Abstract P05-01: A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors
Authors: Ramalingam Suresh , Fakih Marwan , Strickler John , Govindan Ramaswamy , Li Bob T. , Goldberg Sarah , Gandara David , Burns Timothy , Barve Minal , Shu Catherine , Frank Richard , Sohal Davendra , Jafarinasabian Pegah , Dai Tian , Mather Omar , Hong David 
Published: December 2021

Abstract
Background KRAS p.G12C is an oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently approved by the FDA for treatment of adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy. Sotorasib combined with trametinib, a selective allosteric MEK1/MEK2 inhibitor, displayed synergist antitumor activity in tumor xenografts. Here we report the first safety and interim efficacy of sotorasib in combination with trametinib in advanced KRAS p.G12C-mutated solid tumors in this phase 1b CodeBreaK101 master study. Methods In this dose exploration/expansion study, patients (pts) with KRAS p.G12C-mutated solid tumors were treated with 960 mg QD sotorasib and trametinib (1 or 2 mg QD). For NSCLC, prior anti-PD1/PD-L1 and/or platinum-based combination chemotherapy and targeted therapy (if applicable) was required. For CRC, at least 1 prior systemic regimen including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens was required. 1° endpoint was safety/tolerability. 2° endpoint was efficacy. Results Based on a July 12, 2021 snapshot, 41 pts (22 male, median age: 60.0 y [34-84]) were enrolled and treated with combination of sotorasib and trametinib (18 pts NSCLC, 18 pts CRC, 5 pts other). Thirty-three pts (80.5%) received ≥2 prior lines of therapy (range, 0–8); 11 pts (26.8%) received prior KRASG12C inhibitor. Median treatment duration of the sotorasib and trametinib combination was 84.0 days (Q1, 42.0; Q3, 140.0). No new or unexpected toxicities were identified. The most common treatment-related adverse events (TRAEs) included diarrhea (43.9% pts), rash (34.1% pts), nausea (29.3% pts), and vomiting (22.0% pts), predominantly ≤grade 2. Ten pts (24.4%) discontinued sotorasib and/or trametinib due to a TRAE (2 pts-diarrhea). One dose-limiting toxicity (grade 3 maculo-papular rash, trametinib-related) was observed out of 33 pts treated with 2 mg trametinib/960 mg sotorasib QD. For the 1 mg trametinib/960 mg sotorasib QD CRC exploration cohort (N=3); 1 confirmed partial response (PR) and 1 stable disease (SD) were reported in pts with prior KRASG12C inhibitor; 1 SD was reported in a KRASG12C inhibitor-naïve pt. For the 2 mg trametinib/960 mg sotorasib QD CRC cohort (N=15), all 4 pts with prior KRASG12C inhibitor had SD; for naïve pts, 1-confirmed PR, 7-SD, and 3-progressive disease (PD) were reported. In NSCLC pts (N=18) treated with 2 mg trametinib/960 mg sotorasib QD, of pts with prior KRASG12C inhibitor, 2-SD and 1-PD were reported; of naïve pts, 3-confirmed PR, 10-SD, 1-PD, and 1-not evaluable were reported. Conclusions Combination of sotorasib and trametinib is safe and tolerable. The maximum tolerated dose tested was 2 mg trametinib/960 mg sotorasib QD. Antitumor activity was observed including responses in pts with prior KRASG12C inhibitor. Triplet combination therapy of sotorasib with trametinib and panitumumab currently are under investigation in solid tumors.
Citation Format: Suresh Ramalingam, Marwan Fakih, John Strickler, Ramaswamy Govindan, Bob T. Li, Sarah Goldberg, David Gandara, Timothy Burns, Minal Barve, Catherine Shu, Richard Frank, Davendra Sohal, Pegah Jafarinasabian, Tian Dai, Omar Mather, David Hong. A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P05-01.