Abstract LB001: Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers
Authors: Koczywas Marianna , Haura Eric , Janne Pasi A. , Pacheco Jose M. , Ulahannan Susanna , Wang Judy S. , Burris Howard A. , Riess Jonathan W. , McCoach Caroline , Gordon Michael S. , Capasso Anna , Dua Richa , Wang Zhengping , Chen Ariel , Hayes Josie , Yang Luxi , Masciari Serena , Wang Xiaolin , Ou S Ignatius 
Published: July 2021

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node regulating RAS signaling. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Here we report data from the dose-escalation phase of this study. A total of 104 patients were dosed across three schedules: daily dosing (n = 49) and two intermittent dosing schedules, twice weekly on D1D4 (n = 31) or D1D2 (n = 24). Based on PK and tolerability, the recommended phase 2 dose and schedule (RP2DS) was determined to be 200 mg D1D2, delivering a 400 mg weekly dose intensity. Of the 80 efficacy evaluable patients, there was 1 CR (NF1LOF uterine carcinosarcoma), 1 PR (KRASG12C NSCLC), and 1 unconfirmed PR (KRASG12D NSCLC). Tumor regressions were observed in another 11 patients (-2.4% to -27.1%). Disease control rate was 61% (23/38) in patients with KRASMUT NSCLC and 80% (12/15) in KRASG12C NSCLC specifically. The safety and tolerability profile of RMC-4630 were consistent with the mechanism of action and RAS pathway inhibition. The most frequent adverse events (AEs) were edema (48%), diarrhea (47%), fatigue (36%), anemia (34%), and thrombocytopenia (33%). Most AEs were grade 1 or 2 and were manageable. Intermittent dosing with either D1D2 or D1D4 weekly was generally better tolerated than daily dosing at an equivalent weekly dose intensity. Plasma concentrations of RMC-4630 after dosing with 200 mg D1D2 were above those predicted to be clinically active based on preclinical models. Cmax reached and often exceeded the ‘apoptotic threshold' defined as plasma exposures that were associated with induction of tumor regressions in preclinical models. Trough concentrations at the end of each week were at or around the EC50 for RAS pathway inhibition in tumor which is predicted to be sufficient to allow normal tissue recovery and therefore maintain tolerability with sustained dosing up to 6 months. Sequential analysis of pERK levels in peripheral blood cells and paired pre- and on-treatment tumor biopsies showed evidence of RAS pathway inhibition. Tumor and blood-based immune-oncology biomarkers showed preliminary evidence of anti-tumor immune activation. Longitudinal analysis of circulating tumor DNA indicated molecular responses consistent with anti-tumor activity in tumors carrying specific driver mutations in the RAS signaling pathway. An expansion cohort of patients with gynecologic cancers with NF1LOF is underway with monotherapy at the RP2DS. RMC-4630 continues to be evaluated in combination with the MEK inhibitor cobimetinib (Cotellic), the KRASG12C(OFF) inhibitor sotorasib, the PD1 inhibitor pembrolizumab (Keytruda) and the EGFR inhibitor osimertinib (Tagrisso). Additional combination studies are also planned.

Citation Format: Marianna Koczywas, Eric Haura, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Richa Dua, Zhengping Wang, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari, Xiaolin Wang, S Ignatius Ou. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB001.