The landscape of adjuvant immunotherapy for high-risk cutaneous squamous cell carcinoma (CSCC) has become increasingly complex following mixed results from recent phase 3 trials, with one study failing to meet its primary endpoint while another demonstrated significant clinical benefit.
KEYNOTE-630 Trial Results Present Complex Picture
The phase 3 KEYNOTE-630 trial, led by Cleveland Clinic researchers and presented at the American Society of Clinical Oncology 2025 Annual Meeting, enrolled 450 patients across 30 countries who had undergone surgery and completed adjuvant radiation for high-risk, locally advanced CSCC. Participants were randomized 1:1 to receive either pembrolizumab 400 mg or placebo intravenously once every six weeks for nine cycles.
While pembrolizumab showed a 24% reduction in the risk of recurrence or death compared with placebo (HR 0.76 [95% CI, 0.53-1.10]), the reduction was not statistically significant, causing the study's data monitoring committee to recommend discontinuation for futility in August 2024.
"Pembrolizumab did not provide significant benefit in the adjuvant setting for patients with resected, high-risk, locally advanced cSCC," says Shlomo Koyfman, MD, a radiation oncologist at Cleveland Clinic Cancer Institute and co-principal investigator of the KEYNOTE-630 trial. "But when we drilled deeper, what we found was that the chances of the cancer coming back were dramatically reduced – about a 50 percent reduction in recurrence rates."
The trial revealed notable differences in recurrence patterns. Locoregional recurrence occurred in 13.8% of patients receiving pembrolizumab versus 25.3% receiving placebo, and distant metastasis in 4.4% versus 11.6% of patients.
Unexpected Mortality Findings Complicate Interpretation
A key factor in the trial's failure to meet its primary endpoint was an unexpected increase in deaths in the immunotherapy arm, though these were not directly attributed to treatment toxicity.
"The problem was when you look at progression-free survival, it's either recurrence or death that's an event, and the immunotherapy arm had significantly more deaths," explains Jessica Geiger, MD, co-principal investigator of the study and Cleveland Clinic Cancer Institute head medical oncologist for skin cancer. "Notably, though, there were no grade five toxicities, which means there were no deaths due to the drug itself."
The deaths were attributed to infections and cardiac disease but weren't directly linked to the immunotherapy. Researchers speculate that the international scope of the trial and the COVID-19 pandemic may have contributed to these unexpected results.
Cemiplimab Shows Promise in Competing Trial
In contrast to KEYNOTE-630's results, the phase 3 C-POST trial evaluating adjuvant cemiplimab-rwlc (Libtayo) versus placebo in patients with high-risk CSCC met its primary endpoint of disease-free survival. At a median follow-up of 24 months (range, 2-64), cemiplimab reduced the risk of recurrence or death by 68% versus placebo (HR, 0.32; 95% CI, 0.20-0.51; P < .0001).
In the cemiplimab (n = 205) and placebo (n = 204) arms, any-grade adverse effects occurred in 91% versus 89% of patients, respectively. Grade 3 or greater adverse effects were reported in 24% versus 14% of patients, respectively, with adverse effects leading to treatment discontinuation recorded in 10% and 1.5% of patients in the respective arms.
According to Sapna Patel, MD, professor in the Division of Medical Oncology and leader of the Cutaneous Oncology Program at University of Colorado Cancer Center, researchers expect the FDA to approve cemiplimab for use after surgery and radiation based on these results.
Shifting Treatment Paradigms
The field is evolving beyond adjuvant approaches toward neoadjuvant immunotherapy strategies. An upcoming phase 3 trial called NRG HN014 will randomize patients between standard care versus neoadjuvant immunotherapy followed by risk-response adapted surgery and radiation.
"If patients have a dramatic response to neoadjuvant immunotherapy, you can do much smaller surgery, and if there's no tumor at the time of surgery, you don't have to do any radiation," Dr. Geiger explains.
Clinical Context and Future Directions
Cutaneous squamous cell carcinoma represents one of the most common cancers, with more than one million cases diagnosed annually. While most cases are curable with surgery alone, approximately 5-10% present as higher-risk tumors requiring more aggressive treatment approaches.
"For the larger, more aggressive, more bulky tumors, we are moving towards a neoadjuvant paradigm," Dr. Koyfman concludes. "And there's still going to be a role for adjuvant immunotherapy because there's a lot of cancers that you don't realize how bad they are until you cut them out."
Patel anticipates that more real-world data will be released in 2025, which could help identify the magnitude of benefit cemiplimab will provide for patients with high-risk CSCC, potentially establishing clearer treatment guidelines for this challenging patient population.
