May 31, 2025 — A phase II clinical trial led by the Alliance for Clinical Trials in Oncology has met its primary endpoint, demonstrating that the combination of avelumab and cetuximab improved progression-free survival (PFS) compared to avelumab alone in patients with advanced cutaneous squamous cell carcinoma (cSCC). The results, presented as an oral abstract at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, and published in the Journal of Clinical Oncology , suggest a promising new approach for patients with this aggressive form of skin cancer.
"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 cSCC," said Dan Zandberg, MD, principal investigator and Director of Head and Neck and Thyroid Cancer Disease Sections at UPMC Hillman Cancer Center. "It opens the door to future research and new strategies for improving outcomes in this difficult disease."
Cutaneous squamous cell carcinoma is one of the most common cancers in the United States, with approximately 700,000 to 1 million new cases diagnosed annually. While most cases are treatable, over 12,500 cases progress to nodal or distant metastases each year, contributing to an estimated 2,000 to 8,000 deaths annually.
Approved immune checkpoint inhibitors, cemiplimab and pembrolizumab have advanced the treatment landscape, but many patients still experience disease progression. Preclinical research suggests that combining blockade of the PD-1: PD-L1 pathway plus an IgG1 monoclonal antibody like cetuximab, which targets EGFR and activates innate immunity via antibody-dependent cellular cytotoxicity (ADCC), may create a synergistic effect.
The trial (Alliance A091802) was designed to evaluate whether this dual mechanism could improve PFS. Patients were randomized to one of two groups: avelumab monotherapy every two weeks or combination of avelumab plus cetuximab, also given every two weeks. Patients progressing on avelumab alone were allowed to cross over to combination therapy, allowing for evaluation of efficacy in both frontline and immunotherapy refractory settings.
From 2019 to 2023, the study enrolled 60 patients with advanced cSCC in the United States; 57 were evaluable. The median age of participants was 72 years. The majority were white (96.5%), and male (91.2%), all patients were HIV-negative, and 75.4% expressed PD-L1. Most tumors (84.2%) originated in the head or neck region, and 47.1% of patients had distant metastases. Baseline characteristics were balanced across treatment groups, and the randomization was stratified by PD-L1 status. The combination of avelumab and cetuximab significantly improved the primary endpoint of PFS compared to avelumab alone. The median PFS was 11.1 months (95% confidence interval [CI]: 7.6–not reached [NR]) in the avelumab plus cetuximab group compared to 3.0 months (95% CI: 2.7-13.6) in the avelumab alone group, with a hazard ratio (HR) of 0.48 (95% CI: 0.23–0.97, p = 0.018).
Nine patients in the avelumab monotherapy arm crossed over to the avelumab plus cetuximab group and the median PFS after crossover was 11.3 months (5.8-NR). The median overall survival (OS) of the avelumab plus cetuximab group was not reached (25.2‒NR) compared to the avelumab group which was 35.8 mo (18.6‒NR) HR 0.78 (0.34‒1.80) p = 0.279 The confirmed objective response rate (ORR) was 27.6.% in the avelumab and cetuximab group and 21.4% in the avelumab alone group.
Side effects related to treatment occurred in 93% of patients who received avelumab plus cetuximab; and in 78.6% of those who received avelumab. More serious side effects (grade 3 or higher) were seen in 48.3% of patients receiving avelumab plus cetuximab, and in 21.5% of those receiving avelumab treatment. The most common serious side effects in the combination group were rash (20.7%) and infusion related reactions (20.7%). There were no deaths related to treatment or unexpected toxicity.
Alliance A091802 is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded national clinical trials network (NCTN) as part of a collaboration with EMD Serono, a business of Merck KGaA, Darmstadt, Germany, who provided avelumab and trial support. To learn more about the study, visit ClinicalTrials.gov .
[Support by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology); U24CA196171; U10CA180868 (NRG Oncology); U10CA180888 (SWOG); and EMD Serono, a business of Merck KGaA, Darmstadt, Germany]
