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Poster display session

5442 - LKB1 loss is a novel genomic predictor of de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma

Date

09 Sep 2017

Session

Poster display session

Topics

Cancers in Adolescents and Young Adults (AYA);  Translational Research;  Non-Small Cell Lung Cancer

Presenters

Ferdinandos Skoulidis

Citation

Annals of Oncology (2017) 28 (suppl_5): v460-v496. 10.1093/annonc/mdx380

Authors

F. Skoulidis1, M.D. Hellman2, M.M. Awad3, J.F. Gainor4, H. Rizvi2, B. Carter5, W.L. Denning1, P. Villalobos6, E.R. Parra6, Y.Y. Elamin1, J. Zhang1, G.C. Leonardi7, D.F. Halpenny8, V.A. Papadimitrakopoulou1, I.I. Wistuba6, J.D. Wolchok9, A.T. Shaw10, P.A. Jänne11, C.M. Rudin2, J.V. Heymach1

Author affiliations

  • 1 Thoracic And Head And Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 2 Thoracic Oncology, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 3 Thoracic Oncology, Dana-Farber Cancer Institute, Boston/US
  • 4 Termeer Center For Targeted Therapies, Massachusetts General Hospital, Boston, MA/US
  • 5 Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 6 Translational Molecular Pathology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 7 Thoracic Medical Oncology, Dana-Farber Cancer Institute, 02215-5450 - Boston/US
  • 8 Radiology, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 9 Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York/US
  • 10 Cancer Center, Massachusetts General Hospital, Boston/US
  • 11 Lowe Center For Thoracic Oncology, Dana Farber Cancer Institute  , Boston, MA/US
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Resources

Abstract 5442

Background

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.

Methods

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.

Results

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.

Conclusions

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

Not applicable

Legal entity responsible for the study

SU2C/ACS Lung Cancer Dream Team

Funding

SU2C/ACS Lung Cancer Dream Team, MD Anderson Lung Cancer Moonshot, Cancer Prevention Research Institute of Texas, Andrew Sabin Family Foundation.

Disclosure

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.

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