Similar Incidence of Second Primary Tumors After Libtayo or Placebo for CSCC

Among patients with high-risk cutaneous squamous cell carcinoma (CSCC), postsurgical treatment with Libtayo (cemiplimab-rwlc) has been found to be associated with a similar rate of second primary tumors (SPTs) when compared with placebo following postoperative radiotherapy, research has shown.

Findings from an analysis of the phase 3 C-POST trial were presented at the 2025 ESMO Congress in Berlin.

During the treatment period, the proportion of patients who developed at least one SPT was 11% in the Libtayo arm (209 patients) compared with 12% in the placebo arm (206 patients); during the study’s follow-up period, these rates were 8% and 7%, respectively. During the treatment period, the cumulative number of SPTs was 32 with Libtayo versus 82 for placebo, corresponding to annualized adjusted annualized SPT rates of 1.23 and 2.81, respectively. In the follow-up period, 36 total SPTs occurred in the Libtayo arm versus 41 in the placebo arm, and the annualized SPT rates were 0.72 and 1.17, respectively.

During the treatment period, 9% of patients in the Libtayo arm had one SPT, 1% had two SPTs, less than 1% had three SPTs, 0% had four SPTs, less than 1% had five SPTs and 0% had six or more SPTs. In the placebo arm, these rates were 8%, 2%, less than 1%, less than 1%, 0% and 1%, respectively. Incidence was similar during the follow-up period, with 4% of patients in each arm experiencing one SPT and less than 1% of patients falling into the multiple SPT groups within each arm.

In a post hoc analysis incorporating the first occurrence of SPTs alongside disease-free survival (DFS) events (recurrence or death), efficacy continued to favor Libtayo over placebo. The median DFS in this analysis was not reached not reached in the Libtayo group versus 21.7 months in the placebo group. At 24 months, DFS rates were 81.1% with Libtayo versus 59.1% with placebo, and this benefit was maintained over time, with rates of 73.4% versus 48.7% at 36 months and 68.4% versus 41.5% at 48 months, respectively.

“The lower number of SPTs in the Libtayo arm appeared to be driven by a small number of patients with multiple SPTs observed in the placebo arm. The robust [DFS] efficacy signal with Libtayo versus placebo was maintained in a post hoc analysis in which SPTs were included as [DFS] events,” Dr. Danny Rischin, who serves as the director of Medical Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia noted in the conclusion of his presentation.

“These prospective randomized data suggest that there may be a subset of patients who experience fewer SPTs with Libtayo, although further investigation is required.”

What Was Established in the Primary Analysis of the Trial?

With a median follow-up of 24 months, previously reported findings from the primary analysis showed that patients who received adjuvant Libtayo after surgical resection and postoperative radiotherapy achieved a median DFS that was not reached compared with 49.4 months among those treated with placebo (206 patients). The estimated 24-month DFS rates were 87.1% and 64.1%, respectively.

Based on those findings, on Oct. 8, 2025 the U.S. Food and Drug Administration (FDA) approved Libtayo for the adjuvant treatment of adult patients with CSCC at high risk of recurrence after surgery and radiation.

What Was the Design of the Trial and the Post Hoc Analysis?

The phase 3 trial is a randomized double-blind placebo-controlled study designed to evaluate adjuvant Libtayo in patients with histologically confirmed CSCC who had undergone complete resection with curative intent and completed postoperative radiotherapy. Patients were required to have high-risk features, which included nodal extracapsular extension with at least one lymph node measuring 20 mm or more, or three or more involved lymph nodes; in-transit metastases; perineural invasion; T4 lesions; or recurrent CSCC with one or more additional high-risk characteristics.

Participants were randomly assigned to receive Libtayo or placebo. In part 1 of the study, patients received Libtayo at 350 mg intravenously every three weeks for 12 weeks, followed by Libtayo at 700 mg every six weeks for an additional 36 weeks. Those in the control group received matched placebo on the same schedule. Treatment continued until completion of the planned duration, disease recurrence, or unacceptable side effects.

Patients who experienced recurrence after completing placebo treatment or after at least three months following Libtayo completion were eligible to enter an optional open-label extension phase (part 2) to receive Libtayo at 350 mg every three weeks for up to 96 weeks.

The median age of patients was 71 years in the Libtayo group and 70.5 years in the placebo group. Most patients were 65 years of age or older, representing 73% and 68% of each respective arm. The majority of participants were male (83% in both arms) and White (90% versus 92%).

Geographically, 43% of patients in the Libtayo arm and 44% in the placebo arm were enrolled from Australia or New Zealand, 18% and 15% were from North America, and 39% and 41% were from the rest of the world.

Most patients had resected high-risk tumors located in the head and neck region (79% in the Libtayo group versus 86% in the placebo group), and 21% and 14% had non–head and neck tumors, respectively. Regarding risk classification, 60% of patients in the Libtayo arm and 57% in the placebo arm were categorized as having nodal high-risk disease; 40% and 43%, respectively, had non-nodal high-risk features.

References

“Analysis of second primary CSCC tumors (SPTs) reported during the C-POST trial, a randomized phase 3 study of adjuvant cemiplimab vs placebo for high-risk CSCC” by Dr. Danny Rischin et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1603MO.

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