Mechanisms of resistance to anti-PD1 treatment in recurrent and/or metastatic squamous cell carcinoma of the head and neck: A multi-omics IMMUCAN/EORTC analysis.

6050 Background: Anti-PD1 therapies improve overall survival (OS) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), but only a minority of patients (pts) achieve durable responses. The mechanisms driving resistance to anti-PD1 in SCCHN remain poorly understood. Methods: Using the IMMUcan multi-omics workflow combining WES, RNAseq, multiplex immunofluorescence and Imaging mass cytometry, we characterized the molecular and immune profiles of R/M SCCHN progressing on anti-PD1 treatment and compared them to an anti-PD1-naïve cohort. Results: 74 R/M SCCHN patients who progressed on PD1 inhibitors at the time of tumor biopsy were analysed and compared to a different cohort of 79 R/M SCCHN patients naïve of any anti-PD1 treatment. Among the 74 anti-PD1 resistant patients, 60 patients had primary resistance, and 14 had secondary resistance. Compared to anti-PD1 naïve SCCHN, tumor biopsies from anti-PD1 resistant SCCHN patients exhibited significantly more EGFR , MYCL and RRAGC amplifications, and more genomic alterations of the MYC pathway. Tumor samples harboring MYC pathway alterations were characterized by lower T cell infiltration compared to MYC pathway wild type (WT) tumors, and those harboring an amplification of EGFR had less B cells and dendritic cells in the tumor microenvironment compared to EGFR- WT. Moreover, transcriptomic and proteomic analyses revealed that secondary resistant SCCHN had increased CD8+ T cell infiltration and higher levels of immune exhaustion markers compared to anti-PD1 primary resistant and to anti-PD1-naïve SCCHN. 48 pts from the anti-PD1-naïve cohort were subsequently treated with PD(L)1 inhibitors. In this subgroup, pts with high B2M expression on tumor cells had better OS. SCCHN with high B2M expression on tumor cells also showed greater T cell infiltration compared to SCCHN with low B2M expression. Conclusions: Our data provide a rational to guide the development of therapeutic strategies aimed at reversing acquired resistance to PD-1 blockade in SCCHN. Our data suggest the potential use of B2M expression on tumor cells as predictive biomarker of response to anti-PD1 therapy. Clinical characteristics. Anti-PD1 naïve cohort(N=79) Anti-PD1 resistant cohort(N=74) Substance abuse Smoker and/or drinker 68 (86.1%) 62 (83.8%) HPV-status Positive 11 (13.9%) 10 (13.5%) Primary disease location Oral cavity 19 (24.1%) 17 (23.0%) Oropharynx 34 (43.0%) 33 (44.6%) Hypopharynx 14 (17.7%) 14 (18.9%) Larynx 12 (15.2%) 10 (13.5%) Disease extent at the time of tumor biopsy Locoregional only disease 32 (40.5%) 26 (35.1%) Distant metastatic disease 47 (59.5%) 48 (64.9%) Number R/M treatment lines prior to biopsy 0 57 (72.2%) 5 (6.8%) 1 17 (21.5%) 23 (31.1%) 2+ 5 (6.4%) 46 (62.2%)