RMC-9805, a novel, oral RAS(ON) G12D-selective covalent inhibitor, has demonstrated promising initial safety, tolerability, and anti-tumor activity in patients with previously treated KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC). These preliminary findings from the phase 1/1b RMC-9805-001 trial (NCT06040541) were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. The results offer a potential new treatment avenue for a cancer with limited targeted therapy options.
Clinical Efficacy
As of the data cutoff on September 2, 2024, the objective response rate (ORR) was 30% (n = 12) and the disease control rate (DCR) was 80% (n = 32) among PDAC patients who received RMC-9805 at 1200 mg daily (n = 20) or twice daily (n = 20). These results suggest a clinically meaningful benefit in a population with a high unmet need.
Management Perspective
"We are pleased to report the first clinical data for RMC-9805... which demonstrate encouraging initial safety, tolerability and antitumor activity evidenced by tumor regressions," said Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, in a news release. He added that these data support the potential of RMC-9805 in the treatment of pancreatic cancer, both as a monotherapy and in combination regimens.
Study Design and Patient Population
The RMC-9805-001 phase 1/1b study is a multicenter, open-label trial involving dose-escalation and dose-expansion phases. It is designed to evaluate RMC-9805 in patients with advanced solid tumors harboring a KRAS G12D mutation. The study includes both a monotherapy arm and a combination arm, where RMC-9805 is being evaluated in combination with RMC-6236.
Eligible patients had pathologically documented, locally advanced or metastatic solid tumors with a KRAS G12D mutation, had received prior standard therapy, 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.
Dosage and Administration
During the dose-escalation phase, patients received RMC-9805 orally, either once daily at doses of 150 mg, 300 mg, 600 mg, 900 mg, or 1200 mg; or twice daily at doses of 300 mg, 450 mg, or 600 mg in 21-day cycles. As of the data cutoff, 179 patients had received escalating doses of RMC-9805 in the monotherapy cohort.
Endpoints and Prior Treatments
The key endpoints of the study were safety and tolerability, pharmacokinetic (PK) activity, and anti-tumor activity. All patients had received a median of 2 prior lines of therapy (range, 0-9).
Pharmacokinetic Profile
PK data suggested that the recommended phase 2 dose should be 1200 mg once daily.
Safety and Tolerability
No grade 4 or 5 treatment-related adverse events (TRAEs) or serious adverse events were 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 due to grade 1 events, and no treatment-related discontinuations occurred. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached.
Expert Commentary
"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," said David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston. "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.
