Co-Occurring Alterations Guide Treatment Choice

Rajwanth R. Veluswamy, MD, MSCR, of the Perlmutter Cancer Center at NYU Langone Health, and Chinmay Jani, MD, of the University of Miami Sylvester Comprehensive Cancer Center, discuss how co-occurring alterations guide treatment choice in KRAS G12C-mutated non-small cell lung cancer. Dr. Veluswamy describes TP53, STK11, and KEAP1 as predictive and prognostic co-alterations: TP53 raises tumor mutational burden and preserves immunotherapy responsiveness, STK11 drives an immune-cold microenvironment and primary immunotherapy resistance, and KEAP1 confers broad treatment resistance and a poor prognosis, prompting him to add a CTLA-4 inhibitor to a PD-1 or PD-L1 inhibitor and chemotherapy when either is present. Dr. Jani adds that KRAS mutations ranked among the top mutations across younger and older lung cancer patients alike in a World Conference on Lung Cancer analysis, though TP53 co-mutation data were limited. Dr. Veluswamy notes that CDKN2A co-mutations confer an aggressive phenotype with less outcomes data available, and that STK11 does not diminish KRAS G12C inhibitor efficacy in the second line, whereas KEAP1 does.