SUMMARY: The FDA on October 8, 2025 approved Cemiplimab-rwlc (LIBTAYO®) for the adjuvant treatment of adults with Cutaneous Squamous Cell Carcinoma (CSCC) at high risk of recurrence after surgery and radiation.
Cutaneous Squamous Cell Carcinoma (CSCC) is the second most common skin cancer worldwide, with an estimated 2.4 million new cases annually. While surgery with or without adjuvant radiotherapy achieves cure in the vast majority of patients, approximately 5% experience locoregional or distant recurrence. Patients with high-risk features, such as nodal involvement, perineural invasion, or locally recurrent disease, remain particularly vulnerable to relapse following definitive local therapy.
Previous efforts to improve outcomes through systemic adjuvant approaches have been largely unsuccessful. Notably, the POST/TROG 05.01 trial demonstrated no additional benefit of adjuvant Carboplatin-based chemoradiation over radiotherapy alone, underscoring the unmet need for effective systemic adjuvant strategies in this population.
Trial Design
The C-POST (NCT03969004) is an ongoing, international, randomized Phase 3 study evaluating whether adjuvant immunotherapy with Cemiplimab, a PD-1 inhibitor previously approved for advanced and metastatic CSCC, could reduce recurrence risk following surgery and postoperative radiotherapy in patients with high-risk disease. A total of 415 patients were randomized 1:1 to receive Cemiplimab-rwlc or placebo after completing adjuvant radiation therapy (within 2–10 weeks before randomization). Eligible patients had either nodal high-risk features (e.g., extracapsular extension or 3 or more positive nodes) or non-nodal features (e.g., T4 tumors with bone invasion, in-transit metastases, perineural invasion, or locally recurrent tumors with additional risk factors). Cemiplimab was administered intravenously at 350 mg IV every 3 weeks for 12 weeks, then 700 mg every 6 weeks for up to 36 additional weeks (total of 48 weeks or less). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included freedom from locoregional and distant recurrence, Overall Survival (OS), and safety.
Efficacy Results
After a median follow-up of 24 months, Cemiplimab demonstrated a substantial DFS benefit over placebo.
- Events: 24 with Cemiplimab vs. 65 with placebo
- Hazard Ratio for disease recurrence or death: 0.32 (95% CI, 0.20–0.51; P<0.001)
- Estimated 24-month DFS: 87.1% (95% CI, 80.3–91.6) vs. 64.1% (95% CI, 55.9–71.1)
The Kaplan–Meier curves separated early and remained distinctly apart over time, indicating both a rapid and durable treatment benefit.
Patterns of Recurrence
Cemiplimab significantly reduced both locoregional and distant recurrences:
- Freedom from locoregional recurrence at 24 months: 94.6% vs. 76.7% (HR=0.20; 95% CI, 0.09–0.40)
- Freedom from distant recurrence at 24 months: 94.3% vs. 83.8% (HR=0.35; 95% CI, 0.17–0.72)
The benefit was observed consistently across prespecified subgroups, including those stratified by PD-L1 tumor expression (<1% or ≥1%).
Safety Profile
Adverse events (AEs) of grade ≥3 occurred in 23.9% of Cemiplimab-treated patients compared with 14.2% in the placebo group. Treatment discontinuation due to AEs occurred in 9.8% versus 1.5%, respectively. The overall safety profile was consistent with known Cemiplimab toxicities, and quality-of-life scores remained largely stable throughout treatment. One treatment-related death was reported.
At the time of analysis, Overall Survival (OS) data were immature, with 25 deaths reported (12 in the Cemiplimab group, 13 in placebo). The 2-year OS was 94.8% vs. 92.3% (HR, 0.86; 95% CI, 0.39–1.90). Subsequent analyses will clarify whether the DFS advantage translates into a survival benefit.
Clinical Implications
The C-POST trial establishes adjuvant Cemiplimab as the first systemic therapy to significantly improve DFS in patients with high-risk CSCC following curative-intent surgery and radiotherapy. The 68% reduction in recurrence or death risk, coupled with a manageable safety profile, positions Cemiplimab as a potential new standard of care for this challenging population.
Notably, most recurrences occurred within the first year after local therapy, mirroring the known natural history of CSCC, and Cemiplimab’s early and sustained benefit suggests a durable immune-mediated effect.
While OS data are pending, these findings mark a major advance in the adjuvant management of high-risk CSCC. The results also stand in contrast to the KEYNOTE-630 trial of adjuvant Pembrolizumab, which was discontinued for futility, highlighting possible differences in trial design or patient selection.
Conclusion
Adjuvant therapy with Cemiplimab significantly prolongs Disease-Free Survival compared with placebo in patients with high-risk Cutaneous Squamous Cell Carcinoma after surgery and radiotherapy. The 24-month DFS benefit, 87% versus 64%, represents a meaningful reduction in recurrence risk and provides clinicians with the first evidence-based systemic option in this setting. Ongoing follow-up will determine the ultimate impact on Overall Survival.
Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. Rischin D, Porceddu S, Day F, et al. for the C-POST Trial Investigators. N Engl J Med 2025;393:774-785
