Key Takeaways

1. Modest but real efficacy - Pooled ORR of 21% across 6 trials (181 patients), rising to ~46% with combination strategies vs ~11% with monotherapy alone (Maiorano et al., 2025 meta-analysis).
2. No dedicated FDA approval exists for vulvar cancer specifically - clinical use is guided by tumor-agnostic approvals (MSI-H/dMMR, TMB-H) and extrapolation from cervical cancer data (KEYNOTE-826).
3. All VSCC tumors express PD-L1 (median CPS = 66 in a 2026 study of 108 cases), meaning virtually all patients are technically biomarker-eligible - but CPS does not reliably predict response.
4. Both HPV+ and HPV- subtypes may benefit - HPV-independent tumors paradoxically show higher immune infiltration (CD8+ TILs, CD68+ macrophages, PD-L1), supporting ICI trials across both subtypes.
5. Combination approaches are superior - ICI + chemotherapy, dual ICI (nivo + ipi), and ICI + HDAC inhibitors (pembrolizumab + vorinostat: ORR 19%, OS 11.1 months in PEVOsq Phase II basket trial, Nature Cancer 2025) all outperform monotherapy.
6. The biggest gap is the absence of randomized controlled trials specific to VSCC due to disease rarity. Biomarker-driven, molecularly stratified trials are the top research priority.