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Cancer Discov. 2018 Jul;8(7):822-835. doi: 10.1158/2159-8290.CD-18-0099. Epub 2018 May 17.

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

Author information

1
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Foundation Medicine Inc., Cambridge, Massachusetts.
3
Bristol-Myers Squibb Co., Princeton, New Jersey.
4
Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
7
Michiana Hematology Oncology, Mishawaka, Indiana.
8
Novartis Institute of Biomedical Research, East Hanover, New Jersey.
9
Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California.
10
Thoracic Cancer Unit, Davidoff Cancer Center, Petach Tiqwa, Israel.
11
Tel Aviv University, Tel Aviv, Israel.
12
Sarah Cannon Research Institute, Nashville, Tennessee.
13
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
14
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
15
Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts.
16
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
17
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
18
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
19
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
20
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
21
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
22
Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China.
23
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
24
Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
25
Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
26
Foundation Medicine Inc., Cambridge, Massachusetts. jheymach@mdanderson.org lalbacker@foundationmedicine.com.
27
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jheymach@mdanderson.org lalbacker@foundationmedicine.com.
#
Contributed equally

Abstract

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. ©2018 AACR.See related commentary by Etxeberria et al., p. 794This article is highlighted in the In This Issue feature, p. 781.

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