The combination of avelumab and cetuximab may improve progression-free survival in patients with advanced cutaneous squamous cell carcinoma compared with avelumab alone, according to recent findings presented by Zandberg et al at the 2025 ASCO Annual Meeting (Abstract 6002) and simultaneously published in the Journal of Clinical Oncology. The findings suggest a novel approach to treating patients with this aggressive type of skin cancer.
Background
Cutaneous squamous cell carcinoma is one of the most common cancer types in the United States, with approximately 700,000 to 1 million new diagnoses per year. Although most cases are treatable, more than 12,500 of them progress to nodal or distant metastases annually, contributing to an estimated 2,000 to 8,000 deaths each year.
Approved immune checkpoint inhibitors such as cemiplimab-rwlc and pembrolizumab have advanced the treatment landscape; however, many patients may experience disease progression. Preclinical research has found that combining blockade of the PD-1:PD-L1 pathway plus an immunoglobulin G1 (IgG1) monoclonal antibody like cetuximab—which targets EGFR and activates innate immunity via antibody-dependent cellular cytotoxicity—may create a synergistic effect.
Study Methods and Results
In the phase II Alliance A091802 trial, researchers randomly assigned 60 patients (with a median age of 72 years) who had advanced cutaneous squamous cell carcinoma to receive either a combination of avelumab plus cetuximab or avelumab monotherapy every 2 weeks. They noted that 57 of the patients were evaluable, 96.5% of them were White, 91.2% were male, 100% were HIV-negative, and 75.4% expressed PD-L1.
The researchers detailed that 84.2% of the tumors originated in the head or neck region, and 47.1% of the patients had distant metastases. Baseline characteristics were balanced across treatment groups, and the randomization was stratified by PD-L1 status. The patients who experienced disease progression after receiving avelumab monotherapy were permitted to cross over to combination therapy, allowing for efficacy evaluation in both front-line and immunotherapy-refractory settings.
The combination of avelumab and cetuximab improved the primary endpoint of progression-free survival compared with avelumab alone. The median progression-free survival was 11.1 months (95% confidence interval [CI] = 7.6 months to not reached) among the patients given avelumab plus cetuximab compared with 3 months (95% CI = 2.7–13.6 months) among those given avelumab monotherapy (hazard ratio = 0.48, 95% CI = 0.23–0.97, P = .018). The researchers revealed that nine of the patients in the avelumab monotherapy group crossed over to the avelumab plus cetuximab group. The median progression-free survival after crossover was 11.3 months (95% CI = 5.8 months to not reached).
The median overall survival among the patients who received avelumab plus cetuximab was not reached (95% CI = 25.2 months to not reached) compared with those who received avelumab monotherapy, which was 35.8 months (95% CI = 18.6 months to not reached). The hazard ratio was 0.78 (95% CI = 0.34‒1.80, P = .279). Further, the confirmed objective response rate was 27.6.% with avelumab and cetuximab and 21.4% with avelumab monotherapy.
Among the patients who received avelumab plus cetuximab, the researchers observed higher rates of treatment-related adverse effects (93% vs 78.6%) and more severe adverse effects of grade 3 or higher (48.3% vs 21.5%) compared with those who received avelumab monotherapy, respectively. The most common severe adverse effects with combination treatment included rash (20.7%) and infusion-related reactions (20.7%). No deaths related to treatment or unexpected toxicity were reported.
Conclusions
“These results show that combining immune checkpoint inhibition targeting the PD-1:PD-L1 pathway with avelumab plus EGFR-targeted IgG1 monoclonal antibody cetuximab can provide meaningful clinical benefit compared to avelumab alone for patients with advanced [cutaneous squamous cell carcinoma],” emphasized lead study author Dan Zandberg, MD, Director of Head and Neck and Thyroid Cancer Disease Sections at the UPMC Hillman Cancer Center. “It opens the door to future research and new strategies for improving outcomes in this difficult disease,” he added.
Disclosure: The research in this study was sponsored in part by the National Cancer Institute. For full disclosures of the study authors, visit meetings.asco.org and ascopubs.org.
