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

Abstract

Purpose: KRAS mutations are identified in approximately 30% of patients with non-small cell lung cancer (NSCLC). Novel direct inhibitors of KRAS G12C have shown activity in early-phase clinical trials. We hypothesized that patients with KRAS G12C mutations may have distinct clinical characteristics and responses to therapies.

Experimental design: Through routine next-generation sequencing, we identified patients with KRAS-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.

Results: We identified 1,194 patients with KRAS-mutant NSCLC, including 770 with recurrent or metastatic disease. KRAS G12C mutations were present in 46% and KRAS non-G12C mutations in 54%. Patients with KRAS G12C had a higher tumor mutation burden (median, 8.8 vs. 7 mut/Mb; P = 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 KRAS G12C (13.4 months) and KRAS non-G12C mutations (13.1 months; P = 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 KRAS G12C mutations (40% vs. 58%; P = 0.07).

Conclusions: We provide outcome data for a large series of patients with KRAS G12C-mutant NSCLC with available therapies, demonstrating that responses and duration of benefit with available therapies are similar to those seen in patients with KRAS non-G12C mutations. Strategies to incorporate new targeted therapies into the current treatment paradigm will need to consider outcomes specific to patients harboring KRAS G12C mutations.

Figure 1:

KRAS Mutation subtypes and baseline pathologic and molecular characteristics. A. In cohort of 772 patients with metastatic NSCLC, KRAS G12C was the most common mutation. G12V, and G12D, and G12A were the most common non-G12c subtypes observed. B. Median tumor mutational burden was higher in samples with G12C alterations (8.8 vs 7.0, p=0.006), C. Higher median PD-L1 expression was observed in G12C samples (5% vs 1%, p=0.04).

Figure 2:

Response to immune checkpoint inhibitors in patients with KRAS G12C mutation subtype compared to non-G12C subtypes. A. Best overall response to immune checkpoint inhibitor treatment, depicted in three PD-L1 subgroups reflecting high, intermediate, and absent PD-L1 expression. B. In unselected patient population, median progression free survival for patients treated with immune checkpoint inhibitor was similar (3.3 vs 3.7 months, p=0.8). C. In patients with high expression of PD-L1 (≥50%), patients with G12C mutations had shorter duration of response (14.4 vs 4.7 moths, p=0.07).

Figure 3:

Outcomes to treatment with chemotherapy and comparison of overall survival in patients with KRAS mutant NSCLC. A. In patients treated with platinum-doublet chemotherapy as first- or second-line therapy, time to treatment discontinuation for both KRAS G12C and non-G12C subtypes were similar (3.0 vs 2.8 months, p=0.57). B. Overall survival from time of metastatic diagnosis is similar in G12C and non-G12C subtypes (13.4 vs 13.1 months, p=0.99).