STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.
Ferdinandos Skoulidis,Michael E. Goldberg,Danielle Greenawalt,Matthew D. Hellmann,Mark M. Awad,Justin F. Gainor,Alexa B. Schrock,Ryan J. Hartmaier,Sally E. Trabucco,Siraj M. Ali,Julia A. Elvin,Gaurav Singal,Jeffrey S. Ross,David Fabrizio,Péter Szabó,Han Chang,Ariella Sasson,Sujaya Srinivasan,Stefan Kirov,Joseph D. Szustakowski,Patrik Vitazka,Robin Edwards,Jose A. Bufill,Neelesh Sharma,Sai-Hong Ignatius Ou,Nir Peled,Nir Peled,David R. Spigel,Hira Rizvi,Elizabeth Jimenez Aguilar,Brett W. Carter,Jeremy J. Erasmus,Darragh Halpenny,Andrew J. Plodkowski,Niamh Long,Mizuki Nishino,Warren Denning,Ana Galan-Cobo,Haifa Hamdi,Taghreed Hirz,Pan Tong,Jing Wang,Jaime Rodriguez-Canales,Pamela Villalobos,Edwin Roger Parra,Neda Kalhor,Lynette M. Sholl,Jennifer L. Sauter,Achim A. Jungbluth,Mari Mino-Kenudson,Roxana Azimi,Yasir Elamin,Jianjun Zhang,Giulia Costanza Leonardi,Fei Jiang,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 +69 more
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TLDR
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.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.read more
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PD-1 blockade induces responses by inhibiting adaptive immune resistance
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