We previously reported that KRAS-mutant lung adenocarcinomas (LUAC) with co-occurring genetic events in STK11/LKB1 (KL) or TP53 (KP) define subgroups with marked differences in immune contexture, including paucity of infiltrating CD8+ lymphocytes in KL LUACs. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS-mutant LUAC subsets using data assembled by members of the SU2C/ACS Lung Cancer Dream Team.
Patients (pts) with metastatic KRAS-mutant LUAC who received at least one cycle of PD-1/PD-L1 inhibitor therapy, were alive for ≥14 days thereafter, and had available molecular profiling were identified retrospectively. Efficacy assessment was based on RECIST v1.1. PD-L1 expression was tested using 22C3 pharmDx or E1L3N IHC assays. Isogenic derivatives of the LKR10 KrasLA1/+ murine LUAC cell line with CRISPR/Cas9-mediated Lkb1 knockout were used in preclinical experiments.
192 immunotherapy-treated (82% nivolumab, 12% pembrolizumab, 5% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant LUAC were included in the analysis. The ORR differed significantly between the KL (8.9%), KP (37.9%) and K-only sub-groups (25.8%) (P = 0.00069, Fisher’s exact test) and was concordant for each genotype across patient cohorts [ORR for KL: 8.3% in the MDA cohort, 8.7% in the MSKCC cohort and 9.5% in the DFCI/MGH cohort). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 3m, HR = 0.47, 95% CI 0.32-0.7, P = 0.0002, log-rank test) and OS (mOS 6.8m vs 16.1m, HR 0.48, 95% CI 0.3 to 0.76, P = 0.0018, log rank test) compared to KRAS-mutant LUAC with wild-type LKB1. 11/14 KL tumors with available IHC data were negative for PD-L1 expression. Among 7 PD-L1-negative KP tumors, 3 PRs and 2SDs were recorded. In syngeneic murine models loss of Lkb1 promoted resistance to PD-1 inhibitor monotherapy, suggesting a causative role.
Inactivation of LKB1 represents a novel genomic predictor of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant LUAC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the LKB1 status of individual tumors.
Clinical trial identification
Legal entity responsible for the study
SU2C/ACS Lung Cancer Dream Team
SU2C/ACS Lung Cancer Dream Team, MD Anderson Lung Cancer Moonshot, Cancer Prevention Research Institute of Texas, Andrew Sabin Family Foundation.
M.D. Hellman: Consultant/Advisory Board: Genentech, BMS, Merck, AstraZeneca, Janssen, Novartis Research support- Genentech, BMS. J.V. Heymach: Scientific Advisory Board: Genentech, BMS, AstraZeneca, Eli Lilly, EMD Serono, Boehringer Ingelheim. All other authors have declared no conflicts of interest.