Investigators Present Design of Phase 3 CLEAR CSCC Trial of Cemiplimab for Early-Stage CSCC

At the 2026 Winter Clinical Miami conference in Aventura, Florida, investigators presented the design of the ongoing CLEAR CSCC trial (NCT06585410), a phase 3 study evaluating low-dose intralesional cemiplimab (Libtayo; Regeneron) as a potential alternative to primary surgery in patients with early-stage cutaneous squamous cell carcinoma (CSCC).¹ The study builds on prior pilot data and seeks to address an important unmet need in the management of early-stage disease.

Background

Mohs micrographic surgery or other methods of complete margin surgical assessment remain the standard of care for early-stage CSCC tumors. However, even small lesions located on cosmetically and functionally sensitive sites such as the head and neck, hands, or pretibial surface can result in meaningful morbidity. A nonsurgical option that preserves tissue while maintaining oncologic control would represent a significant advance, as noted by the poster authors.

Cemiplimab, a fully human, high-affinity monoclonal antibody targeting PD-1, is FDA approved at a dose of 350 mg intravenously every 3 weeks for patients with locally advanced or metastatic CSCC who are not candidates for curative surgery or radiation. It is also approved in the adjuvant setting for high-risk CSCC after surgery and radiation. A prior pilot study investigating low-dose intralesional cemiplimab in patients seeking an alternative to surgery demonstrated regression in both injected and noninjected lesions, suggesting potential for localized and systemic antitumor activity.²

Trial Design

The ongoing CLEAR CSCC study is designed to formally test whether low-dose cemiplimab is noninferior to primary surgery in early-stage disease. This randomized, open-label, multicenter phase 3 trial plans to enroll approximately 369 patients across North America and Australia. Participants will be randomly assigned in a 2:1 ratio to receive cemiplimab or standard surgical resection.

Recruitment is currently open. Eligible participants must be adults with a target lesion measuring 1.0 cm to 2.0 cm in longest diameter, located on the head and neck, hand, or pretibial surface. Tumors must be invasive CSCC and amenable to surgical resection with Mohs or equivalent margin-controlled techniques. Patients must have an ECOG performance status of 0 or 1 and adequate hepatic, renal, and bone marrow function. Key exclusions include keratoacanthoma, in situ disease without invasion, prior systemic therapy for CSCC, significant autoimmune disease requiring immunosuppression, solid organ transplant, or other disallowed malignancies.

Treatment Protocol and Assessments

In the experimental arm, patients will receive cemiplimab 5 mg intralesionally once weekly for 6 weeks. The injection technique is standardized: 2 to 5 tangential injections are administered into the cephalad half of the lesion, including at least 1 intradermal injection overlying the tumor and 1 at the cephalad tumor periphery. Injections are delivered slowly over 2 to 3 minutes to minimize leakage.

At week 13, the target lesion is assessed for visual complete response (vCR). Patients achieving vCR undergo biopsy to confirm pathologic response. If vCR is not achieved, surgical excision of the residual lesion is performed. In the control arm, patients undergo surgery at baseline, followed by postsurgical visits at weeks 3 and 13.

End Points and Follow-Up

The primary end point is event-free survival, assessed up to 1 year and extended to 3 years. Secondary end points will include composite clinical response of the target lesion at week 13 in the experimental arm, response in nontarget lesions within the same region, treatment-emergent adverse events through 3 years, and comparative size of surgical or biopsy defects at week 13. Stratification factors include lesion location (head and neck vs non–head and neck) and planned surgical method. All patients will be followed for a total of 3 years after randomization, with visits every 3 months during years 1 and 2 and every 4 months in year 3.

The investigators emphasize that although surgery remains highly effective, there is a clear need for tissue-sparing alternatives in selected patients with early-stage CSCC. If low-dose cemiplimab demonstrates noninferiority to surgery with acceptable safety and durable disease control, it could expand therapeutic options and redefine management paradigms for small but anatomically sensitive tumors.

References

1. Migden MR, Ibrahim S, Strasswimmer J, et al. Trial in progress: a phase 3 randomized study of low-dose intralesional cemiplimab versus primary surgery for patients with early-stage cutaneous squamous cell carcinoma (CLEAR CSCC). Poster presented at: 2026 Winter Clinical Miami; February 27-March 1, 2026; Aventura, FL.

2. Migden MR, 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; February 27-March 1, 2026; Aventura, FL.