Abstract 1282P
Background
Patients with KRAS-mutated aNSCLC benefit from immune-checkpoint blockers (ICB) in nearly half of cases, while aNSCLCs with other oncogenic drivers generally experience primary ICB resistance. The links between oncogenic stresses and ICB resistance are unknown. We aim to identify transcriptomic features associated with immune-suppression in oncogene-addicted aNSCLC.
Methods
ICB naïve oncogene-addicted aNSCLC patients from MATCH R (NCT02517892) with available data from RNA sequencing were included. Tumors were divided into 3 groups: “non-KRAS” (EGFR, ALK, ROS1, BRAF, RET, ROS1, MET alterations), “KRAS ICB-S” (KRAS+, ICB response ≥ 6 months) and “KRAS ICB-PD” (KRAS+, progression in < 6 months of ICB). Differential gene expression (DESeq2), pathway enrichment and identification with MSigDb were performed and compared between groups. Immune cell type contents were evaluated by CIBERSORT Absolute mode and EPIC analytical tools.
Results
Biopsies of 102 patients were included: 82 “non-KRAS”, 12 “KRAS ICB-S” and 8 “KRAS ICB-PD”. Pathways of epithelial to mesenchymal transition (EMT), TNF and hypoxia were upregulated in “KRAS ICB-PD” vs “KRAS ICB-S” (p<0.001, log2fold change (LFC) 2.25, 2.36 and 2.09, respectively) and in “KRAS ICB-PD” vs “non-KRAS” (p<0.001, LFC 2.28, 2.62 and 2.28, respectively). These pathways were not significantly different between “non-KRAS” and “KRAS ICB-S”. Seven upregulated genes were found in both “non-KRAS” and “KRAS ICB-PD” vs “KRAS ICB-S” (SYT8, PLAT, KRT16, GJB6, AC009549.1 , AC008392.1 , AP001527.2). The CD8+ T cell/all immune cells ratio was significantly higher in “KRAS ICB-S” group vs others (p=0.045). There were higher M2/M1 macrophage ratio (p=0.008) and neutrophil/all immune cells ratio (p=0.007) in “KRAS ICB-PD”, while more naïve B cells (p=0.005), activated mast cells (p=0.008) and activated NK cells (0.009) in ”KRAS ICB-S”. These scores were not different between “non-KRAS” and “KRAS ICB-S”.
Conclusions
Genes associated with endosome trafficking (SYT8), T-regs (PLAT, GJB6), cytokeratin (KRT16) or long non-coding RNAs might be associated with ICB resistance in oncogene-addicted NSCLC. In contrast, patterns of resistance in KRAS+ NSCLC imply EMT, hypoxia, TNF, neutrophils and M2 macrophages.
Clinical trial identification
MATCH R Trial NCT02517892.
Editorial acknowledgement
Legal entity responsible for the study
B. Besse.
Funding
Has not received any funding.
Disclosure
A. Gazzah: Financial Interests, Institutional, Principal Investigator: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, BBB Technologies BV, Beigene, Bioalliance Pharma, BioNTech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Sanofi; Financial Interests, Personal, Other, Travel, accommodation: Boehringer Ingelheim, Novartis, Pfizer, Roche. P. Lavaud: Financial Interests, Personal, Other, Travel, accommodation: Janssen, Mundi Pharma, Astellas Pharma, AstraZeneca, Ipsen. D. Planchard: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung.; Financial Interests, Personal, Sponsor/Funding: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung; Financial Interests, Institutional, Principal Investigator: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Financial Interests, Personal, Other, Travel, Accommodation: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. F. Barlesi: Financial Interests, Personal, Other, Personal fees: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. J-C. Soria: Financial Interests, Personal, Advisory Role: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, Takeda; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Gritstone. A. Marabelle: Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/MedImmune, Amgen, Sanofi; Financial Interests, Institutional, Principal Investigator: AbbVie, Aduro biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Bayer Healthcare Ag, BBB Technologies BV, Beigene, Bioalliance Pharma, BioNTech Ag, Blueprint Medicines, Boeh; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Financial Interests, Personal, Invited Speaker, Travel: AstraZeneca, BMS, Merck (MSD), Roche; Financial Interests, Institutional, Research Grant: Merus, BMS, Boehringer Ingelheim, Transgene, Fondation MSD Avenir. B. Besse: Financial Interests, Personal and Institutional, Research Grant: AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma; Financial Interests, Institutional, Principal Investigator: Nerviano, GSK, Pfizer, Roche-Genentech, Lilly, OSE Pharma, MSD, Celgene, Stemcentrx, Ignyta, AbbVie, Loxo Oncology, AstraZeneca, Blueprint Medicines. All other authors have declared no conflicts of interest.