Comparative effectiveness of first-line anti-PD-1 versus cetuximab in advanced cutaneous squamous cell carcinoma: A nationwide population-based study using the French national health data system.

BACKGROUND: Anti-PD-1 agents have demonstrated meaningful response rates in single-arm trials for advanced cutaneous squamous cell carcinoma (acSCC). However, no randomised or large-scale real-world studies have directly compared their effectiveness with cetuximab, used alone or in combination with chemotherapy, which has long been used off-label as first-line systemic therapy in this setting. This study compared survival outcomes with first-line anti-PD-1 therapy versus cetuximab using French nationwide data.

METHODS: We conducted a retrospective nationwide population-based cohort study of the French national health data system (SNDS). Adults with acSCC initiating first-line systemic therapy between 2017 and 2023 were included; those with alternative diagnoses or prior systemic therapy were excluded. The primary endpoint was overall survival (OS); the secondary endpoint was switch-free survival (SFS), used as a proxy for progression-free survival. Cox models with stabilised inverse probability of treatment weighting were used. Predefined subgroup and sensitivity analyses were performed.

RESULTS: Among 3006 patients (median age, 80 years; 74 % men), 2115 received anti-PD-1 (587 cemiplimab, 1118 pembrolizumab, 410 nivolumab) and 891 cetuximab. Median OS was 26 months with anti-PD-1 versus 14 with cetuximab (weighted HR, 0.79; 95 % CI, 0.69-0.90; p < 0.001). Median SFS was 22 versus 8 months (weighted HR, 0.59; 95 % CI, 0.52-0.67; p < 0.0001). Results were consistent across age, sex, and anti-PD-1 subgroups.

CONCLUSIONS: First-line anti-PD-1 therapy significantly improved overall and switch-free survival compared with cetuximab, used alone or in combination with chemotherapy. These findings provide robust real-world evidence supporting anti-PD-1 agents as the preferred first-line systemic treatment for acSCC in dermatologic oncology practice.