STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma.

• DOI: 10.1200/jco.2017.35.15_suppl.9016
• Publication Date: 2018-09-06T15:51:19Z
• Authors: Ferdinandos Skoul...; Matthew David Hel...; Mark M. Awad; Hira Rizvi; Brett W. Carter; Warren Denning; Yasir Elamin; Jianjun Zhang; Giulia Costanza L...; Darragh Halpenny; Andrew Plodkowski; Niamh Long; Jeremy J. Erasmus; Vassiliki Papadim...; Kwok-Kin Wong; Ignacio Ivan Wistuba; Pasi A. Janne; Charles M. Rudin; John Heymach
• Keywords: STK11

9016 Background: Identification of molecular predictors response to PD-1/PD-L1 inhibitors is critical in order maximize their therapeutic potential. We previously reported that KRAS-mutant lung adenocarcinomas (LUAC) with co-occurring genetic events STK11/LKB1(KL) or TP53 (KP) define subgroups marked differences immune contexture, including a paucity CD8+ TILs KL LUAC. Here, we assess clinical responses therapy and KP subsets, data assembled under the auspices SU2C/ACS Lung Cancer Dream Team. Methods: Patients (pts) metastatic LUAC who received at least one cycle therapy, were alive for ≥14 days thereafter, had available profiling identified retrospectively. Efficacy assessment was based on RECIST v1.1. PD-L1 expression tested using 22C3 pharmDx E1L3N IHC assays quantified as percent staining tumor cell membranes. Isogenic derivatives LKR10 Kras LA1/+ murine line CRISPR/Cas9-mediated Lkb1knockout used preclinical experiments. Results: 165 pts included [KL: 27%, KP: 36%, K-only: 37%]. Best overall differed significantly (PR: 9.1%, SD: 15.9%, PD: 75%) 33.3%, 20%, 46.7%) sub-groups (P = 0.005, Fisher’s exact test). PFS longer compared (median 12.9 wks vs 8.4 wks, HR 0.64, 95% CI 0.39-0.95, P 0.032, log-rank ORR K-only tumors 21.3% median 11.4 wks. positivity (≥1%) more frequent (75% 22%, 0.03, In syngeneic models LUAC, loss LKB1 promoted resistance PD-1 inhibitor monotherapy, suggesting causative role. Conclusions: Mutational inactivation STK11/LKB1 represents novel genomic predictor de novo checkpoint blockade whereas co-mutations are associated high likelihood response. Precision immunotherapy will require tailoring co-mutation status individual tumors.