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Two genes long blamed for immunotherapy failure in lung cancer turn out to matter only when the tumour also has a mutated KRAS gene. In tumours without it, the same mutations made no difference at all.
Clinicopathological and genomic data were collected from patients with advanced lung adenocarcinoma at two multi-institutional cohorts, and outcomes on PD-(L)1 inhibition were analysed by KRAS, STK11 and KEAP1 mutation status. In the combined cohort of 1,261 patients, KRAS mutations were detected in 536 cases, 42.5%, deleterious STK11 mutations in 260 of 1,261, 20.6%, and deleterious KEAP1 mutations in 231 of 1,202 assessable cases, 19.2%. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free survival (hazard ratios 2.04 and 2.05) and overall survival (2.09 and 2.24) on immunotherapy uniquely among KRAS-mutant but not KRAS wild-type adenocarcinomas. Gene expression and immune cell enrichment analyses showed that STK11 or KEAP1 mutation produced distinct immunophenotypes only in KRAS-mutant tumours.
It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.
Shares Ferdinandos Skoulidis, STK11 / KEAP1 co-mutations, KEAP1-NRF2 antioxidant pathway, KEAP1.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1-NRF2 antioxidant pathway, KEAP1.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, KEAP1, STK11, T-cell exhaustion.
Shares STK11 / KEAP1 co-mutations, STK11, PD-1 / PD-L1 immune checkpoint & T-cell activation, Memorial Sloan Kettering Cancer Center.
Shares Hot vs cold tumours, Dana-Farber Brigham Cancer Center, PD-1 / PD-L1 immune checkpoint & T-cell activation, Memorial Sloan Kettering Cancer Center.