Intralesional Cemiplimab Shows Promise as a Non-Surgical Alternative for Early-Stage CSCC

While surgery remains the standard treatment for early-stage cutaneous squamous cell carcinoma (CSCC), there is a significant unmet clinical need for effective non-surgical therapies, particularly for patients who are ineligible for surgery or prefer alternative options.¹ At the Winter Clinical Miami conference in Aventura, Florida, a poster from Migden et al. demonstrated results from a phase 1 pilot study exploring the safety, tolerability, and efficacy of low-dose intralesional cemiplimab (Libtayo; Regeneron) in patients with early-stage CSCC.² The study offers encouraging data supporting a novel, less invasive approach with rapid clinical responses and manageable safety profiles.

Background

Cemiplimab, a programmed cell death-1 (PD-1) inhibitor, is already approved at a 350 mg intravenous dose every 3 weeks for locally advanced or metastatic CSCC, as well as the adjuvant treatment post-surgery and radiation. However, systemic administration can be associated with immune-related adverse events, and alternatives are needed for select populations. Intralesional administration of immunotherapy agents like cemiplimab is hypothesized to facilitate localized immune activation, potentially reducing systemic exposure and related toxicity while promoting tumor regression.

Study Design and Methods

This open-label, dose-escalation, phase 1 pilot study (NCT03889912) included 2 expansion cohorts:

• Cohort A received 5 mg intralesional cemiplimab once weekly for 6 weeks (QW × 6).
• Cohort B received 5 mg intralesional cemiplimab every 2 weeks on weeks 1, 3, and 5 (Q2W × 3).

Twenty-four patients with early-stage CSCC (index lesion size 1.0 to 2.0 cm) and ECOG performance status ≤1 were enrolled, with 12 patients in each cohort. Key exclusion criteria included immunosuppression, recent autoimmune disease requiring systemic immunosuppressants, prior systemic PD-1/PD-L1 therapy, or recent anticancer treatment. Visual tumor responses were assessed using modified WHO criteria at weeks 7 and 13, with surgery planned at week 13 after completion of intralesional treatment. The primary endpoints were safety and tolerability, while secondary endpoints included visual objective response rate (ORR) and pathologic complete response (pCR) rates.

Patients had a median age of 76.0 years in Cohort A and 72.5 years in Cohort B, with two-thirds of patients in each group being male. Most had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. The primary lesion sites included head and neck and non-head/neck regions.

Safety and Efficacy Outcomes

The treatment was generally well tolerated. Any-grade treatment-emergent adverse events occurred in 75% of patients in Cohort A and 83.3% in Cohort B, but importantly, no Grade ≥3 adverse effects or deaths were reported. The most common one was COVID-19 infection, but other infrequent reactions included skin rash, post-inflammatory pigmentation changes, injection-site reactions, pruritus, and mild thyroid-stimulating hormone elevation. There were no treatment-related discontinuations, and only 1 serious adverse event occurred in Cohort A. Compared with the well-characterized safety profile of the higher IV dose of cemiplimab used in advanced CSCC, this intralesional approach demonstrated a distinctly favorable safety profile.

Robust anti-tumor activity was also observed. Visual ORR at week 7 was 66.7% (95% CI, 34.9–90.1%) in Cohort A and 75.0% (95% CI, 42.8–94.5%) in Cohort B, with overall response rates of 66.7% at week 13 in both cohorts. Visual complete responses were noted in 41.7% of patients in Cohort A and 16.7% in Cohort B at week 7, increasing by week 13. Pathologic complete response rates were notably high at 58.3% and 66.7% in Cohorts A and B, respectively, indicating substantial tumor eradication by histopathology. Interestingly, regression was documented not only in injected lesions but also in non-injected lesions within the same anatomic region, suggesting a systemic immune activation even with localized dosing.

Additionally, 2 case studies further highlighted sustained tumor regressions in both injected and non-injected lesions after treatment. A 65-year-old female with CSCC on the right lower extremity and a 75-year-old male with multiple recurrent CSCC involving the scalp demonstrated marked lesion reduction at week 13 following intralesional cemiplimab administered according to the study regimens.

Next Steps

This phase 1 pilot study provides strong evidence that low-dose intralesional cemiplimab is highly active against early-stage CSCC, offering rapid tumor responses with an acceptable safety profile distinct from systemic administration. The weekly dosing regimen (5 mg QW × 6) showed particularly promising kinetics and tolerability, establishing it as the recommended dose for the ongoing phase 3 CLEAR CSCC trial (NCT06585410) comparing intralesional cemiplimab directly to primary surgery. If confirmed in larger studies, intralesional cemiplimab could emerge as a novel non-surgical treatment for select early-stage CSCC patients, addressing the unmet need for less invasive and better-tolerated therapies.

References

1. Linos E, Parvataneni R, Stuart SE, Boscardin WJ, Landefeld CS, Chren MM. Treatment of nonfatal conditions at the end of life: nonmelanoma skin cancer. JAMA Intern Med. 2013;173(11):1006-1012. doi:10.1001/jamainternmed.2013.639

2. Migden M, Ibrahim S, Strasswimmer J, et al. Intralesional cemiplimab for patients with early-stage cutaneous squamous cell carcinoma (CSCC): results from a phase 1 pilot study expansion cohort. Poster presented at: 2026 Winter Clinical Miami Dermatology Conference; February 27-March 1, 2026; Aventura, FL