| Literature DB >> 29773717 |
Ferdinandos Skoulidis1, Michael E Goldberg2, Danielle M Greenawalt3, Matthew D Hellmann4, Mark M Awad5, Justin F Gainor6, Alexa B Schrock2, Ryan J Hartmaier2, Sally E Trabucco2, Laurie Gay2, Siraj M Ali2, Julia A Elvin2, Gaurav Singal2, Jeffrey S Ross2, David Fabrizio2, Peter M Szabo3, Han Chang3, Ariella Sasson3, Sujaya Srinivasan3, Stefan Kirov3, Joseph Szustakowski3, Patrik Vitazka3, Robin Edwards3, Jose A Bufill7, Neelesh Sharma8, Sai-Hong I Ou9, Nir Peled10,11, David R Spigel12, Hira Rizvi4, Elizabeth Jimenez Aguilar5, Brett W Carter13, Jeremy Erasmus13, Darragh F Halpenny14, Andrew J Plodkowski14, Niamh M Long14, Mizuki Nishino15, Warren L Denning1, Ana Galan-Cobo1, Haifa Hamdi1, Taghreed Hirz1, Pan Tong16, Jing Wang16, Jaime Rodriguez-Canales17, Pamela A 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, J Jack 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 Albacker26, John V Heymach27.
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. ©2018 American Association for Cancer Research.Entities:
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Year: 2018 PMID： 29773717 PMCID： PMC6030433 DOI： 10.1158/2159-8290.CD-18-0099
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397