In a significant advancement for the treatment of advanced cutaneous squamous cell carcinoma (cSCC), a phase II clinical trial spearheaded by the Alliance for Clinical Trials in Oncology has revealed compelling evidence supporting the combination of avelumab and cetuximab. Presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the Journal of Clinical Oncology, this study demonstrated that dual therapy markedly improves progression-free survival (PFS) compared to avelumab monotherapy, ushering in new hope for patients battling this aggressive skin malignancy.
Cutaneous squamous cell carcinoma represents one of the most prevalent skin cancers in the United States, with an estimated incidence ranging from 700,000 to 1 million new cases annually. While the majority of these cases respond well to existing treatment modalities, a stubborn subset—approximately 12,500 patients each year—progresses to regional lymph node involvement or distant metastases, leading to a grim prognosis with an annual death toll estimated between 2,000 and 8,000 individuals. These advanced cases present significant clinical challenges due to the aggressive nature of the disease and limited effective options after initial therapies fail.
Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have reshaped the therapeutic landscape for advanced cSCC by targeting the PD-1 or PD-L1 axis, offering patients improved outcomes. However, despite this progress, a substantial proportion of patients experience disease progression during or after checkpoint blockade. The trial conducted by the Alliance aimed to explore whether adding cetuximab—a monoclonal antibody directed against the epidermal growth factor receptor (EGFR)—to avelumab could potentiate antitumor immunity through complementary mechanisms, thereby enhancing clinical benefit.
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Cetuximab’s role in this combination is particularly innovative. Beyond inhibiting EGFR signaling, cetuximab is an IgG1 monoclonal antibody capable of engaging innate immunity via antibody-dependent cellular cytotoxicity (ADCC). By recruiting immune effector cells such as natural killer cells and macrophages, cetuximab may amplify immune-mediated tumor cell destruction. The rationale for combining cetuximab with avelumab, an anti-PD-L1 agent, lies in the potential synergy between checkpoint blockade and enhanced innate immune activation, which preclinical models suggest could overcome resistance mechanisms prevalent in advanced cSCC.
The Alliance A091802 study randomized 60 patients diagnosed with advanced cSCC to receive either avelumab alone or avelumab combined with cetuximab, both administered biweekly. Patients who experienced progression on avelumab monotherapy were permitted to cross over to the combination arm, allowing the investigators to assess efficacy in both frontline and immunotherapy refractory contexts. The median age of study participants was 72 years, with most patients being white males. Importantly, the majority of tumors originated in the head and neck region, reflecting the common anatomical distribution of aggressive cSCC.
The trial’s findings were striking. The median progression-free survival for patients receiving the combination therapy reached 11.1 months, a significant improvement compared to just 3.0 months for those on avelumab monotherapy. This translated to a hazard ratio of 0.48, indicating nearly a 52% reduction in the risk of disease progression or death with dual therapy. Notably, the confidence interval for median PFS in the combination arm extended beyond the study follow-up period (not reached), suggesting durable disease control in many patients.
Among patients who crossed over from avelumab alone to the combination regimen upon progression, median progression-free survival post-crossover was similarly prolonged, at 11.3 months. These data underscore the potential value of the combination even in cases where initial monotherapy with checkpoint inhibition had failed. Overall survival data, while not yet mature, indicated a favorable trend for the combination arm, though differences did not reach statistical significance, likely due to limited events and sample size.
The confirmed objective response rates were 27.6% for the combination therapy group versus 21.4% for those treated with avelumab alone. While modest in absolute terms, these responses were clinically meaningful and complemented the PFS findings, supporting the hypothesis that dual targeting can elicit enhanced antitumor effects. Tumor PD-L1 expression, observed in approximately 75% of patients, was balanced between groups and continues to be explored as a possible biomarker predicting response to checkpoint blockade.
Safety profiles, a critical consideration in combination regimens, revealed that treatment-related adverse events were more frequent with the addition of cetuximab. Ninety-three percent of patients on avelumab plus cetuximab experienced side effects, compared to 78.6% in the monotherapy group. Grade 3 or higher toxicities also increased, observed in 48.3% versus 21.5%, respectively. The predominant serious adverse events in the combination cohort were rash and infusion-related reactions, each affecting about one in five patients. Importantly, there were no treatment-related deaths or unexpected toxicities, and adverse events were manageable with appropriate medical intervention.
From a mechanistic standpoint, the study validates the concept that integral targeting of both adaptive and innate immune pathways can provide enhanced and durable tumor control. While avelumab inhibits the PD-L1 protein that cancer cells exploit to evade T cell-mediated immunity, cetuximab’s direct engagement with EGFR and activation of ADCC recruits immune cells capable of immediate cytotoxic action. This dual-pronged approach may disrupt tumor immune evasion more effectively than either strategy alone.
The trial’s design and implementation were enabled through a partnership between the National Cancer Institute-funded Alliance for Clinical Trials in Oncology and EMD Serono, which provided avelumab and trial support. This collaboration exemplifies the critical role of public-private partnerships in advancing cancer therapeutics through rigorous clinical investigation. The Alliance’s expansive network, comprising over 25,000 specialists and 115 institutions, facilitated comprehensive patient enrollment across the United States, ensuring robust and generalizable data.
Looking ahead, these encouraging findings open avenues for further exploration of combination immunotherapies in cSCC and potentially other squamous cell malignancies. They also raise pertinent questions about optimal sequencing, patient selection, and biomarkers predictive of response or resistance. Moreover, future studies might investigate whether integrating other agents that modulate the tumor microenvironment or innate immunity could magnify the benefits observed here.
In conclusion, the Alliance A091802 trial marks a pivotal step forward in the management of advanced cutaneous squamous cell carcinoma. By harnessing the synergy between checkpoint inhibition and EGFR-targeted immunologic activation, the study provides a promising therapeutic avenue that could improve outcomes for patients facing this challenging disease. As oncology continues to evolve towards more personalized and mechanistically informed therapies, such integrative approaches exemplify the future of cancer care.
Subject of Research: Advanced cutaneous squamous cell carcinoma treatment with combination immunotherapy
Article Title: Phase II Trial Demonstrates Enhanced Progression-Free Survival with Avelumab plus Cetuximab in Advanced Cutaneous Squamous Cell Carcinoma
News Publication Date: May 31, 2025
Web References:
Journal of Clinical Oncology article
ClinicalTrials.gov NCT03944941
References: Alliance A091802 clinical trial data presented at 2025 ASCO Annual Meeting
Keywords: Skin cancer, cutaneous squamous cell carcinoma, immunotherapy, checkpoint inhibitors, avelumab, cetuximab, EGFR, antibody-dependent cellular cytotoxicity, progression-free survival, clinical trial
Tags: Alliance clinical trial findingsASCO Annual Meeting 2025avelumab and cetuximab combination therapyclinical challenges in skin malignanciesdual immunotherapy for advanced skin cancerimmune checkpoint inhibitors in skin cancerincidence and prognosis of cSCCJournal of Clinical Oncology publicationmanaging advanced squamous cell carcinomanovel therapies for aggressive skin cancerprogression-free survival in cutaneous squamous cell carcinomatreatment advancements in cSCC