OA03.06 CodeBreaK 100/101: First Report of Safety/Efficacy of Sotorasib in Combination with Pembrolizumab or Atezolizumab in Advanced KRAS p.G12C NSCLC

Abstract

Introduction: Sotorasib monotherapy has demonstrated a durable objective response rate (ORR) of 41%, and 33% 2-year overall survival (OS) in advanced pre-treated KRAS p.G12C-mutated NSCLC. In preclinical studies, sotorasib combined with anti-PD-1 therapy increased CD8+ T-cell infiltration and enhanced anti-tumor efficacy. Here we provide the first assessment of safety and efficacy of sotorasib with either pembrolizumab (Pembro) or atezolizumab (Atezo) anti-PD-(L)1 immunotherapy (IO) from CodeBreaK 100/101 phase 1b dose exploration. Methods: KRASG12C inhibitor-naïve patients with KRAS p.G12C-mutated NSCLC were treated in 12 dose exploration cohorts at varying doses of sotorasib (120-960mg QD) in combination with either intravenous Atezo 1200mg or Pembro 200mg, administered concurrently every 3 weeks until intolerability or disease progression. Half of the cohorts were lead-in cohorts, where patients received sotorasib monotherapy for either 21 or 42 days prior to their first dose of IO, then received Atezo or Pembro together with sotorasib. Primary objective was safety/tolerability; secondary efficacy objectives included ORR (investigator assessment per RECIST v1.1) and disease control rate (DCR). The dose limiting toxicity (DLT) window was 21 days following initiation of combination treatment. Results: 58 patients were treated with a median follow-up of 12.8 months (range: 1.6, 29.9). Median prior lines of therapy were 1 (range 0-7); 67% patients received prior IO. The median doses of sotorasib were 83 [range: 22-791], and median doses of IO were 3 [range: 1-26]). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased ALT and AST (Table). Of patients with grade 3-4 hepatotoxicity TRAEs, first occurrence was outside the DLT window in 22 of 25 (88%) patients, most were managed with corticosteroids, and 97% of events resolved. No fatal TRAEs occurred. Grade 3-4 TRAEs and TRAEs leading to treatment discontinuation occurred less often in the lead-in versus concurrent cohorts (Table). Across all 12 cohorts, confirmed response was observed in 17 of 58 patients (29%; range, 0-67). Among the 17 responders, median duration of response was 17.9 months (range: 1.5+, 23.4). For all 58 patients across cohorts, median OS was 15.7 months (95% CI: 9.8, 17.8). Conclusions: In this mostly pre-treated NSCLC population, combining sotorasib with IO led to a higher incidence of grade 3-4 TRAEs than previously observed with monotherapy, primarily liver enzyme elevations. Lead-in cohorts demonstrated durable clinical activity with lower rates of grade 3-4 TRAEs compared to concurrent cohorts. Dose expansion is ongoing in treatment-naïve patients using sotorasib lead-in followed by combination of sotorasib with Pembro. [Formula presented] Keywords: sotorasib, pembrolizumab, atezolizumab