Neoadjuvant Nivolumab/Chemo Shows Promise in HPV-Negative HNSCC

Head and neck cancer image: © CLIPAREA.com- stock.adobe.comHead and neck cancer image: © CLIPAREA.com- stock.adobe.com

Among patients with HPV-negative locoregionally advanced head and neck squamous cell carcinoma (HNSCC), neoadjuvant nivolumab (Opdivo) plus chemotherapy with subsequent response-adapted de-escalated chemoradiation therapy (CRT) elicited promising efficacy with reduced acute toxicity occurring in deep responders.^1,2

These results, which come from the phase 2 DEPEND trial (NCT03944915),¹ showed that at a median follow-up of 20 months (range, 13-40), 53% (95% CI, 35%-70%) of patients reached a deep response to neoadjuvant nivolumab/chemotherapy, and 86% (95% CI, 71%-95%) of patients reached an objective response to the neoadjuvant induction regimen. Based on response to induction therapy, 19 patients were administered de-escalated CRT and 16 patients were treated with standard CRT. The 2-year progression-survival (PFS) and overall survival (OS) rates were 66% (95% CI, 34%-76%) and 73% (95% CI, 52%-86%), respectively.

Safety data showed that common treatment-emergent adverse events for both patients receiving de-escalated CRT and standard CRT included mucositis (74% vs 94%, respectively), radiation dermatitis (68% vs 88%), and dry mouth (37% vs 63%).

“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,” stated Ari Rosenberg, MD, Assistant Professor of Medicine at UChicago Medicine and the corresponding author of the study.²

“This is the first study, to our knowledge, that evaluates neoadjuvant chemo-immunotherapy followed by response-adaptive de-escalation treatment in nonsurgical HPV-negative HNSCC patients,” added 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.”²

Study Schema and Patient Characteristics

The investigator-initiated, nonrandomized, phase 2, single-site study was conducted at the University of Chicago Medicine Comprehensive Cancer Center. The study enrolled 36 patients with stage IVa/b HPV-negative HNSCC between 2019 and 2022, and the researchers analyzed the data from February 2023 to January 2024. The median patient age was 58.9 years (range, 27-77) and 78% of patients were male.

The primary end point of the study was deep response rate, which the study defined as having tumor shrinking of 50% or higher (RECIST version 1.1) following induction therapy. Other key outcomes measures included ORR (30% or greater tumor reduction per RECIST version 1.1), progression-free survival, and overall survival.

All patients received neoadjuvant nivolumab combined with carboplatin and paclitaxel as induction therapy, followed by CRT stratified by response to the induction regimen. Patients who reached a deep response to induction therapy were stratified to de-escalated CRT to 66 Gy with elimination of elective nodal volumes. Patients not reaching a deep response to induction nivolumab/chemotherapy were administered standard CRT to 70-75 Gy.

The study remains open to enrollment, with an estimated study completion date of July 1, 2025.³

References

1. Rosenberg AJ, Juloori A, Jelinek MJ, et al. Neoadjuvant Nivolumab Plus Chemotherapy Followed by Response-Stratified Chemoradiation Therapy in HPV-Negative Head and Neck Cancer: The DEPEND Phase 2 Nonrandomized Clinical Trial [published online ahead of print March 6, 2025]. JAMA Oncol. doi: 10.1001/jamaoncol.2025.0081

2. Abburi C. Chemo-immunotherapy approach shows potential benefit in patients with advanced HPV-negative head and neck cancer. Posted March 6, 2025. Accessed April 12, 2025. https://www.uchicagomedicine.org/forefront/cancer-articles/chemo-immunotherapy-approach-study

3. NIH National Library of Medicine. De-Escalation Therapy for Human Papillomavirus Negative Disease (DEPEND). NCT03944915. Last update posted August 15, 2024. https://clinicaltrials.gov/study/NCT03944915