Researchers from the University of Chicago Medicine Comprehensive Cancer Center demonstrated the potential of a novel treatment approach including immunotherapy to treat advanced human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). More than half of study participants had 50% or more of their tumors shrink after receiving the immunotherapy drug nivolumab with chemotherapy, followed by response-adaptive chemo-radiation therapy. The results of the Phase 2, nonrandomized clinical trial were published on March 6, 2025 in JAMA Oncology.
Challenges of treating advanced HPV-negative HNSCC
HPV-negative HNSCC is often diagnosed in older patients with a history of heavy smoking and alcohol use. These patients typically experience a poor quality of life and have the worst treatment outcomes among head and neck cancer patients. When the tumors are small in the early stages (Stage 1 or 2), they can be cured with surgery or radiation. However, many cases are diagnosed at advanced stages (Stage 3 or 4) due to a lack of notable symptoms, which in turn makes treatment more challenging and contributes to high mortality rates.
The current standard of treatment—including chemo-radiation therapy or surgery—offers limited survival benefit for advanced, non-metastatic, HPV-negative HNSCC. Moreover, these treatments negatively impact speech, swallowing, and overall quality of life. There are two major unmet needs in this patient population: improving survival/recurrence rates and optimizing treatments to minimize long-term side effects.
Use of immunotherapy in neoadjuvant setting
"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," said Ari Rosenberg, MD, Assistant Professor of Medicine at UChicago Medicine and the corresponding author of the study.
Neoadjuvant therapy involves administering treatment prior to any surgery or radiation to shrink tumors. In this study of 36 patients with advanced HPV-negative HNSCC, researchers tested a regimen of three cycles of neoadjuvant chemotherapy combined with an immunotherapy drug, nivolumab, followed by chemo-radiation therapy. The group of patients who experienced more than 50% tumor shrinkage were assigned to the trial's de-escalation arm, while the other arm received standard chemo-radiation therapy.
Survival benefits with immunotherapy
The main goal of the clinical trial was to evaluate the deep response rate, defined as the proportion of patients who achieved 50% or greater tumor shrinkage with neoadjuvant chemo-immunotherapy.
The findings were encouraging: 53% of patients achieved a deep response with neoadjuvant chemo-immunotherapy. "This result exceeded our expectations over our historical data with chemotherapy alone," said Rosenberg.
Deeper responses were observed in patients with higher expression of programmed death-ligand 1 (PD-L1) suggesting that PD-L1 expression could serve as a potential biomarker to predict treatment response and a potential survival benefit for PD-L1-positive patients.
The study also assessed survival outcomes, treatment toxicities, patient function and quality of life. In this high-risk population with locally advanced Stage 4 head and neck cancer, the chemo-immunotherapy treatment approach led to impressive survival outcomes and fewer toxic side effects, especially among patients who responded favorably to neoadjuvant 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," said 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."
The study " Neoadjuvant nivolumab plus chemotherapy followed by response-stratified chemoradiation therapy in HPV-negative head and neck cancer: The DEPEND Phase 2 nonrandomized clinical trial ," was supported by a UChicago investigator-initiated clinical trial funded by Bristol Myers Squibb and Celgene, the University of Chicago Medicine Comprehensive Cancer Center Support Grant (NIH/NCI P30 CA014599), and the UChicago Medicine Head and Neck Cancer Program.
Additional authors included Evgeny Izumchenko, Jeffrey Chin, Alexander Pearson, Everett Vokes, Aditya Juloori, Nishant Agrawal, Nicole Cipriani, Mark Lingen, Rohan Katipally, Daniel Ginat, Olga Pasternak-Wise, Zhen Gooi, Elizabeth Blair, Daniel Haraf and John Cursio from the University of Chicago and Michael Jelinek from Rush University Chicago.
