Immune Checkpoint Inhibitors Effective in KRAS-Mutant NSCLC

More than 30% of patients with advanced non-small cell lung cancer (NSCLC) carry mutations in the KRAS gene. Mutated KRAS is associated with a poor prognosis, and there are currently no effective targeted therapies directed against this mutation. Immunotherapy with immune checkpoint inhibitors (ICI) targeting PD-1 and PD-L1 have become a standard treatment option for patients with advanced NSCLC who do not carry targetable mutations, but little is known about their efficacy in patients harboring KRAS mutations.

A retrospective French study of 282 patients with advanced NSCLC treated with ICI (first line or beyond) assessed the efficacy of ICI in patients with KRAS mutations compared to those without KRAS mutations.  Molecular analysis for mutations in EGFR, ALK, ROS1, KRAS, BRAF, PIK3CA, and HER2 were available for all patients. KRAS mutations were found in 57.4% of patients, while 9.6% carried other mutations and 33.0% were wildtype. Most patients received PD-1 or PD-L1 targeted immunotherapy, with the exception of 11 patients who received anti-CTLA-4 immunotherapy. There were no significant differences in treatment outcomes for patients with KRAS mutations compared to those without KRAS mutations. Overall response rate (ORR: 18.7% vs 14.4%; P = .348), progression-free survival (3.09 months vs 2.66 months; P = .584), and overall survival (OS: 14.29 months vs 11.14 months; P = .682) were similar between the two groups of patients. KRAS mutation subtype did not significantly impact outcomes.

Among 85 patients with KRAS mutations for whom PD-L1 expression analysis was available, 49.5% had PD-L1 expression ³1% and 21.2% had expression ³50%. Of interest, the expression of PD-L1 was significantly different between different KRAS-mutation subtypes, though this requires further validation due to the small number of patients. There was a trend toward improved ORR and prolonged PFS in patients with KRAS mutation with PD-L1 expression ³1% compared to those who were PD-L1 negative. Best results were seen in patients with KRAS mutation-positivetumors with PD-L1 expression ³50%. Analysis of immunotherapy efficacy according to PD-L1 expression in different KRAS-mutation subtypes suggests the benefit immunotherapy may vary across mutation subtypes.

The investigators concluded that the clinical benefit of immunotherapy in patients with advanced, KRAS mutation-positive NSCLC is similar to that seen in patients without KRAS mutations, and that these agents are viable treatment option for patients with KRAS mutations. The impact of PD-L1 expression on outcomes in patients with different KRAS mutations should be explored further in a prospective, randomized trial.

J Thorac Oncol. 2019 Feb 6. [Epub ahead of print].

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