Adjuvant anti-PD-1 therapy in high-risk cutaneous squamous-cell carcinoma: post hoc insights from the C-POST and KEYNOTE-630 studies.

Background: Cutaneous squamous-cell carcinoma (cSCC) is cured with surgery with or without radiotherapy in most cases, but patients with high-risk features remain prone to recurrence. Until recently, no systemic adjuvant therapy was available. Recently, two phase III trials assessed post-operative anti-programmed cell death protein 1 (PD-1): C-POST (cemiplimab), which met its primary endpoint, and KEYNOTE-630 (pembrolizumab), which did not. Methods: We compared the eligibility criteria and risk definitions of both trials. Published disease-free survival (DFS) curves were digitized, and individual patient data (IPD) were reconstructed with validated algorithms. DFS was analyzed using Kaplan-Meier estimates, log-rank tests, Cox models, and restricted mean survival time. Subgroup analyses considered nodal high-risk patients in the two studies. Hazard ratios (HRs) informed a meta-analysis with the generic inverse variance method. Results: The placebo arms showed no DFS difference. Although no direct comparisons can be made across trials and in spite of the different eligibility criteria of the two studies, cemiplimab achieved superior DFS versus pembrolizumab. Pooling experimental arms confirmed a DFS benefit with PD-1 therapy [HR 0.53, 95% confidence interval (CI) 0.40-0.71]. Cemiplimab (HR 0.36) and pembrolizumab (HR 0.44) consistently reduced recurrence risk in nodal high-risk patients, yielding a combined HR of 0.40 (95% CI 0.26-0.62) with no heterogeneity. Conclusion: Adjuvant PD-1 blockade significantly improves DFS in high-risk cSCC. With the caveats of indirect comparisons and the pending full publication of one of the two trials, these post hoc findings are hypothesis generating and may help inform the selection of high-risk patients deserving adjuvant therapy.