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

Cancer Discovery - Tập 8 Số 7 - Trang 822-835 - 2018
Ferdinandos Skoulidis1, Michael E. Goldberg2, Danielle Greenawalt3, Matthew D. Hellmann4, Mark M. Awad5, Justin F. Gainor6, Alexa B. Schrock2, Ryan J. Hartmaier2, Sally E. Trabucco2, Laurie M. Gay2, Siraj M. Ali2, Julia A. Elvin2, Gaurav Singal2, Jeffrey S. Ross2, David Fabrizio2, Péter M. Szabó3, Chang Han3, Ariella Sasson3, Sujaya Srinivasan3, Stefan Kirov3, Joseph D. Szustakowski3, Patrik Vitazka3, Robin Edwards3, José A. Bufill7, Neelesh Sharma8, Sai‐Hong Ignatius Ou9, Nir Peled10,11, David R. Spigel12, Hira Rizvi4, Elizabeth Jiménez Aguilar5, Brett W. Carter13, Jeremy J. Erasmus13, Darragh Halpenny14, Andrew J. Plodkowski14, Niamh M. Long14, Mizuki Nishino15, Warren L. Denning1, Ana Galán‐Cobo1, Haïfa Hamdi1, Taghreed Hirz1, Pan Tong16, Jing Wang16, Jaime Rodriguez‐Canales17, Pamela Villalobos17, Edwin R. Parra17, Neda Kalhor18, Lynette M. Sholl19, Jennifer L. Sauter20, Achim A. Jungbluth20, Mari Mino‐Kenudson21, Roxana Azimi6, Yasir Y. Elamin1, Jianjun Zhang1, Giulia C. Leonardi5, Fei Jiang22,23, Kwok‐Kin Wong24, John Lee23, Vassiliki A. Papadimitrakopoulou1, Ignacio I. Wistuba17, Vincent A. Miller2, Garrett M. Frampton2, Jedd D. Wolchok25, Alice T. Shaw6, Pasi A. Jänne5, Philip J. Stephens2, Charles M. Rudin4, William J. Geese3, Lee A. Albacker2, John V. Heymach1
11Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
22Foundation Medicine Inc., Cambridge, Massachusetts.
33Bristol-Myers Squibb Co., Princeton, New Jersey.
44Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
55Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
66Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
77Michiana Hematology Oncology, Mishawaka, Indiana.
88Novartis Institute of Biomedical Research, East Hanover, New Jersey.
99Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California.
1010Thoracic Cancer Unit, Davidoff Cancer Center, Petach Tiqwa, Israel.
1111Tel Aviv University, Tel Aviv, Israel.
1212Sarah Cannon Research Institute, Nashville, Tennessee.
1313Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1414Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
1515Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts.
1616Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1717Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1818Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1919Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
2020Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
2121Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
2222Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China.
2323Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2424Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
2525Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.

Tóm tắt

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. 794. This article is highlighted in the In This Issue feature, p. 781

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