A groundbreaking Phase 2 clinical trial conducted by researchers at the University of Chicago Medicine Comprehensive Cancer Center has revealed promising results for patients with advanced human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), a particularly challenging form of cancer to treat.
The nonrandomized clinical trial, published in JAMA Oncology on March 6, 2025, demonstrated that more than half of the study participants experienced significant tumor shrinkage when treated with a novel combination of the immunotherapy drug nivolumab and chemotherapy, followed by response-adaptive chemo-radiation therapy.
Understanding the Treatment Challenge
HPV-negative HNSCC predominantly affects older patients with a history of heavy smoking and alcohol use, typically presenting poor treatment outcomes and quality of life. While early-stage tumors can be effectively treated with surgery or radiation, many cases are diagnosed at advanced stages due to subtle initial symptoms, resulting in higher mortality rates.
Current standard treatments, including chemo-radiation therapy or surgery, have shown limited survival benefits for advanced, non-metastatic cases while significantly impacting patients' ability to speak, swallow, and maintain quality of life.
Innovative Treatment Approach
The study enrolled 36 patients with advanced HPV-negative HNSCC, implementing a novel treatment regimen consisting of three cycles of neoadjuvant chemotherapy combined with nivolumab. Dr. Ari Rosenberg, Assistant Professor of Medicine at UChicago Medicine and the study's corresponding author, explained, "Immunotherapy, specifically immune checkpoint inhibitors, has revolutionized the way we treat recurrent or metastatic head and neck cancers, improving survival outcomes. However, they have not played a significant role in curative intent thus far."
Remarkable Clinical Outcomes
The trial's primary endpoint focused on achieving a deep response rate, defined as 50% or greater tumor shrinkage with neoadjuvant chemo-immunotherapy. The results exceeded expectations, with 53% of patients achieving this significant tumor reduction. Patients who demonstrated this level of response were assigned to a de-escalation arm of treatment, while others received standard chemo-radiation therapy.
Biomarker Implications
A notable finding emerged regarding programmed death-ligand 1 (PD-L1) expression. Patients with higher PD-L1 levels showed deeper responses to treatment, suggesting its potential role as a biomarker for predicting treatment outcomes. This discovery could help identify patients most likely to benefit from this therapeutic approach.
Impact on Patient Care
The study marks a significant advancement in treating this challenging cancer type, particularly for patients with locally advanced Stage 4 disease. The treatment protocol demonstrated impressive survival outcomes while reducing toxic side effects, especially in patients who responded well to the initial chemo-immunotherapy and received de-escalated treatment.
"This is the first study, to our knowledge, that evaluates neoadjuvant chemo-immunotherapy followed by response-adaptive de-escalation treatment in non-surgical HPV-negative HNSCC patients," noted Dr. Rosenberg. "These promising results pave the way for new treatment paradigms that not only improve survival but also enhance the quality of life for these patients."
