Clinical characteristics and anti-PD-(L)1 treatment outcomes of KRAS-G12C mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung cancer.

Abstract

9596 Background: KRAS mutations are identified in approximately 30% of NSCLC. There are no FDA approved targeted therapies for patients with KRAS-mutant non-small cell lung cancer (NSCLC) but novel direct inhibitors of KRAS G12C have shown some activity in early phase clinical trials. We hypothesized that patients with KRAS-G12C mutations may have distinct clinical characteristics and responses to systemic therapies compared to patients with non-G12C subtypes. Methods: We identified patients with KRAS-mutant lung cancers who underwent next-generation sequencing with MSK-IMPACT, between January 2014 and December 2018. Baseline characteristics were compared with the Chi-square and Fisher’s exact test for categorical data and Wilcoxon rank-rum test for continuous data. Overall survival was calculated from time of diagnosis of metastatic/recurrent disease to date of death or last follow up, with left truncation to account for time of MSK-IMPACT. Overall survival was compared between groups using the Cox proportional-hazards model. Response evaluations where performed by independent thoracic radiologists according to RECIST 1. and compared between group with the Fisher’s exact test. Results: We identified 1194 patients with KRAS -mutant NSCLC, 772 with recurrent or metastatic disease. Of patients with advanced disease, 46% (352/772) had mutations in KRAS-G12C and 54% harbored non-G12C mutations (15% G12D, 16% G12V, 8% G12A, 4% G13D). Co-mutation patterns were similar with respect to KEAP1 (p=0.9) and STK11 (p=1.0). Patients with non-G12C mutations had a higher proportion of never smokers (10% vs 1.4% p<0.001). The median OS from diagnosis was 13 months for G12C and non-G12C patients (p=0.99). 45% (347/772) received 1L or 2L line treatment with PD-(L)1 inhibitor. RECIST measurements were available for 290/347 cases (84%). ORR with anti-PD-(L)1 treatment was 24% vs 28% in G12C vs non-G12C patients (p=0.5). In patients with PD-L1 50% (n=103), ORR was 39% for G12C vs 58% non-G12C patients (p=0.06). Conclusions: KRAS G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development. Baseline characteristics including co-mutation patterns are similar between patients with G12C and non-G12C, except for smoking history. The efficacy of KRAS G12C direct inhibitors will need to be compared to other available therapies for KRAS mutant NSCLC (chemotherapy and PD-(L)1 inhibitors) to identify most effective therapeutic strategy.