186P - Post-anti-PD1 tumor characterization of HPV-negative R/M SCCHN: an EORTC IMMUcan sub-project

Background

Characterization of the tumor molecular landscape and immune micro-environment (TIME) of recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) patients (pts) that progress after platinum therapy and PD-1 inhibitors will guide the rational development of new therapeutic approaches.

Methods

EORTC-1559 is a biomarker-driven study including pts with R/M SCCHN. Tumor biopsies are undergoing WES, RNA-seq, multiplex immunofluorescence (mIF) and Imaging Mass Cytometry (IMC) within the IMMUcan consortium.

Results

132 HPV-negative R/M SCCHN in disease progression were biopsied, including 112 who progressed on/after anti-PD1 treatment (anti-PD1-exposed) and 20 anti-PD1 naive pts. Pathogenic mutations in KEAP1 and focal amplifications in MDM2, LRP5 and deletions in APLNR were more frequent in the anti-PD1-exposed pts compared to anti-PD1 naive pts. RNA-seq analyses on 108 pts were mined to accommodate possible confounding factors based on regression models using feature selection. Compared to anti-PD1 naïve tumors, anti-PD1 exposed tumors were enriched in cytoskeleton, cell adhesion and DNA repair gene modules. Those genes were enriched in specific loci characterized by high GC content and specific transcriptional factor motifs like DNMT1. Among the anti-PD1 exposed pts, those treated with anti-PD1 as last treatment before tumor biopsy, were enriched in interferon response and immune activation gene sets, and had higher expression of LAG3. Finally, IMC was analyzed in 91 pts. Pts with anti-PD1 as last treatment had a trend for higher CD4, CD8, Treg and PDL1 + macrophages global densities. The local densities of 13 immune cell types within the radius of tumor cells were compared to their global density. Cluster analysis identified 3 groups: group 1 was infiltrated by neutrophils, group 2 by diverse immune cells excluding neutrophils, and group 3 was excluded for all immune cell types.

Conclusions

We report the global landscape of genetic, phenotypic and TIME changes associated with the selective pressure of PD1 inhibition of R/M SCCHN. The implications and validation in another prospective cohort of IMMUcan are underway.

Clinical trial identification

NCT03088059, EORTC-HNCG-1559.

Legal entity responsible for the study

EORTC.

Funding

IMI2 JU grant agreement 821558, supported by EU’s Horizon 2020 and EFPIA.

Disclosure

D. Herrero Saboya: Financial Interests, Personal, Full or part-time Employment: Servier Research & Develpment. M. Morfouace: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare. R. Galot: Other, Personal, Other, Travel expenses: Merck. H.S. Hong: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare. C. Lefebvre: Financial Interests, Personal, Full or part-time Employment: Servier Research & Development. C. Even: Financial Interests, Personal, Advisory Board: BMS, MSD, Innate Pharma, Merck Serono; Financial Interests, Institutional, Advisory Board: F Star Therapeutics, Novartis, Elevar; Financial Interests, Institutional, Local PI: BMS, AstraZeneca, ISA pharmaceutics, MSD, Debiopharma, Ayala, Gilead; Financial Interests, Institutional, Coordinating PI: BMS, Novartis, Sanofi. C. Le Tourneau: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck Serono, Nanobiotix, Roche, Rakuten, Seattle Genetics, GSK, Celgene, ALX Oncology, Exscientia. A. Daste: Financial Interests, Personal, Advisory Board: Merck, BMS, MSD. P. Saintigny: Financial Interests, Personal, Funding: HTG Molecular Diagnostics, Inivata, ArcherDx, Bristol Myer Squibb, Roche Molecular Diagnostics; Financial Interests, Personal, Research Funding: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, BMSFoundation, Illumina; Financial Interests, Institutional, Advisory Board: Omicure; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Illumina, Bristol Myer Squibb, AstraZeneca, Roche. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Merck Serono, Boehringer Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, Nektar, F-star, Seagen, Astellas, Genmab; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, Sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Ceylad, MSD, Novartis, KURA, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck - Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GSK; Non-Financial Interests, Personal, Leadership Role, Chair: EORTC head and neck group. All other authors have declared no conflicts of interest.