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
Authors: Jänne Pasi A. , Bigot Frédéric , Papadopoulos Kyriakos , Eberst Lauriane , Sommerhalder David , Lebellec Loic , Voon Pei Jye , Pellini Bruna , Kalinka Ewa , Arbour Kathryn , Herzberg Benjamin , Boni Valentina , Bordenave Stephanie , Lee Hyun Woo , Ou Sai I. , Riess Jonathan Wesley , Beck Joseph T. , Ponz-Sarvise Mariano , Ascierto Paolo Antonio , Choi Yoon Ji , Yang Michelle , Bao Lei , Raman Rakesh , Yang Luxi , Mu Yunming , Wong Sofia , Dua Richa , Johnson Melissa 
Published: December 2023

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 of 1.8 hours. Modeling projected average target occupancy of ≥~90% at 100mg BID and above. Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were nausea (34%), diarrhea (30%), QTc prolongation (21%), vomiting and fatigue (15% each). The most common Gr3 TRAEs were QTc prolongation reported in 5 patients (3 at 400mg BID, 1 at 300mg, 1 at 200mg BID). Only one out of these 5 patients had an average QTc interval &gt;501ms. Most events of Gr3 QTc prolongation resolved to Gr1 or normal following dose interruption and/or reduction, and all 5 patients were asymptomatic and remained on treatment at a reduced dose. No treatment-related ≥Gr3 hepatotoxicity was observed. No patients experienced a treatment-related Gr4 or 5 AE, or a treatment-emergent AE that led to treatment discontinuation. Efficacy analysis was conducted in two dominant subgroups and included patients enrolled ≥8 weeks before data cutoff across all dose levels. The objective response rate was 57% (4/7; 3 confirmed) in NSCLC patients with recent prior KRASG12C(OFF) inhibitor treatment, and 44% (4/9; 3 confirmed) in CRC patients naive to KRASG12C(OFF) inhibitor treatment.
Conclusions This preliminary data set shows promising anti-tumor activity of RMC-6291 in KRASG12C-mutated NSCLC with recent prior KRASG12C(OFF) inhibitor treatment, and in KRASG12C-mutated CRC naive to KRASG12C(OFF) inhibitor treatment. Tolerability was acceptable below 400mg BID, suggesting the potential for combination with standard therapy, including immunologic agents. Dose optimization is ongoing.
Citation Format: Pasi A. Jänne, Frédéric Bigot, Kyriakos Papadopoulos, Lauriane Eberst, David Sommerhalder, Loic Lebellec, Pei Jye Voon, Bruna Pellini, Ewa Kalinka, Kathryn Arbour, Benjamin Herzberg, Valentina Boni, Stephanie Bordenave, Hyun Woo Lee, Sai I. Ou, Jonathan Wesley Riess, Joseph T. Beck, Mariano Ponz-Sarvise, Paolo Antonio Ascierto, Yoon Ji Choi, Michelle Yang, Lei Bao, Rakesh Raman, Luxi Yang, Yunming Mu, Sofia Wong, Richa Dua, Melissa Johnson. 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 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR014.