<i>STK11/LKB1</i> Mutations and PD-1 Inhibitor Resistance in <i>KRAS</i>-Mutant Lung Adenocarcinoma

<i>KRAS</i> is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that <i>STK11/LKB1</i> (KL) or <i>TP53</i> (KP) comutations define distinct subgroups of <i>KRAS</i>-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 (<i>P</i> < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with <i>KRAS</i>-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; <i>P</i> = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (<i>P</i> < 0.001) and overall (<i>P</i> = 0.0015) survival compared with <i>KRAS</i>^MUT;<i>STK11/LKB1</i>^WT LUAC. Among 924 LUACs, <i>STK11/LKB1</i> alterations were the only marker significantly associated with PD-L1 negativity in TMB^{Intermediate/High} LUAC. The impact of <i>STK11/LKB1</i> alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In <i>Kras</i>-mutant murine LUAC models, <i>Stk11/Lkb1</i> loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify <i>STK11/LKB1</i> alterations as a major driver of primary resistance to PD-1 blockade in <i>KRAS</i>-mutant LUAC.<b>Significance:</b> This work identifies <i>STK11/LKB1</i> alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in <i>KRAS</i>-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. <i>Cancer Discov; 8(7); 822-35. ©2018 AACR.</i><i>See related commentary by Etxeberria et al., p. 794</i><i>This article is highlighted in the In This Issue feature, p. 781</i>.