On October 13, 2023 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported encouraging preliminary clinical data for RMC-6236, its RASMULTI(ON) Inhibitor, and RMC-6291, its RASG12C(ON) Inhibitor, from the respective Phase 1/1b studies (Press release, Revolution Medicines, OCT 13, 2023, View Source [SID1234635955]). These data were presented during the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) ("Triple Meeting") in Boston, October 11-15, 2023.
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"We are pleased to report encouraging clinical data for both RMC-6236 and RMC-6291, two pioneering RAS(ON) Inhibitors that are providing strong validation of our RAS(ON) Inhibitor platform broadly. The RMC-6236 safety data support that this highly innovative, oral RASMULTI Inhibitor is generally well tolerated across dose levels in patients, exhibits dose-dependent pharmacokinetics reaching exposures predicted preclinically to induce tumor regressions and induces molecular responses (ctDNA) and radiographic regressions suggestive of anti-tumor activity targeting multiple common RAS mutants that cause cancer, including KRASG12D and KRASG12V," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "The RMC-6291 data provide important initial evidence that this mutant-selective, oral RASG12C(ON) Inhibitor can provide mechanistic and clinically meaningful differentiation from KRASG12C(OFF) inhibitors, as indicated by encouraging clinical responses in NSCLC patients previously treated with a KRASG12C(OFF) inhibitor and in KRASG12C(OFF) inhibitor naïve CRC patients at doses that are generally well tolerated."
"These data support our ongoing development of RMC-6236 and RMC-6291, both as monotherapy and in various combinations, including as a RAS(ON) Inhibitor doublet. We will continue evaluating these exciting compounds toward the goal of bringing new and effective therapies to patients living with RAS-addicted cancers, and remain committed to our rich pipeline of differentiated mutant-selective RAS(ON) Inhibitors, as there is significant need for new treatment options."
Phase 1/1b Trial of RMC-6236, RASMULTI(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6236 as monotherapy in patients with advanced solid tumors harboring KRASG12X mutations. As of the September 11, 2023 data cut-off, the most common G12 mutations in patients enrolled included G12D (51%); G12V (28%); G12R (11%); G12A (6%); and G12S (4%). Patients with KRASG12C mutations were excluded from the study due to the availability of currently approved KRASG12C(OFF) inhibitors. A total of 131 patients (69 PDAC, 47 NSCLC, 10 CRC, 5 other tumor types) were treated across multiple dose levels administered once daily (QD): 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200/220 mg, 300 mg, and 400 mg. Patients had received a median of two prior lines of therapy (range 1–7) with standard of care appropriate for tumor type and stage.
As of the data cut-off, RMC-6236 demonstrated an acceptable safety profile that was generally well tolerated across dose levels. The most common treatment-related adverse events (TRAEs) were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. Of these, the reported Grade 3 TRAEs were rash (5%), stomatitis (2%), and diarrhea (1%). One previously reported Grade 4 TRAE occurred in a PDAC patient at the 80 mg QD dose level who had a large intestine perforation at the site of an invasive tumor that reduced in size while on treatment, which resulted in treatment discontinuation. No safety signals were observed that indicated an elevated risk of hepatotoxicity, which has been reported for some KRASG12C(OFF) inhibitors.
RMC-6236 demonstrated dose-dependent increases in exposure at steady state with minimal accumulation after repeated daily oral dosing, which is compatible with once daily dosing. Clinical exposures achieved at dose levels of 80 mg QD and above were comparable to those that induced tumor regressions in preclinical xenograft models with KRASG12X mutations. Circulating tumor DNA (ctDNA) was assessed in 27 patients with detectable baseline plasma KRASG12X alleles and evaluable for changes in KRAS variant allele frequency (VAF) on-treatment. Molecular responses were observed across two tumor types (NSCLC and PDAC) and 4 different KRAS mutations (KRASG12D, KRASG12V, KRASG12R, and KRASG12A) with reductions in KRAS VAF consistent with anti-tumor activity. Three clinical case reports illustrated tumor regressions induced by RMC-6236 in patients with ovarian cancer (KRASG12V), NSCLC (KRASG12D) or PDAC (KRASG12D).
Phase 1/1b Trial of RMC-6291, RASG12C(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6291 as monotherapy in patients with advanced solid tumors harboring KRASG12C mutations. As of the October 5, 2023 data cut-off, a total of 63 patients (23 NSCLC, 33 CRC, 7 with other tumor types) received RMC-6291 at various doses, beginning at 50 mg once daily (QD), escalating to 100 mg QD, 200 mg QD, 100 mg twice daily (BID), 200 mg BID, 300 mg BID and 400 mg BID. Patients across all histologies had received a median of three prior therapies (range 1–7) with standard of care appropriate for tumor type and stage.
As of the data cut-off, RMC-6291 demonstrated preliminary evidence of clinical activity and an acceptable safety profile that was generally well tolerated across dose levels. The activity analysis included 37 patients (17 NSCLC, 20 CRC) who were evaluable for efficacy. Of the 10 NSCLC patients previously treated with a KRASG12C(OFF) inhibitor, 50 percent (n=5; one unconfirmed PR) achieved a partial response (PR) as best response, with a 100 percent disease control rate (DCR). Of the 7 NSCLC patients naïve to KRASG12C(OFF) inhibitors, 43 percent (n=3; two unconfirmed PRs) achieved a PR, with a 100 percent DCR. Among the 20 CRC patients naïve to KRASG12C(OFF) inhibitors, 40 percent (n=8; 3 unconfirmed PRs) achieved a PR as best response, with an 80 percent DCR. The median time to response was 1.3 months (range 1.1–4.1) and 1.4 months (range 1.2–4.1) for NSCLC and CRC patients, respectively. As of the data cut-off, no disease progressions had occurred among patients with an objective response, and 68 percent of all patients remained on treatment.
The most common TRAEs were QTc prolongation and GI-related toxicities that were primarily Grade 1 or 2 in severity. Grade 3 TRAEs were QTc prolongation (11.1%) and diarrhea (1.6%), and only one Grade 3 case was reported with a QTc ≥ 501 msec. All QTc prolongations were asymptomatic with no cardiac sequalae reported. No Grade 4 or 5 AEs or SAEs were reported. Nine patients (14.3%) were dose reduced due to TRAEs, and one patient (1.6%) discontinued treatment due to a Grade 3 QTc prolongation. No safety signals were observed that suggest an increased risk of hepatotoxicity, which has been reported for some KRASG12C(OFF) inhibitors.
Investor Webcast
Revolution Medicines will host an investor webcast on Sunday, October 22, 2023 at 12:30 p.m. Eastern Time to discuss the data presented at both the Triple Meeting and the 2023 European Society for Medical Oncology Congress, in addition to other clinical updates. To participate in the live webcast, participants may register in advance here: View Source A live webcast of the call will also be available on the Investors section of Revolution Medicines’ website at View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.