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.

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

The immune system’s ability to recognize and eliminate cancer cells hinges on effective antigen presentation, a process primarily mediated by the human leukocyte antigen class I (HLA-I) complex. Tumor antigens are processed and presented on HLA-I molecules on the cancer cell surface, flagging aberrant cells for destruction by CD8+ cytotoxic T lymphocytes. Paradoxically, BCC cells suppress the expression of HLA-I, effectively cloaking themselves in immunological invisibility. This suppression results from a sophisticated epigenomic mechanism connected to the tumor’s cell of origin and its intrinsic stemness programs.

Dr. Demehri’s team meticulously compared BCC samples to cutaneous squamous cell carcinomas (SCCs), which exhibit higher responsiveness to immune checkpoint inhibitors. Through single-cell RNA sequencing and histological analyses, they demonstrated that BCCs harbor an "immune-excluded" microenvironment, characterized by minimal infiltration of CD4+ and CD8+ T cells within tumor foci. This contrasts sharply with SCCs, where immune cells readily penetrate the tumor stroma. The immune exclusion observed in BCC correlates tightly with the downregulation of antigen presentation machinery (APM), evident even at early disease stages, suggesting an inherent, developmental basis for immune evasion.

Central to this suppression is the transcription factor Foxc1, which is normally involved in maintaining quiescence of hair follicle stem cells — the presumptive cell of origin for BCC. Foxc1 directly represses genes encoding key components of the APM, including HLA-I and interferon regulatory factor 1 (IRF1), through epigenomic modifications that silence their expression. This pharmacologically reversible epigenetic repression provides a molecular explanation for why BCCs, despite their heavy mutational load, remain largely undetected and refractory to immune attack.

The clinical implications of these discoveries are profound. Dr. Demehri’s research shows that topical application of entinostat, a histone deacetylase inhibitor, can epigenetically reverse APM suppression in BCC cells in vivo. When used in combination with imiquimod, a topical immune response modifier approved for skin cancers, entinostat significantly enhances antigen presentation and stimulates immune cell infiltration, producing a synergistic antitumor effect. This dual-regimen effectively overcomes the immune exclusion barrier, transforming BCC from an immunologically "cold" tumor into one more amenable to immune-mediated clearance.

Such findings challenge the existing paradigm that high tumor mutational burden necessarily predicts immunotherapy success. Instead, they emphasize the pivotal role of a cancer’s cellular and epigenetic context, particularly the intrinsic stemness programs inherited from their cell of origin, in dictating immunogenicity. By targeting these epigenomic regulators, it may be possible to sensitize otherwise resistant tumors to immune-based treatments, broadening the therapeutic horizon beyond BCC.

Beyond immediate treatment strategies, this work raises critical questions about how tissue-specific stemness pathways modulate tumor-immune interactions more broadly. Could similar epigenetic constraints on antigen presentation operate in other cancers arising from quiescent stem cell populations? If so, unraveling these intrinsic immunosuppressive mechanisms may unlock new generalizable approaches to cancer immunotherapy.

Furthermore, these insights offer hope for organ transplant recipients and immunosuppressed patients, who are disproportionately susceptible to SCC yet relatively spared from BCC development. This differential risk underscores the clinical relevance of BCC’s low immunogenicity and may inform personalized surveillance and therapeutic strategies for high-risk populations.

In essence, this study elegantly combines molecular immunology, epigenomics, and clinical oncology to redefine our understanding of tumor immune evasion. The identification of Foxc1 as a master regulator of antigen presentation heralds a new chapter in skin cancer research and immunotherapy, anchored in the biology of the tumor’s origin rather than mutation burden alone.

Looking forward, Dr. Demehri and colleagues advocate for clinical trials testing the efficacy and safety of entinostat-primed immunotherapy in patients with BCC. Such trials could validate this novel combination as a frontline or adjunct treatment, potentially improving outcomes for thousands of patients afflicted with this common yet challenging cancer.

This research exemplifies the power of combining cutting-edge single-cell technologies with translational oncology to unravel the complex interplay between cancer cell states and immune recognition. As the field of cancer immunotherapy continues to evolve, studies like this underscore the importance of considering tumor cell origin and epigenetic regulation when designing effective treatments.

In conclusion, the elucidation of epigenomic mechanisms governing stemness and immune suppression opens promising avenues not only for the treatment of basal cell carcinoma but also for a broader understanding of cancer immunobiology. By leveraging these insights, the oncology community stands poised to overcome longstanding barriers in combating immune-resistant tumors, heralding a new era of precision medicine and immunotherapy.

Subject of Research: Cells

Article Title: Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer

News Publication Date: 17-Apr-2025

Web References:

• https://www.cell.com/cell-reports/fulltext/S2211-1247(25)00332-8
• http://dx.doi.org/10.1016/j.celrep.2025.115561

Image Credits: Shawn Demehri, Massachusetts General Hospital

Keywords: Skin cells, Immunogenicity, Combination therapies, Cancer immunotherapy