RMC-9805 Hits Milestone in Early-Phase Clinical Trial of KRAS G12D+ Solid Tumors

The oral, covalent, mutant-selective KRAS inhibitor, RMC-9805, has been dosed for the first time in a patient with a KRAS-G12D-mutant solid tumor, marking the beginning of a phase 1/1b clinical trial (NCT06040541).¹

The study follows a multicenter, open-label, dose-escalation, and dose-expansion design. The key goal of the study is to determine the safety and tolerability of RMC-9805 in patients with KRAS G12D-mutant solid tumors by evaluating a cohort of 290 patients with KRAS-driven solid tumors.

“The initiation of patient dosing with RMC-9805 marks a major milestone for Revolution Medicines as its third oral RAS(ON) Inhibitor to begin clinical evaluation,” said Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, in a press release. “We are now studying in the clinic, 3 highly-innovative RAS(ON) Inhibitors derived from our pioneering tri-complex inhibitor platform that we believe have complementary profiles – RMC-6236 for patients with cancers caused by a wide range of RAS mutations, and the mutant-selective compounds RMC-6291 [KRAS G12C] and RMC-9805 [KRAS G12D] for patients with cancers harboring selected mutations.”

The primary end points to be assessed in the phase 1/1b study include the incidence and severity of adverse events, and dose-limiting toxicities. The secondary end points of the study related to tolerability include maximum observed blood concentration of RMC-9805 time to reach maximum blood concentration of RMC-9805, area under blood concentration time curve of RMC-9805, ratio accumulation of RMC-9805 from single dose to steady state with the repeated dosing, and elimination half-life of the drug. Other secondary end points of the study include overall response rate, duration of response, disease control rate, time to response, and progression-free survival.²

Patients eligible for inclusion in the study are those with a pathologically documented locally advanced or metastatic solid tumor and a KRAS G12D mutation. Patients are required to have progressed on or developed intolerance to prior standard therapy, have an ECOG performance status of 0 or 1, and adequate organ function.

Patients excluded from the study are those with primary central nervous system tumors, known or suspected leptomeningeal or active brain metastases or spinal cord compression, known or suspected gastrointestinal illness, and those who were previously treated with an investigational KRAS G12D inhibitor or RAS-directed targeted agent.

“With this strong clinical portfolio, as well as a rich collection of additional mutant-selective drug candidates and research-stage assets, we believe our pipeline has the potential to change the standard of care for patients living with a wide range of RAS-addicted cancers including NSCLC, pancreatic cancers, and colorectal cancers,” said Goldsmith.¹

_REFERENCES:

_{1. Revolution Medicines doses first patient in phase 1/1b clinical trial of RMC-9805, an oral, covalent, mutant-selective KRASG12D(ON) Inhibitor. News release. Revloution Medicines, Inc. September 19, 2023. Accessed September 22, 2023. https://tinyurl.com/yp435j7j}

_{2. Study of RMC-9805 in participants with KRAS G12D-mutant solid tumors. ClinicalTrials.gov. September 15, 2023. Accessed September 22, 2023. https://tinyurl.com/4n8ndhvx}