First Patient Dosed in Study of RMC-6236 in KRAS-Driven Advanced Solid Tumors

A phase 1/1b monotherapy clinical trial of RMC-6236 for the treatment of patients with advanced solid tumors driven by a variety of RAS mutations has dosed its first patient.

The first patient has been dosed in the phase 1/1b monotherapy clinical trial (NCT05379985) of RMC-6236, for the treatment of patients with advanced solid tumors driven by a variety of RAS mutations, according to an announcemnet by Revolution Medicines, Inc.1

RMC-6236 is an oral, potent, tri-complex RAS(ON) inhibitor which works to uniquely target a variety of RAS(ON) variants responsible for many cancers.

The study’s first patient to be given RMC-6236 has pancreatic cancer with a KRASG12D mutation.

“Beginning clinical evaluation of the first compound from our broad portfolio of RAS(ON) Inhibitors marks a significant milestone in our efforts to serve unmet needs of patients with RAS-addicted cancers,” said Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, in the press release. “To our knowledge, RMC-6236 is the first oral, direct RAS inhibitor to be deployed against a tumor harboring the KRASG12D variant, and it ushers in a wave of groundbreaking RAS(ON) Inhibitors we expect to advance.”

The multicenter, open-label, dose-escalation, dose-expansion phase 1/1b trial is examining RMC-6236 in patients with advanced solid tumors who harbor selected KRASG12 mutations, including KRASG12D, KRASG12V and KRASG12R.2

Adult patients aged 18 years and older with histologically confirmed advanced solid tumor with KRAS p.G12A, KRAS p.G12D, KRAS p.G12R, KRAS p.G12S, or KRAS p.G12V mutations identified through DNA sequencing are eligible for enrollment in the trial. Patients must have received prior standard therapy appropriate for their tumor type and stage, an ECOG performance status of 0-1, and adequate organ function.

Those with any advanced solid tumor type with specific KRASG12 mutations can be enrolled into phase 1, the dose-exploration portion of the trial and administered RMC-6236 orally. The dose-expansion portion may continue with 1 or more groups of patients who have a single histotype/genotype receiving oral RMC-6236.

Main objectives of the study are to evaluate safety and tolerability of RMC-6236 in this patient population and to inform the recommended phase 2 dose and schedule. The primary end points include incidence of severity of treatment-emergent adverse events (AEs) and serious AEs, as well as number of patients with dose-limiting toxicity.

Additionally, secondary end points of the study consist of overall response rate, duration of response, disease control rate, time to response, progression-free survival, maximum observed blood concentration, time to reach maximum observed blood concentration, area under blood concentration time curve, and elimination half-life of RMC-6236.

“RMC-6236 is a compelling drug candidate with the potential to demonstrate broad utility across many RAS cancer variants, particularly those harboring KRASG12 mutations. We are enthusiastic about its potential both to display first-in-class single agent activity as an inhibitor of mutant RAS and to be deployed as a RAS companion inhibitor in combination with mutant-selective RAS(ON) Inhibitors we have in development,” added Steve Kelsey, MD, president, research and development at Revolution Medicines, in the press release.

References:
  1. Revolution medicines advances first RAS(ON) inhibitor into clinic, dosing first patient in phase 1/1b trial of RMC-6236. News release. Revolution Medicines, Inc. June 28, 2022. Accessed June 29, 2022. https://yhoo.it/3yrwCu4
  2. Evaluation of RMC-6236 in subjects with advanced solid tumors harboring specific mutations in KRAS. ClinicalTrials.gov. Accessed June 29, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05379985?term=RMC-6236&draw=2&rank=1