RMC-9805 Triggers Tumor Regressions in KRAS G12D–Mutant Pancreatic Cancer

KRAS G12D–mutant pancreatic ductal adenocarcinoma

RMC-9805 was proven safe and active in patients with previously treated, KRAS G12D–mutant pancreatic ductal adenocarcinoma (PDAC), according to preliminary data from the phase 1/1b RMC-9805-001 trial (NCT06040541) that were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.¹

At the data cutoff date of September 2, 2024, the objective response rate was 30% (n = 12) and the disease control rate was 80% (n = 32) among patients with PDAC who received 1200 mg once daily (n = 20) or twice daily (n = 20).²

“We are pleased to report the first clinical data for RMC-9805, our novel, oral RAS(ON) G12D-selective covalent inhibitor, which demonstrate encouraging initial safety, tolerability and antitumor activity evidenced by tumor regressions,” Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, said in a news release.1 “While preliminary, these data bolster our belief that RMC-9805 has the potential to play a role in an emerging treatment paradigm for patients living with pancreatic cancer, both as monotherapy and in combinations. With [this] presentation, RMC-9805 becomes the third tri-complex compound from the Revolution Medicines pipeline to demonstrate clinical proof-of-concept, and it reaffirms our commitment to bringing novel RAS(ON) inhibitors to patients with RAS-addicted cancers.”

The RMC-9805-001 phase 1/1b study is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-9805 in patients with advanced solid tumors harboring a KRAS G12D mutation. The study is comprised of a monotherapy and combination arm, in which RMC-9805 will be evaluated in combination with RMC-6236.^1,3

To be eligible for enrollment in the phase 1 study patients needed to have a pathologically documented, locally advanced or metastatic solid tumor with a KRAS G12D mutation, received prior standard therapy, and had an ECOG performance status of 0 or 1, adequate organ function, and no active brain metastases. Patients who had previously received an investigational KRAS G12D inhibitor, pan- or multi-RAS inhibitor, or had prior exposure to any direct RAS-targeted therapy were excluded from enrollment.^2,3

Within the dose-escalation phase, patients received RMC-9805 orally, once daily at 150 mg, 300 mg, 600 mg, 900 mg, or 1200 mg; or twice daily at 300 mg, 450 mg, or 600 mg in 21-day cycles.² As of the data cutoff date, 179 patients had received escalating doses of RMC-9805 in the monotherapy cohort.¹

Key end points were safety and tolerability, pharmacokinetic (PK) activity, and anti-tumor activity.²

All treated patients had received a median of 2 prior lines of therapy (range, 0-9).¹

PK data indicated that a candidate recommended phase 2 dose should be 1200 mg once daily.²

Regarding safety, no grade 4 or 5 treatment-related adverse effects (TRAEs) or serious AEs have been reported at the 1200 mg daily dose (n = 99). TRAEs included nausea (grade 1, 23%; grade 2, 4%), diarrhea (grade 1, 16%; grade 2, 4%), vomiting (grade 1, 13%; grade 2, 2%), rash (grade 1, 10%), alanine aminotransferase elevation (grade 1, 5%; grade 3, 1%), and aspartate aminotransferase elevation (grade 1, 3%; grade 2, 1%). TRAEs led to dose reduction in 4 patients, all owing to grade 1 events, and no treatment-related discontinuation occurred.²

No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached.¹

“Pancreatic cancer is the most RAS-addicted of all major cancers and the G12D variant is the most common RAS mutation in pancreatic cancer. No approved targeted therapies are available for these patients, making this an area of significant unmet need,” David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston, stated in a news release.¹ “This is a challenging disease, but we observed a promising level of antitumor activity at generally tolerable doses in this phase 1 study.”

Dose optimization in KRAS G12D–mutant PDAC and other solid tumors is ongoing.²

References

1. Revolution Medicines presents initial data from RMC-9805 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines, Inc. October 25, 2024. Accessed October 28, 2024. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy
2. Pancreatic cancer update. Revolution Medicines. 2024. Accessed October 28, 2024. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf
3. Study of RMC-9805 in participants with KRAS G12D-mutant solid tumors. ClinicalTrials.gov. Updated July 25, 2024. https://clinicaltrials.gov/study/NCT06040541