STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma

Ferdinandos Skoulidis, Michael E. Goldberg, Danielle M. Greenawalt, Matthew D. Hellmann, Mark M. Awad, Justin F. Gainor, Alexa B. Schrock, Ryan J. Hartmaier, Sally E. Trabucco, Laurie Gay, Siraj M. Ali, Julia A. Elvin, Gaurav Singal, Jeffrey S. Ross, David Fabrizio, Peter M. Szabo, Han Chang, Ariella Sasson, Sujaya Srinivasan, Stefan KirovJoseph Szustakowski, Patrik Vitazka, Robin Edwards, Jose A. Bufill, Neelesh Sharma, Sai Hong I. Ou, Nir Peled, David R. Spigel, Hira Rizvi, Elizabeth Jimenez Aguilar, Brett W. Carter, Jeremy Erasmus, Darragh F. Halpenny, Andrew J. Plodkowski, Niamh M. Long, Mizuki Nishino, Warren L. Denning, Ana Galan-Cobo, Haifa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez-Canales, Pamela A. Villalobos, Edwin R. Parra, Neda Kalhor, Lynette M. Sholl, Jennifer L. Sauter, Achim A. Jungbluth, Mari Mino-Kenudson, Roxana Azimi, Yasir Y. Elamin, Jianjun Zhang, Giulia C. Leonardi, Fei Jiang, Kwok Kin Wong, J. Jack Lee, Vassiliki A. Papadimitrakopoulou, Ignacio I. Wistuba, Vincent A. Miller, Garrett M. Frampton, Jedd D. Wolchok, Alice T. Shaw, Pasi A. Jänne, Philip J. Stephens, Charles M. Rudin, William J. Geese, Lee A. Albacker, John V. Heymach

Research output: Contribution to journalArticlepeer-review

1095 Scopus citations

Abstract

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define dis tinct 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.

Original languageEnglish
Pages (from-to)822-835
Number of pages14
JournalCancer Discovery
Volume8
Issue number7
DOIs
StatePublished - 1 Jul 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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