In a significant advancement in the treatment of advanced cutaneous squamous cell carcinoma (cSCC), a randomized phase II clinical trial has revealed that combining the immune checkpoint inhibitor avelumab with the epidermal growth factor receptor (EGFR) targeted therapy cetuximab results in markedly improved patient outcomes compared to avelumab alone. This breakthrough was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and concurrently published in the highly regarded Journal of Clinical Oncology. The study, led by Dr. Dan Zandberg, associate professor of medicine at the University of Pittsburgh and medical oncology co-leader at UPMC Hillman Cancer Center, unveils a potential new immunotherapy-based treatment paradigm for this challenging malignancy.
Cutaneous squamous cell carcinoma is among the most common forms of skin cancer, with approximately 1.8 million new cases diagnosed annually in the United States. Although the majority of cSCC cases are detected early and resolved with straightforward surgical interventions, a small but clinically urgent subset of patients develop either locally advanced disease that is unresectable or metastatic cancer. At this advanced stage, therapeutic options have historically been limited, and the prognosis remains poor despite systemic therapies. It is within this context that the new trial’s results offer a beacon of hope.
The Alliance A091802 trial, sponsored by the National Cancer Institute’s National Clinical Trials Network and developed collaboratively by researchers across the United States, enrolled 57 patients with advanced cSCC. Patients were randomly assigned to receive either the combination of avelumab plus cetuximab or avelumab monotherapy. Importantly, the trial employed a crossover design that allowed patients initially treated with avelumab alone whose disease progressed to subsequently receive the combination therapy, enabling nuanced insights into therapeutic sequencing.
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Avelumab functions as an immune checkpoint inhibitor specifically targeting the protein programmed death-ligand 1 (PD-L1) expressed on tumor cells. By binding PD-L1, avelumab prevents it from engaging PD-1 receptors on T cells, a mechanism that tumors exploit to evade immune destruction. This blockade releases inhibitory signals—or “immune brakes”—restoring T cell activity against the tumor. Although anti-PD-1/PD-L1 therapies have transformed cancer treatment landscapes, their efficacy in advanced cSCC remains variable, underscoring the need for improved combinations.
Cetuximab, on the other hand, is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor frequently overexpressed in cSCC cells. EGFR activation fuels tumor cell proliferation, survival, and metastatic potential. Beyond direct tumor targeting, cetuximab has immune-modulatory effects, enhancing natural killer (NK) cell-mediated cytotoxicity and promoting dendritic cell activation, both critical in orchestrating a robust anti-tumor immune response. Prior seminal research by Dr. Robert Ferris and colleagues at UPMC Hillman elucidated cetuximab’s role in modulating these immune effector pathways.
Dr. Zandberg explained the strategic rationale behind this combination approach: by pairing avelumab’s release of immune brakes with cetuximab’s immune activation—the metaphorical “accelerator pedal”—the immune system’s attack on tumor cells can be synergistically amplified. Rather than additive effects, the combined therapy was hypothesized and now demonstrated to invoke synergistic immunological mechanisms that translate into substantial clinical benefit.
The trial’s primary endpoint, progression-free survival (PFS), was dramatically improved with the combination regimen. Patients receiving avelumab plus cetuximab had a median PFS of 11 months, nearly quadrupling the 3-month median observed in those treated with avelumab alone. This striking enhancement in disease control highlights the potential of dual immune checkpoint and targeted antibody therapy in transforming outcomes for advanced cSCC patients, a group for whom survival extensions have long been elusive.
Despite these positive signals, the combination of avelumab and cetuximab is not yet recommended as the new standard of care, largely because it was compared to avelumab monotherapy in the trial, while two other anti-PD-1/PD-L1 agents—cemiplimab and pembrolizumab—have since gained FDA approvals based on superior efficacy profiles in cSCC. Nevertheless, this trial is the first prospective randomized study directly contrasting cetuximab plus PD-1/PD-L1 blockade against PD-1/PD-L1 blockade alone in cSCC or related head and neck cancers. Its findings pave the way for future investigations testing cetuximab in combination with the existing first-line immunotherapies.
Interestingly, patients in the crossover arm—who initially received avelumab alone and switched to the combined regimen upon disease progression—exhibited progression-free survival comparable to those treated with the combination upfront. This finding is clinically significant, as current treatments typically transition patients who fail anti-PD-1 monotherapy to chemotherapy or cetuximab alone. The data suggest that continuing checkpoint inhibition while adding cetuximab may produce enhanced outcomes, advocating for rethinking salvage therapy strategies in this population.
These results underscore the urgent need for innovative immunotherapy combinations and the value of understanding the interplay between antibody-dependent cellular cytotoxicity and immune checkpoint modulation. By intricately harnessing both direct tumor targeting and immune system activation, the dual approach exemplifies a promising paradigm shift in treating immune-evasive skin cancers.
The study was supported through a robust collaboration facilitated by the National Cancer Institute and the Alliance for Clinical Trials in Oncology, with additional drug supply from EMD Serono. UPMC Hillman Cancer Center served as the primary site for patient enrollment, reflecting a comprehensive network of community cancer centers engaged in advancing clinical research.
Looking ahead, Dr. Zandberg and his team emphasize that these findings warrant further exploration into combining cetuximab with the more potent, currently approved PD-1 inhibitors for cSCC, such as pembrolizumab and cemiplimab, to fully realize improved therapeutic options. This line of inquiry holds promise not only for cSCC but also for other malignancies in which EGFR-targeting and checkpoint blockade may synergize.
In conclusion, this trial represents a compelling step forward in the quest to extend and improve patient lives in advanced cutaneous squamous cell carcinoma. By integrating mechanistic insight with rigorous clinical evaluation, it opens new avenues for immuno-oncology research and sets the stage for future breakthroughs in cancer immunotherapy.
Subject of Research: Advanced cutaneous squamous cell carcinoma (cSCC) treatment with immunotherapy and targeted therapy combination.
Article Title: A phase II (Alliance A091802) randomized trial of avelumab plus cetuximab vs. avelumab alone in advanced cutaneous squamous cell carcinoma (cSCC).
News Publication Date: 31-May-2025
Web References:
Journal of Clinical Oncology Article DOI
American Society of Clinical Oncology (ASCO)
References:
Alliance A091802 clinical trial (NCT03944941)
Ferris RL et al., research on cetuximab’s immune effects (PMID: 23444227)
Image Credits: UPMC (Photo of Dan Zandberg, M.D.)
Keywords: cutaneous squamous cell carcinoma, cSCC, immunotherapy, avelumab, cetuximab, EGFR, PD-1/PD-L1 blockade, checkpoint inhibitor, monoclonal antibodies, clinical trial, cancer treatment, immune synergism, cancer immunology
Tags: advanced cutaneous squamous cell carcinoma treatmentASCO Annual Meeting 2025avelumab and cetuximab combinationDr. Dan Zandberg researchepidermal growth factor receptor therapyimmune checkpoint inhibitors in cancerimmunotherapy trial findingsimproving patient outcomes in oncologyJournal of Clinical Oncology publicationlocally advanced cSCC managementmetastatic skin cancer treatment optionsnew treatment paradigms for skin cancer