STK11/LKB1 Mutations and PD 1 Inhibitor Resistance in KRAS Mutant Lung Adenocarcinoma.
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC) We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS mutant LUAC. Here, we examine the efficacy of PD 1 inhibitors in these subgroups. Objective response rates to PD 1 blockade differed significantly among KL (7.4% KP (35.7% and K only (28.6% subgroups (P 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS mutant LUAC and in patients treated with nivolumab in the CheckMate 057 phase III trial (0% vs. 57.1% vs. 18.2% P 0.047) In the SU2C cohort, KL LUAC exhibited shorter progression free (P 0.001) and overall (P 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD 1/PD L1 inhibitors extended to PD L1 positive non small cell lung cancer. In Kras mutant murine LUAC models, Stk11/Lkb1 loss promoted PD 1/PD L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD 1 blockade in KRAS mutant LUAC.Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD 1 axis inhibitors in KRAS mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7) 822 35. (c)2018 AACR.See related commentary by Etxeberria et al. p. 794This article is highlighted in the In This Issue feature, p. 781.
Cancer discovery