Better Response, Survival in Head and Neck Cancer With Dual Pre-Op Immunotherapy

Oncology/Hematology
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Other Cancers

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Four times as many major responses versus single agent, potential for biomarker-guided treatment

by
Charles Bankhead, Senior Editor, MedPage Today
March 18, 2025 • 3 min read

Nivolumab plus ipilimumab or relatlimab nearly doubled response rates compared to nivolumab alone in head and neck cancer.Patients with major pathologic responses had better disease-free and overall survival at 3 years.Different combination therapies had different effects on T-cell dynamics, suggesting potential for treatment personalization.

Two neoadjuvant immunotherapy combinations for head and neck cancer substantially increased the response rate versus a single drug, a small randomized trial showed.

The pathologic tumor response (pTR) rate increased from 41.6% with single-agent nivolumab (Opdivo) to 63.6% with nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy) and 73.3% with nivolumab plus the LAG3 inhibitor relatlimab (Opdualag). The combinations led to more major pathologic responses, which were associated with better disease free and overall survival at 3 years.

Biomarker analyses showed distinct patterns of response with the different combination therapies, suggesting a potential to tailor treatment to baseline characteristics, reported Robert Ferris, MD, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, and co-authors in Cancer Cell.

“We already know that preoperative anti-PD-1 monotherapy will become standard of care later this year for advanced head and neck cancer,” Ferris told MedPage Today. “We’ve already seen a press release about that, and we know that a clinical trial was positive for event-free survival. Our trial demonstrates that while that may be a reasonable approach for a subset of patients, doublet immunotherapy has a better response rate, with a survival benefit. We should be able to add anti-CTLA-4 or anti-LAG3 and have double or triple the response rate.”

Monoclonal antibodies targeting PD1/L1 have transformed cancer therapy, but only a minority of patients obtain durable responses, Ferris and co-authors noted in the introduction to their report. The limited number of patients who benefit from the treatment highlights the need for reliable biomarkers that predict response to therapy. Understanding the underlying mechanisms of tumor susceptibility and identifying combinations to overcome immunosuppression are additional priorities.

Neoadjuvant immune checkpoint inhibitors (ICIs), primarily PD1/L1 inhibitors, have shown promise for several types of resectable cancers, including head and neck squamous cell carcinoma (HNSCC), the authors continued. Beyond clinical benefit, the brief preoperative time frame offers an opportunity to study early immune response and identify predictive biomarkers.

Ferris and colleagues conducted a phase II randomized trial to compare single versus dual neoadjuvant immunotherapy in 40 patients with resectable HNSCC. The trial included translational studies to evaluate immune mechanisms of different immunotherapy regimens and to determine mechanisms of anti-tumor immunity: maintenance/reprogramming of CD8+ tumor infiltrating lymphocytes (TILs) versus recruitment of novel tumor-specific cells from circulation.

Patients with resectable HNSCC were randomized to one of three neoadjuvant strategies: single-agent nivolumab, nivolumab/ipilimumab, or nivolumab/relatlimab. They categorized pTR by extent of viable residual tumor: pTR-0 (91-100%), pTR-1 (51-90%), and pTR-2 (≤50%).

The combination regimens resulted in higher pathologic response rates and higher rates of pTR-2 responses (26.7%, 36.4%, 8.4%). The only pathologic complete response occurred in the nivolumab/relatlimab arm.

Almost twice as many patients in the combination arms had any radiographically confirmed decrease in target lesion size (42.9% with nivolumab/relatlimab, 41.7% with nivolumab/ipilimumab, and 23% with nivolumab). Similar differences existed for clinical to pathologic downstaging after neoadjuvant therapy (46.7%, 41.7%, and 23%). Patients who had a major pathologic response had substantially better 3-year disease-free survival (100% vs 83.7%) and 3-year overall survival (100% vs 87.1%).

Investigators examined the relationship between LAG3 and/or PD-L1 expression with pathologic response (≥50% vs