety, pharmacokinetic and single agent activity data in 2022.

The company reported preclinical data at the 2021 AACR annual meeting demonstrating that bi-steric mTORC1-selective inhibitors drive significant anti-tumor activity as monotherapy and in combination with KRAS^G12C inhibitors in genetically-defined models of human cancers.

The company recently announced the publication of an original scientific paper in Nature Chemical Biology describing anti-tumor effects of bi-steric mTORC1-selective inhibitors that potently suppress phosphorylation of 4EBP1, a key translational regulator of oncogene expression. In preclinical models, a series of bi-steric inhibitors demonstrated the favorable anti-tumor effects and tolerability of such compounds compared to earlier generations of mTOR inhibitors.

The company intends to evaluate RMC-5552 in combination with RAS inhibitors for the treatment of tumors driven by co-occurring RAS mutations and genomic activation of the mTORC1 pathway.

RMC-5845 (SOS1 Inhibitor) – RMC-5845 is a potent, selective, oral inhibitor of SOS1, a major switch in the cycling of RAS(OFF) to RAS(ON).

The company expects RMC-5845 to be IND-ready in the second half of 2021. Due to its current focus on other priorities, including the continued advancement of its RAS(ON) Inhibitor programs and the initiation of the RMC-4630-03 study, the company no longer intends to submit an IND for RMC-5845 in 2021 and will determine timing for a potential IND at a future date.

Flavia Borellini, Ph.D. elected to board of directors – Dr. Borellini has more than 25 years of executive management experience in the pharmaceutical and biotechnology industry, with a particular focus on global development of targeted oncology drugs, from preclinical to commercial stage.

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