738P - Penile squamous cell carcinoma with high and very high tumor mutational burden (TMB): A genomic landscape and "real-world" clinical outcome study

Background

TMB is an established biomarker of efficacy with immune-checkpoint inhibitors (ICI) in a pan-cancer indication. TMB, however, has not been specifically considered for penile squamous cell carcinoma (PSCC).

Methods

We analyzed 397 PSCC cases to identify genomic alterations (GA) in >300 cancer-associated genes, genomic signatures, and TMB using a hybrid capture-based comprehensive genomic profiling (CGP) assay. TMB was categorized as low (<10 mutations [mut]/Mb), high (10-19), and very high (≥20). Tumor cell programmed cell-death ligand-1 (PD-L1) expression was determined by immunohistochemistry (IHC, Dako 22C3) and defined as tumor proportion score (TPS) ≥1%. Germline status of GA was predicted using a validated somatic-germline computational method. Separately, real-world clinical outcomes (RWCOS) data of patients with metastatic penile cancer receiving first-line ICI were obtained from the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB), which originated from approximately 280 US cancer clinics (∼800 sites of care).

Results

There were 339 (85.4%) TMB-low, 40 (10.1%) TMB-high and 18 (4.5%) TMB-very high PSCC. TMB ≥10 vs TMB-low PSCC revealed an enrichment of GA of PIK3CA (48.3% vs 18.3%; p<0.001) and KMT2D (29.3% vs 7.7%; p<0.001), and less frequent GA of CDKN2A (25.9% vs 45.7%, p=0.050). Most of these GA did not co-occur. PD-L1 expression was not impacted by TMB status. HPV identification was more frequent as TMB increased: 28.3% for the TMB-low, 50% for the TMB-high and 58.8% for the TMB-very high groups. In total, 95/1,377 (6.9%) GA were predicted to be of germline nature. In the FH-FMI CGDB cohort, 10 patients receiving ICI, 4 (40%) had a real-world overall survival (rwOS) >12 months with sustained benefit in 3/3 patients with TMB ≥10 mut/Mb.

Conclusions

Evaluation of advanced/metastatic PSCC by CGP based on TMB level revealed significant differences in biomarkers for the near 15% of cases that have high and very high TMB ≥10 mut/Mb. These PSCC cases represented a distinct tumor subgroup deserving further clinical investigation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

P. Spiess: Non-Financial Interests, Personal, Other, Vice Chair for Bladder and Penile Cancer: NCCN. R. Li: Financial Interests, Personal, Research Funding, Predicine; Veracyte; CG Oncology; Valar labs: Predicine; Veracyte; CG Oncology; Valar labs; Financial Interests, Personal, Advisory Board, CG Oncology: CG oncology; Financial Interests, Speaker, Consultant, Advisor, BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology: BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology. P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Bristol Myers Squibb, Asieris Pharmaceuticals, Merck KGaA, Seattle Genetics, Aadi Bioscience, Pfizer, Janssen, Boston Gene, Mirati Therapeutics, Exelixis, Genentech/Roche, Gilead Sciences, CG Oncology, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, ImmunityBio, Lucence Health, G1 Therapeutics, Fresenius Kabi, Guardant Health, PureTech, Regeneron Pharmaceuticals, Strata Oncology, Urogen, Silverback Therapeutics, Astellas Pharma; Financial Interests, Institutional, Local PI: Pfizer, Clovis Oncology, Bavarian Nordic, Gilead Sciences, Bristol Myers Squibb, Debiopharm Group, MSD, QED Therapeutics, GSK, Mirati Therapeutics, G1 Therapeutics, Merck KGaA. R. Huang: Financial Interests, Personal, Stocks/Shares: Roche. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. D.C. Pavlick: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche AG,. A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Steering Committee Member: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Coordinating PI: Incyte; Financial Interests, Local PI: Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). All other authors have declared no conflicts of interest.