Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C-Mutant Non-Small Cell Lung Cancer.

Abstract

<i>KRAS</i> mutations are identified in approximately 30% of patients with non-small cell lung cancer (NSCLC). Novel direct inhibitors of <i>KRAS</i> G12C have shown activity in early-phase clinical trials. We hypothesized that patients with <i>KRAS</i> G12C mutations may have distinct clinical characteristics and responses to therapies. Through routine next-generation sequencing, we identified patients with <i>KRAS</i>-mutant NSCLC treated at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 and reviewed tumor characteristics, overall survival, and treatment outcomes. We identified 1,194 patients with <i>KRAS</i>-mutant NSCLC, including 770 with recurrent or metastatic disease. <i>KRAS</i> G12C mutations were present in 46% and <i>KRAS</i> non-G12C mutations in 54%. Patients with <i>KRAS</i> G12C had a higher tumor mutation burden (median, 8.8 vs. 7 mut/Mb; <i>P</i> = 0.006) and higher median PD-L1 expression (5% vs. 1%). The comutation patterns of STK11 (28% vs. 29%) and KEAP1 (23% vs. 24%) were similar. The median overall survivals from diagnosis were similar for <i>KRAS</i> G12C (13.4 months) and <i>KRAS</i> non-G12C mutations (13.1 months; <i>P</i> = 0.96). In patients with PD-L1 ≥50%, there was not a significant difference in response rate with single-agent immune checkpoint inhibitor for patients with <i>KRAS</i> G12C mutations (40% vs. 58%; <i>P</i> = 0.07). We provide outcome data for a large series of patients with <i>KRAS</i> G12C-mutant NSCLC with available therapies, demonstrating that responses and duration of benefit with available therapies are similar to those seen in patients with <i>KRAS</i> non-G12C mutations. Strategies to incorporate new targeted therapies into the current treatment paradigm will need to consider outcomes specific to patients harboring <i>KRAS</i> G12C mutations.