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

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 <50%) using a cutoff of 1%. The nivolumab/ipilimumab regimen had a significantly higher response rate in the absence of PD-L1 expression (P=0.003) or absence of PD-L1 and LAG3 expression (P=0.045). Combined PD-L1 and LAG3 expression was associated with higher pathologic response to nivolumab/relatlimab (P=0.05) but not individual PD-L1 or LAG3 expression. PD-L1 and/or LAG3 expression had no association with pathologic response to nivolumab monotherapy.

To examine underlying mechanisms of activity for the doublet regimens, investigators studied transcriptional and proteomic dynamics of CD8+ TILs. Anti-PD1/LAG3 reprogrammed CD8+ TILs with type 1 interferon and exhaustion-gene programs into effector and resident memory (T_EM/T_RM).

Anti-PD1/CTLA-4 activated and expanded existing T_EM/T_RM CD8+ TILs but did not rejuvenate exhausted phenotypes into T-effector cells. Anti-PD1/LAG3 but not anti-PD1/CTLA-4 induced widespread T-cell receptor sharing and increased T-cell receptor diversity. The observations suggest regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells, the authors concluded.

Ferris said the investigation will continue with only the doublet regimens in a second group of 40 patients with resectable HNSCC.

“You have deeper and more frequent responses [with the doublets],” he said. “We had four major pathologic responses in each [doublet] group compared to one in the PD-1 monotherapy group. This was a small study and the results need to be replicated, but we consider the findings very promising.”

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