Systematic Reviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. May 24, 2022; 13(5): 388-411
Published online May 24, 2022. doi: 10.5306/wjco.v13.i5.388
Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials
Jissy Vijo Poulose, Cessal Thommachan Kainickal
Jissy Vijo Poulose, National Fellowship in Palliative Medicine (Training Program), Institute of Palliative Medicine, Calicut 673008, Kerala, India
Cessal Thommachan Kainickal, Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram 695011, Kerala, India
Author contributions: Kainickal CT contributed to conceptualization; Poulose JV contributed to the methodology and literature search; Both authors participated in drafting and critically revising the manuscript.
Conflict-of-interest statement: Authors have nothing to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Cessal Thommachan Kainickal, MBBS, MD, Additional Professor, Department of Radiation Oncology, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India.
Received: August 26, 2021
Peer-review started: August 26, 2021
First decision: October 22, 2021
Revised: November 3, 2021
Accepted: May 5, 2022
Article in press: May 5, 2022
Published online: May 24, 2022

The outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.


To evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials.


We searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials.


Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.


Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.

Keywords: Head and neck squamous cell carcinoma, Recurrent/metastatic head and neck squamous cell carcinoma, Locally advanced head and neck squamous cell carcinoma, Immune checkpoint inhibitors, Immunotherapy, Monoclonal antibody

Core Tip: Immune checkpoint inhibitors have demonstrated better survival outcomes and acceptable toxicity profiles in recurrent/metastatic head and neck squamous cell carcinoma in the first and second-line treatment settings. While anti- programmed cell death protein-1 agents demonstrated efficacy, evidence on the effectiveness of anti-programmed death ligand-1 and anti-cytotoxic T lymphocyte-associated antigen-4 agents is lacking. There is no proven efficacy in the curative setting to date. Gaps in knowledge were found in terms of predictive biomarkers and identification of patients who would benefit from immunotherapy based on biomarker assessment. Several promising trials are currently ongoing to fill this knowledge gap. Novel combination strategies to potentiate and prolong the anti-tumor activity of immune checkpoint inhibitors are also being evaluated currently.