Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy. The multi-arm phase 1b CodeBreaK101 master study is designed to evaluate the safety and tolerability of sotorasib in combination with both targeted and non-targeted therapies. Here we report the first safety and interim efficacy of sotorasib and afatinib, a pan-ErbB tyrosine kinase inhibitor, that had displayed synergistic antitumor activity in vitro. Methods: Patients with advanced KRAS p.G12C mutated NSCLC who had disease progression on prior therapies, including KRASG12C inhibitors, were enrolled in this dose exploration/expansion study. Patients were treated with 960 mg sotorasib QD and afatinib (20 mg or 30mg QD). Primary endpoint was safety/tolerability. Secondary endpoint was efficacy, including objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Results: Based on a July 12, 2021 snapshot, 33 pts with NSCLC (median age: 65.0 yrs) were enrolled. Ten pts received 20 mg afatinib/960 mg sotorasib QD (cohort 1) and 23 pts received 30 mg afatinib/960 mg sotorasib QD (cohort 2). Across both cohorts, the median number of prior therapies was 2 (range 0-7; 66.7% ≥ 2 prior lines) and 5 pts (15.2%) received prior sotorasib. The most common treatment-related adverse events (TRAEs) included diarrhea (23 pts [69.7%], 7 pts [21.2%] grade 3), nausea (7 pts [21.2%], all grade ≤ 2), and vomiting (6 pts [18.2%], all grade ≤ 2). Grade ≥ 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common. Eight pts (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 pts. Median treatment duration of sotorasib/afatinib combination was 64.0 days (Q1, 29.0; Q3, 128.0). For cohort 1 (N=10 that includes 4 pts who received prior sotorasib), the ORR was 20.0% and DCR was 70.0% (2-confirmed partial response (PR), 5-stable disease (SD), 1-progressive disease (PD), 2-not available); among the KRASG12C inhibitor-naïve patients, the ORR was 33.3%. For cohort 2 (N=23 that includes 1 pt who received prior sotorasib), the ORR was 34.8% and DCR was 73.9% (8-confirmed PR, 9-SD, 4-PD, 2-not available). Among 5 pts receiving prior sotorasib, 3 had SD, 1 PD, and 1 withdrew from study due to an AE prior to any scan. EGFR co-mutation at baseline was detected in 4 of 24 pts; 2 of 4 pts responded to combination therapy. Conclusions: In this first report of a combination of sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib. The AEs observed are not new or novel to either agent, with diarrhea being the most common. Investigation is ongoing to further explore this combination in an expansion cohort of the CodeBreaK101 master protocol.

Citation Format: David Gandara, Kristen Marrone, Ramaswamy Govindan, Ferdinandos Skoulidis, Gregory Durm, Jeffrey Clarke, Richard Frank, John Krauss, Wendy Snyder, Tian Dai, Omar Mather, Paul Cifuentes, Antreas Hindoyan, Abraham Anderson, Timothy Burns. A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC) [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 P05-02.