Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer

Importance: The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma (HNSCC) treatment. Objective: To assess the reported efficacy and safety of neoadjuvant immunotherapy for resectable HNSCC. Data Sources and Study Selection: Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched for published and ongoing cohort studies and randomized clinical trials that evaluate neoadjuvant immunotherapy for resectable HNSCC. The search results generated studies from 2015 to July 2021. Data Extraction and Synthesis: Two investigators (R.M. and L.K.) independently identified and extracted articles for potential inclusion. Random and fixed models were used to achieve pooled odds ratios. All results are presented with 95% CIs. Data quality was assessed by means of the Cochrane Collaboration's risk of bias tool. Main Outcomes and Measures: The primary outcomes were reported efficacy, evaluated by major pathological response and pathological complete response in the primary tumors and lymph nodes separately, and safety, assessed by preoperative grade 3 to 4 treatment-related adverse events and surgical delay rate. Results: A total of 344 patients from 10 studies were included. In 8 studies, neoadjuvant immunotherapy only was administered, and the other 2 studies combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy. The overall major pathological response rate in the primary tumor sites from studies reporting on neoadjuvant immunotherapy only was 9.7% (95% CI, 3.1%-18.9%) and the pathological complete response rate was 2.9% (95% CI, 0%-9.5%). Preoperative grade 3 to 4 treatment-related adverse events were reported at a rate of 8.4% (95% CI, 0.2%-23.2%) and surgical delay at a rate of 0% (95% CI, 0%-0.9%). There was a favorable association of neoadjuvant immunotherapy with all outcome measures. The subgroup analyses did not find one specific anti-PD-1/PD-L1 agent to be superior to another, and the favorable association was demonstrated by either immunotherapy alone or in combination with anti-CTLA-4. Conclusions and Relevance: In this systematic review and meta-analysis, neoadjuvant anti-PD-1/PD-L1 immunotherapy for resectable HNSCC was well tolerated and may confer therapeutic advantages implied by histopathological response. Long-term outcomes are awaited.