Tag: Non-Melanomatous Skin Cancers

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

SUMMARY: The FDA on February 9, 2021, granted regular approval to LIBTAYO® (Cemiplimab-rwlc) for patients with locally advanced Basal Cell Carcinoma (laBCC) previously treated with a HedgeHog pathway Inhibitor (HHI) or for whom a HHI is not appropriate, and granted accelerated approval to LIBTAYO® for patients with metastatic BCC (mBCC) previously treated with a HHI or for whom a HHI is not appropriate.

BCC is the most common type of skin cancer in the U.S., with approximately two million new cases diagnosed every year. Exposure to UltraViolet rays is a significant risk factor. Majority of BCCs are diagnosed early and cured with surgery and radiation. However, a small proportion of tumors can become locally advanced or progress to metastatic disease and can be painful and disfiguring. The primary systemic treatment options for these patients with advanced BCC are oral HedgeHog pathway inhibitors such as ERIVEDGE® (Vismodegib) and ODOMZO® (Sonidegib). There are however no FDA-approved treatment options available, for patients who progress on, or are intolerant to HedgeHog Inhibitors (HHIs).

LIBTAYO® is a fully human IgG4, high affinity anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor on tumor-infiltrating T cells and blocks its interaction with tumor derived ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. LIBTAYO® was previously approved by the FDA in 2018 as the first systemic treatment for adults with metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC, who are not candidates for curative surgery or curative radiation.

The present FDA approval of LIBTAYO® was based on results from an interim analysis of an ongoing open-label, multi-center, non-randomized Phase II trial (Study 1620), involving patients with unresectable locally advanced BCC or metastatic BCC (nodal or distant). This was the first and largest prospective clinical trial (N=132) among this patient population, with 112 patients included in the efficacy analysis. Patients in both cohorts (locally advanced and metastatic) had either progressed on HHI therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy. Eligibility required that locally advanced BCC patients were not candidates for curative surgery or curative RT, per multidisciplinary assessment. All patients received LIBTAYO® 350 mg IV over 30 minutes every 3 weeks for up to 93 weeks, until disease progression, unacceptable toxicity, or completion of planned treatment. No PD-L1 or Tumor Mutational Burden (TMB) testing was required before starting treatment with LIBTAYO®. The Primary efficacy endpoint was confirmed Objective Response Rate (ORR) and a key Secondary endpoint was Duration of Response (DOR), as assessed by Independent Central Review.

Among the 84 patients with locally advanced BCC, the confirmed ORR was 29% with a median DOR not reached, and 79% of responders maintained their response for at least 6 months. Among 28 patients with metastatic BCC, the confirmed ORR was 21%, with a median DOR not reached, and all responders maintained their responses for at least 6 months. The most common adverse reactions (incidence 20% or more) were fatigue, musculoskeletal pain, diarrhea, rash, and pruritis.

It was concluded from this study that LIBTAYO® is the first agent to provide clinically meaningful anti-tumor activity including durable responses, in patients with advanced BCC, after progression or intolerance on HHI therapy.

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs). Lewis KD, Peris K, Sekulic A, et al. Presented at the 2021 Winter Clinical Dermatology Conference, January 16–24, Virtual Conference (encore of SITC 2020 poster presentation).