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

By F. Skoulidis, M. Goldberg, D. Greenawalt, M. Hellmann, M. Awad, J. Gainor, A. Schrock, R. Hartmaier, S. Trabucco, L. Gay and 59 more. Cancer Discovery, 2018

1,344 citations recorded by the source corpus.

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations 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 SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 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 survival (P=0.0015) compared to KRASMUT;STK11/LKB1WT LUAC. Among 924 LUAC, 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 NSCLC. 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.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/31fc53b97e27eda644b14849efa3e5295222c9e8

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Citations in the corpus

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry (2019, background): “Recently, STK11/LKB1 co-mutation in KRAS-mutant NSCLC was reported as a new predictive marker for tumor resistance to ICI therapy [21].”
Advances in immunotherapy for hepatocellular carcinoma (2021, background): “I.M. receives funding from MINECO SAF2014-52361-R and SAF 2017- 83267-C2-1R; Worldwide Cancer Research Grant (15-1146); the Asociacion Española Contra el Cancer (AECC) Foundation under grant GCB15152947MELE; and the European Union’s Horizon 2020 Program (grant agreement no. 635122 PROCROP).”
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic (2018, background): “Some immunologically relevant genes that can become mutated in cancers include JAK1, JAK2, B2M, STK11, and others [51, 52].”