Pathologic Treatment Effect and Survival in HPV-Negative HNSCC Following Neoadjuvant Nivolumab

Importance: Neoadjuvant immunotherapy shows promise in the treatment of head and neck squamous cell carcinoma (HNSCC). Pathologic treatment effect (pTE) is one way to assess response to treatment; however, the association of this response with survival outcomes is not yet clear. The current study sought to determine whether treatment response to neoadjuvant nivolumab, as measured by pTE, correlates with survival outcomes. Objective: To determine whether patients with HNSCC with pathologic response to neoadjuvant nivolumab have improved survival outcomes. Design, Setting, and Participants: A cohort study performing a pooled analysis of 2 multi-institutional neoadjuvant clinical trials (NCT03238365, NCT03854032) enrolling patients from July 2017 to January 2022, was performed. Patients with resectable HNSCC enrolled in 1 of 2 clinical trials and treated with neoadjuvant immunotherapy and surgical resection were included in the analysis. Patients were followed up for a median (range) of 36 (4-72) months. Analysis took place on April 15, 2024. Intervention: Patients were treated with neoadjuvant nivolumab with or without the addition of immunomodulating medications (tadalafil or indoleamine 2,3 dioxygenase inhibitor). Main Outcome and Measure: Pooled analysis was performed to plot Kaplan-Meier 3-year survival outcomes for pTE responders and low or nonresponders. A pTE response threshold was determined using recursive partitioning analysis. Results: Seventy-nine patients were included in the analysis, of whom 40 (51%) had human papillomavirus (HPV)-negative disease. Recursive partitioning analysis identified a pTE threshold of 57%, which was used to define pathologic responders vs low or nonresponders. Pathologic responders with HPV-negative disease had significantly improved disease-free survival (100% for responders vs 66.8% for low or nonresponders; 95% CI, 46.1%-80.6%) and overall survival (100% for responders vs 73.3% for low or nonresponders; 95% CI, 53.4%-85.7%). In patients with HPV-positive disease, disease-free survival was high for both responders (90%; 95% CI, 47.3%-98.5%) and low or nonresponders (92.4%; 95% CI, 72.8%-98.1%). Conclusion and Relevance: This cohort study found that patients with HPV-negative disease who are deemed pathologic responders (pTE >57%) to neoadjuvant nivolumab may have improved survival outcomes compared with those who are low or nonresponders. Not only does this suggest a role for using pathologic response as a surrogate marker, but it further highlights the neoadjuvant strategy in HNSCC as associated with improved survival.