Immunotherapy Strategies in Cutaneous Squamous Cell Carcinoma: ASCO25 Insights

Shlomo Koyfman, MD, a radiation oncologist at Cleveland Clinic, discusses the MK-3475-630/​KEYNOTE-630 trial (NCT03833167), which focused on patients with high-risk cutaneous squamous cell cancer (CSCC). The trial compared adjuvant pembrolizumab (Keytruda) to placebo post-surgery and radiation.¹

Despite a 50% reduction in recurrence (28% vs 14%), the trial failed to meet its primary end point of event-free survival due to higher death rates in the pembrolizumab arm (22 deaths vs 9).

However, Koyfman notes that the C-POST trial (NCT03969004), also presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that using cemiplimab (Libtayo) led to positive results in this patient population. Previously, it was reported that with a 68% reduction in the risk of disease recurrence or death in patients with high-risk CSCC after surgery (HR, 0.32; 95% CI, 0.20-0.51; P <.0001) vs placebo at the first prespecified interim analysis for DFS and a median duration of follow-up of 24 months (range, 2-64 months), the primary end point of DFS in the C-POST trial was met.²

“The C-POST Regeneron trial was positive with an event-free survival benefit. The KEYNOTE-630 trial was negative. It did not meet its event-free survival end point, but it did show dramatic reduction in recurrence,” Koyfman explains.

Both trials suggest adjuvant immunotherapy may reduce recurrence, but questions remain about timing and overall survival.

“Now, a confirmatory, large, phase 3 trial is currently underway and open,” Koyfman shares. “We will be opening it along with many other centers in the US and Australia, and that will actually be a randomized trial looking at neoadjuvant immunotherapy vs the standard surgery-first approach.”

“We are all very optimistic that that will potentially lead to benefit and a new standard of care for patients who do get neoadjuvant immunotherapy. I think the role of adjuvant immunotherapy is totally up in question, but for patients who get surgery first and adjuvant radiation, my hope is that by looking at the C-POST trial and the KEYNOTE-630 trial, adjuvant immunotherapy for surgery-first patients becomes embedded in our future standards of care,” concludes Koyfman.

REFERENCES:

1. Koyfman SA, Lee JH, Mortier L, et al. Phase 3 randomized trial (KEYNOTE-630) of adjuvant pembrolizumab (pembro) versus placebo (pbo) for high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) following surgery and radiation (RT). J Clin Oncol. 2025;43(suppl 17):6000. doi:10.1200/JCO.2025.43.16_suppl.6000

2. Adjuvant Libtayo® (cemiplimab) significantly improves disease-free survival (DFS) after surgery in high-risk cutaneous squamous cell carcinoma (CSCC) in phase 3 trial. News release. Regeneron Pharmaceuticals, Inc. January 13, 2025. Accessed January 13, 2025. https://tinyurl.com/46b9f65k