Neoadjuvant Pembrolizumab is Active in Surgically Resected Head and Neck Cancer

Abstract

Approximately 60% of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced disease. Surgical candidates often receive postoperative radiation and cisplatin if they have high-risk pathological features. Despite intensive therapy, up to 50% of patients will suffer relapse. Therefore, improved treatment modalities are desperately needed. The checkpoint inhibitor, programmed death-ligand 1 (PD-L1), is upregulated in HNSCC and treatment with anti-PD-1 inhibitor (pembrolizumab) was shown to decrease tumor burden in patients with recurrent/metastatic HNSCC. Additionally, PD-L1 expression is increased in response to radiation treatment both in vitro and in vivo. Importantly, pretreatment with anti-PD-L1 antibody prior to radiation resulted in increased survival of mice with implanted HNSCC tumors compared to radiation alone. Therefore, we hypothesized that neoadjuvant pembrolizumab is active in previously untreated HNSCC and concurrent adjuvant treatment with pembrolizumab combined with standard of care would result in decreased relapse. To test this hypothesis, a multisite “Phase 2 Investigation of Adjuvant Combined Cisplatin and Radiation with Pembrolizumab in Resected HNSCC” (NCT02641093) funded by Merck was initiated. Eligible patients with high-risk (Stage III/IV) locally advanced HNSCC were consented to receive pembrolizumab 200 mg I.V. 1-3 weeks before planned surgical resection. Pretreatment biopsies and postoperative specimens were archived for H&E and immunohistochemistry. Peripheral blood was collected for ELISA. Following resection, patients were stratified based on pathological risk to receive adjuvant standard of care (SOC) combined with pembrolizumab every three weeks for a total of seven doses. Patients are followed for disease-free and overall survival. Safety was determined by delays in SOC treatment. Sixteen of 80 planned patients have been enrolled. To date, 3 patients were replaced due to pre-surgical infection, discovery of a secondary medullary thyroid cancer, and withdrawal of consent. Preliminary results show 8 of 10 patients demonstrated a pathological tumor response after a single dose of pembrolizumab. Tumor immune cell infiltration was not significantly changed, however, there was an increase in plasma proinflammatory cytokines with treatment. Interestingly, only the 2 patients without a pathological tumor response after pembrolizumab recurred (8 month [range 2-21 months] median time to follow-up). No delays in SOC treatment have occurred. Preliminary results demonstrated tumor responses after just one dose of pembrolizumab in previously untreated HNSCC patients that may predict patient outcome.