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Original Investigation
September 2, 2021

Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck and Maxillofacial Surgery, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 2Institute of Radiation Therapy, Division of Oncology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
JAMA Otolaryngol Head Neck Surg. Published online September 2, 2021. doi:10.1001/jamaoto.2021.2191
Key Points

Question  What is the efficacy and safety profile of neoadjuvant programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors in patients with resectable head and neck cancer?

Findings  This systematic review and meta-analysis of 10 clinical trials of patients with resectable head and neck cancer revealed that neoadjuvant immunotherapy with PD-1/PD-L1 inhibitors had a favorable association with outcome measures of efficacy (pathological complete response) and safety (grade 3-4 adverse events and surgical delay).

Meaning  Neoadjuvant anti–PD-1/PD-L1 immunotherapy for resectable head and neck cancer appears to be well tolerated and therapeutically efficacious, as implied by pathological response.


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.

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