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BackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate. MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10-49%), and pTR-2 ([&ge;]50%). Co-primary endpoints were pTR-2 among all patients, and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 expression and T-cell infiltration with pTR were assessed, and tumor clonal dynamics were evaluated. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov(NCT02296684), and is ongoing but closed to accrual. FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR [&ge;]10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-{gamma} pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%). ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical. FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

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