Nivolumab and Response-Adapted Chemoradiotherapy in HPV-Negative Head and Neck Cancer

Head and Neck Cancers in Brief

Head and neck cancers are a major public health problem, with approximately 900000 new cases diagnosed worldwide annually and more than 500000 deaths . These tumors develop in the oral cavity, pharynx (particularly the oropharynx), larynx, nasal cavity, sinuses, and salivary glands. HPV (human papillomavirus)is particularly implicated in oropharyngeal cancers of the tongue base and tonsils. Approximately 60-70% of oropharyngeal cancers are HPV-positive , whereas HPV positivity is much lower at other head and neck sites. Major risk factors include tobacco and alcohol, HPV and EBV infections, poor oral hygiene, and environmental exposures such as asbestos and wood dust. At diagnosis, approximately 60% of patients have advanced-stage (stage III or IV) disease, negatively affecting survival and limiting treatment options. HPV prevention strategies and early diagnosis are therefore important.

Head and neck cancer treatment generally combines surgery, radiotherapy, chemotherapy, and immunotherapy. HPV-negative head and neck squamous cell carcinoma (HNSCC) is particularly challenging because of treatment resistance and aggressive behavior. New approaches are needed to improve effectiveness while reducing adverse reactions. The University of Chicago's DEPEND study, published on March 6, 2025, in JAMA Oncology , the DEPEND study stands out as an innovative treatment strategy in this field.

DEPEND: Scope and Methods

DEPEND enrolled patients with HPV-negative, locally advanced stage IVa/b head and neck squamous cell carcinoma (HNSCC). Stage IVa/b describes regionally very advanced disease without distant-organ metastases . Standard treatment at these stages is concurrent chemotherapy and radiotherapy (chemoradiotherapy).

DEPEND was a single-center, nonrandomized phase II trial conducted between September 2019 and June 2022. A total of 36 patients with advanced stage IVa/b HPV-negative head and neck cancer received three 21-day cycles of neoadjuvant (before the main treatment) therapy:

• Day 1: 360 mg nivolumab and carboplatin AUC=5

• Days 1, 8, and 15: 100 mg/m² paclitaxel

. Patients with at least 50% tumor shrinkage then received reduced-dose chemoradiotherapy (66 Gy), excluding elective nodal areas. Those with less than 50% shrinkage received standard chemoradiotherapy (70-75 Gy). All patients also received 9 cycles of adjuvant nivolumab afterward.

Key DEPEND Findings

Median follow-up was 20 months (range: 13-40 months). The primary objective, deep response defined as at least 50% reduction in tumor volume, was achieved in 53% (95% confidence interval [CI]: 35-70%), meeting the study's success criterion. The objective response rate, defined as at least 30% tumor shrinkage, was 86% (95% CI: 71-95%).

Survival with Response-Adapted Treatment

Effectiveness of response-adapted chemoradiotherapy was assessed in two groups:

• Reduced-dose CRT (19 patients):

  • 2-year disease-free survival: 69% (95% CI: 39-87%),

  • Overall survival: 74% (95% CI: 41-90%)

• Standard-dose CRT (16 patients):

• 2-year disease-free survival: 69% (95% CI: 40-86%),

• Overall survival: 79% (95% CI: 47-93%)

Patients receiving reduced-dose chemoradiotherapy had similar survival rates with fewer acute adverse reactions.

Treatment-Related Adverse Reactions

The most common adverse reactions in the groups were:

• Mucositis (mouth sores): Reduced CRT 74%, standard CRT 94%

• Radiation dermatitis: Reduced CRT 68%, standard CRT 88%

• Dry mouth: Reduced CRT 37%, standard CRT 63%

These findings confirm lower toxicity in the reduced-dose group.

DEPEND: Clinical Significance and Conclusions

DEPEND demonstrated the effectiveness of neoadjuvant nivolumab plus chemotherapy in advanced HPV-negative head and neck cancer, with promising deep response rates. Personalized, response-adapted chemoradiotherapy also provided similar survival with fewer acute adverse reactions. This strategy may lay the groundwork for an important change in head and neck cancer care.

Interpretation

These findings highlight immunotherapy's potential in HPV-negative head and neck cancer and provide a strong basis for larger, multicenter randomized controlled trials. Future studies in larger populations may further improve treatment protocols.

Given the importance of personalized care and the potential long-term benefits of this innovative strategy, DEPEND makes an important contribution to clinical practice.