Multiomic analysis of cutaneous squamous cell carcinoma (cSCC) and association with response to anti-PD1 therapy (PD1).

9585 Background: PD1 induces a durable response and improves the survival of patients (pts) with advanced cSCC; however, about 40% of pts are resistant to this treatment. Multiomic analysis (e.g., tumor mutational burden [TMB] and gene expression profiling [GEP]) has shown predictive value for PD1 response in various cancer types. This study aims to perform multiomic analysis of cSCC and study its association with the response to PD1. Methods: cSCC pts were prospectively enrolled in the PIP-PREDICT study (NCT06536257). Baseline tumor tissues were sent for: a) targeted TSO500 DNAseq (NGS), for TMB and mutational status, and b) NanoString Pancancer 360IO, for GEP. Baseline characteristics and clinical outcomes were collected. Pts treated with PD1 were categorized as responders (complete/partial response) or non-responders (progressive disease) based on RECIST 1.1. Pts with stable disease were further categorized into responders/ non-responders based on PET response (PERCIST). Results: 26 cSCC pts were enrolled; the median age was 79 (range 39-98) and 73% (n=19) were male. 7 pts (27%) were immunocompromised and 4 were on immunosuppressants. Head and neck (HN) primaries were present in 54% (n=14), and 58% (n=15) of the pts had stage IV disease. NGS was performed on 21 pts, revealing a median TMB of 39.2 mut/Mb (range 17.3-122.2). TP53 mutations were present in all cases (100%), with other frequent mutations observed in CDKN2A (43%), TERT promoter (43%), FAT1 (38%), NF1 (24%), PIK3CA (24%), TGFBR2 (19%), and CREBBP (19%). GEP of 22 pts showed that cSCC with HN primaries exhibited higher cancer-associated fibroblast (p=0.018) and stromal (p=0.035) signatures (sig), compared to non-HN pts. Pts on immunosuppressants demonstrated lower expression of cytokine (p=0.031), effector cell (p=0.019), and NK cytotoxicity (p=0.0498) sig compared to those not on immunosuppressants. 18 pts received PD1 for advanced cSCC with evaluable disease; ORR was 61.1% and DCR was 72.2%. After a median follow-up of 12.4 months (95% CI, 4.1-20.7), the 12-months PFS and OS rates were 57.9% and 94.7%, respectively (the median PFS and OS were not reached). Responders to PD1 exhibited higher expression of MHC-I (p=0.003), T cells (p=0.039), NK cells (p=0.009), interferon-gamma (p=0.03), cell adhesion molecules (p=0.039), and antigen presentation (p=0.03) sig. Conversely, non-responders showed higher levels of angiogenesis (p=0.005), endothelium (p=0.005), hypoxia (p=0.039), and CCR8 (p=0.017) sig. No differences were observed in the expression of immune checkpoints (e.g. PD-1, LAG3), TMB, or specific mutations in responders vs. non-responders. Conclusions: cSCC responsive to PD1 have higher expression of immune sig and lower expression of stromal and hypoxic sig. Well-known predictive features of response to immunotherapy (e.g. TMB, PD-1 sig) were not associated with response in this cohort.