Insights on KEYNOTE-630: Immunotherapy's Role in High-Risk CSCC

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Shlomo Koyfman, a radiation oncologist at Cleveland Clinic, presented significant findings from the KEYNOTE-630 trial, which investigated the use of adjuvant pembrolizumab (Keytruda) in patients with high-risk cutaneous squamous cell carcinoma (CSCC). This phase 3 trial aimed to evaluate the efficacy of pembrolizumab following surgical intervention and radiation therapy in reducing recurrence rates among patients identified as high-risk due to advanced disease characteristics.

The trial included patients with T4 tumors, extensive nodal disease, or recurrent tumors with multiple risk factors. The primary endpoint was event-free survival (EFS), which is defined as the duration until recurrence or death. Despite the trial's inability to meet its primary endpoint in the first interim analysis, notable differences in recurrence rates emerged. Specifically, the two-year recurrence rate in the placebo group was 28%, while the pembrolizumab group reported a significantly lower rate of 14%. However, the trial also recorded higher mortality in the pembrolizumab group, with 22 deaths compared to 9 in the placebo group, leading to concerns about the implications of these findings.

In an interview with Targeted Oncology, Dr. Koyfman elaborated on the challenges faced during the trial, particularly the timing of treatment initiation following surgery and radiation. He noted that many patients in the placebo arm experienced recurrences shortly after treatment, highlighting the importance of prompt administration of adjuvant therapies. This complexity was exacerbated by the COVID-19 pandemic, which may have influenced patient outcomes and trial logistics.

The adverse outcomes observed in the pembrolizumab arm raised critical questions regarding patient selection and the timing of immunotherapy. While the reduction in recurrence is promising, the lack of overall survival benefit from the KEYNOTE-630 trial necessitates further scrutiny. Furthermore, ongoing trials, such as the C-POST trial evaluating cemiplimab (Libtayo), demonstrated more favorable results by achieving significant improvements in EFS, indicating that different immunotherapeutic agents may yield varying outcomes in similar patient populations.

Experts in the field, including Dr. Koyfman, express optimism about the evolving role of immunotherapy in treating high-risk CSCC. The potential for neoadjuvant therapies is also being explored, with trials indicating promising rates of pathologic complete responses. As the field progresses, it is hoped that adjuvant immunotherapy will become a more standardized component of treatment protocols for patients who undergo surgery for high-risk CSCC.

In summary, while the KEYNOTE-630 trial did not meet its primary endpoint, the significant reduction in recurrence rates suggests that adjuvant pembrolizumab may still play a valuable role in managing high-risk CSCC. Continued research and comparison with other immunotherapeutic agents will be crucial in establishing more effective treatment strategies for this patient demographic. As our understanding of immunotherapy develops, it is imperative to refine patient selection criteria and treatment timelines to enhance outcomes in this challenging area of oncology.