Abstract PR014: Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment

作者：Pasi A. Jänne, Frédéric Bigot, Kyriakos P. Papadopoulos, Lauriane Eberst, David Sommerhalder, Loïc Lebellec, Pei Jye Voon, Bruna Pellini, Ewa Kalinka‐Warzocha, Kathryn C. Arbour, Benjamin Herzberg, Valentina Boni, Stéphanie Bordenave-Juchereau, Hyun Woo Lee, Sai I. Ou, Jonathan W. Riess, J. Thaddeus Beck, Mariano Ponz‐Sarvisé, Paolo A. Ascierto, Yoon Ji Choi, Michelle Yang, Lei Bao, Rakesh Raman, Luxi Yang, Yunming Mu, Sofia Wong, Richa Dua, Melissa L. Johnson · 发表于：Molecular Cancer Therapeutics · 年份：2023 · DOI：10.1158/1535-7163.targ-23-pr014 · 被引用次数：60 · 研究领域：Ubiquitin and proteasome pathways、14-3-3 protein interactions、Biochemical and Molecular Research

Abstract Background RMC-6291 is a potent, covalent, orally bioavailable KRASG12C(ON) inhibitor that uses a novel tri-complex mechanism to selectively target the active, GTP-bound state of the oncogenic KRASG12C. In preclinical models, RMC-6291 achieved a superior response rate, deeper regressions and longer duration of response compared to the KRASG12C(OFF) inhibitor, adagrasib. Receptor tyrosine kinase (RTK) overexpression and/or hyperactivating alterations and new synthesis of KRASG12C(ON) have been identified as potential resistance mechanisms to KRASG12C(OFF) inhibitors. Preclinical modeling shows KRASG12C(ON) inhibitors retain potency in cells with RTK activation and further are expected to rapidly extinguish newly synthesized KRASG12C(ON). Methods Patients with previously treated, advanced KRASG12C-mutated solid tumors received escalating doses of RMC-6291. Doses included 50, 100, and 200mg once daily (QD) and 100, 200, 300, and 400mg twice daily (BID). Each cycle had 21 days, with efficacy assessed every 6 weeks. Additional patients were enrolled to backfill cohorts at dose levels that cleared dose-limiting toxicity evaluation to further characterize PK, safety, and anti-tumor activity of RMC-6291. Results As of August 8, 2023, 47 patients with KRASG12C mutated solid tumors were treated, and 35 remained on treatment. The median number of prior therapies was 3 (range, 1-7). RMC-6291 exhibited dose-dependent exposure with a median Tmax of 1.0 hour and terminal half-life ...