Abstract 3431: Molecular determinants of KRAS p.G12C inhibitor efficacy in advanced NSCLC

Abstract Background: Irreversible allosteric KRAS p.G12C inhibitors (KG12Ci) such as sotorasib and adagrasib have revolutionized the therapeutic landscape of advanced KG12C-mutant NSCLC, however individual responses are heterogeneous and curtailed by innate and adaptive/acquired resistance. Molecular determinants of KG12Ci efficacy in NSCLC are poorly defined. We dissected the impact of major KG12C co-mutations and explored the effects of less prevalent co-alterations on the clinical activity of KG12Ci in the largest treated cohort to date of patients (pts) with advanced NSCLC. Key findings were validated in preclinical KG12C NSCLC models. Methods: Baseline clinico-genomic features and clinical outcome data from pts with stage IV KG12C NSCLC (ECOG PS 0-2) treated with single-agent KG12Ci were collected retrospectively from 20 centers in the US and Europe. The Kaplan-Meier method was used to estimate PFS and OS and differences were assessed with the log-rank test. Hazard ratios (HR) and their 95% CI were estimated using a Cox proportional hazards model stratified for clinical co-variates. The impact of selected co-alterations on sotorasib efficacy was assessed in syngeneic (C57BL/6) KG12C NSCLC models. Results: 411 eligible pts were included in the study. Median age was 68 years, 77% of pts had received both platinum-based chemotherapy and PD-(L)1 inhibitors and 35% had brain metastases. 83% of pts received sotorasib. ORR with KG12Ci was 32.4% (95% CI, 27.9-37.1), PFS was 5.1m (95% CI, 4.5-5.6) and OS was 10.2m (95% CI, 8.4-12.1). Co-alterations in KEAP1, SMARCA4 and CDKN2A/B were each associated with significantly shorter PFS (KEAP1: 2.8m vs 5.5m, HR 2.50, P<0.001; SMARCA4: 1.7m vs 5.5m, HR 2.64, P=0.001; CDKN2A/B: 2.3m vs 5.3m, HR 2.57, P<0.001) and OS with KG12Ci even after adjustment for clinical covariates. STK11 co-mutations without concurrent KEAP1 alterations did not impact clinical outcomes with KG12Ci. In an exploratory analysis, co-mutations in DNA damage repair (DDR) genes and genes encoding components of the ATRX/DAXX/EZH2 pathway were associated with improved KG12Ci efficacy, whereas PI3K/AKT/MTOR/PTEN alterations and missense ROS1/ALK/BRAF/NTRK1-3 mutations resulted in inferior outcomes. The impact of SMARCA4 and DDR gene inactivation was validated in isogenic syngeneic KG12CNSCLC models; additional co-alterations are under evaluation. Integration of KEAP1/SMARCA4/CDKN2A/B co-mutations identified a subgroup (KSCMUT, 37.6% of all pts) with significantly shorter PFS (2.7m vs 6.2m, P<0.001) and OS (6.3m vs 14.6m, P<0.001) that accounted for 57.3% of pts with primary refractory (PFS≤3m) disease. Conclusions: Co-mutations in KEAP1, SMARCA4 and CDKN2A/2B define subgroups of KG12C NSCLC pts with markedly distinct outcomes with KG12Ci monotherapy. Tailoring of KG12C inhibitor-anchored therapeutic strategies and patient stratification should take into account the co-mutation status of individual tumors. Citation Format: Marcelo V. Negrao, Haniel A. Araujo, Giuseppe Lamberti, Alissa J. Cooper, Teng Zhou, Neal Akhave, Lukas Delasos, J Kevin Hicks, Mihaela Aldea, Gabriele Minuti, Jacobi Hines, Jacqueline V. Aredo, Michael J. Dennis, Turja Chakrabarti, Susan Scott, Paolo Bironzo, Matthias Scheffler, Petros Christopoulos, So Yeon Kim, Sarah Goldberg, Ying Ni, Blerina Resuli, Lorenza Landi, Shu-Chi Tseng, Mizuki Nishino, Dwight Owen, Collin Blakely, Giannis Mountzios, Catherine A. Shu, Christine Bestvina, Marina Garassino, Kristen Marrone, Jhanelle Gray, Sandip Pravin Patel, Amy L. Cummings, Heather A. Wakelee, Jurgen Wolf, Giorgio V. Scagliotti, Federico Cappuzzo, Fabrice Barlesi, Pradnya Patil, Don L. Gibbons, Funda Meric-Bernstam, J Jack Lee, John V. Heymach, David S. Hong, Rebecca S. Heist, Mark M. Awad, Ferdinandos Skoulidis. Molecular determinants of KRAS p.G12C inhibitor efficacy in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3431.