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
Research background

Head and neck squamous cell carcinoma (HNSCC) is one of the major causes of cancer-associated morbidity and mortality globally, especially in developing countries. Treatment approaches for HNSCC vary according to the stage of the disease at presentation. For recurrent/metastatic HNSCC (R/M HNSCC), platinum-based chemotherapy was the only available treatment option until recently. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICI).

Research motivation

Advanced HNSCCs are often associated with significant functional limitations, and aggressive treatment may adversely affect the quality of life of these patients who are already suffering from the effect of advanced cancer. The median survival of R/M HNSCC patients receiving platinum-based chemotherapy is 7.4 mo. Some patients become refractory to platinum and die within a period of 4 mo. The safety profile and anti-tumor activity of ICIs demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field. Therefore, we decided to gather the current evidence on the effectiveness of these agents in advanced head and neck cancer based on the findings from phase-3 clinical trials of ICI published so far. We also wanted to examine the feasibility of incorporating these agents into routine clinical practice in resource-poor settings.

Research objectives

The objective of this systematic review was to gather the evidence from phase-3 randomized controlled trials (RCTs) evaluating the effectiveness of immunotherapy among patients with advanced HNSCC. We aimed to synthesize the evidence from the published phase-3 studies that investigated the efficacy and toxicity profile of ICIs administered either alone or in combination with chemotherapy, radiation therapy, or with another checkpoint inhibitor, in advanced HNSCC.

Research methods

We conducted this systematic review according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. We searched four major databases including PubMed, Scopus, Embase, and COCHRANE library, without any language limit. A combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, 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 were used for searching the literature. Studies were included if they were completed phase-3 RCTs conducted among patients with R/M HNSCC or LAHNSCC, in which the intervention patients received ICI either alone or in combination with chemotherapy, radiation therapy, or with another ICI and the control patients received the standard of care treatment (SOC). Anatomical sites of primary tumors were oral cavity, oropharynx, hypopharynx, and larynx in the included studies.

Research results

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 improvement in overall survival (OS) in the second-line treatment setting compared to the SOC. While the net gain in OS with nivolumab was 2.4 mo, that with pembrolizumab was 1.5 mo. However, the study that investigated the anti-PD-L1 agent durvalumab with or without the anti-CTLA-4 agent tremelimumab in the second-line treatment setting did not demonstrate any beneficial outcomes.

In the first-line setting, pembrolizumab together with platinum-based chemotherapy demonstrated statistically significant improvement in survival with a net gain in OS of 2.3 mo in the overall population and a net gain in OS of 4.2 mo in the population with a combined positive score of > 20 compared to the SOC treatment. Pembrolizumab monotherapy was found to be non-inferior to EXTREME in terms of OS (11.6 mo vs 10.7 mo) in the total population. In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to SOC. In LAHNSCC, immunotherapy using the anti-PD-L1 agent avelumab along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.

Research conclusions

This systematic review helped us to conclude that anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings with manageable toxicity profiles. However, it is important to weigh the marginal survival benefits provided by these therapeutic agents against their cost, especially in resource-poor settings. The review showed that the evidence on the effectiveness of anti-PD-L1 and anti-CTLA-4 agents in advanced head and neck cancer is lacking. To date, there is no evidence on the effectiveness of ICIs in the curative setting either. We believe that the ongoing clinical trials (discussed in the article) will help to define better the role of ICI in R/M HNSCC and LAHNSCC in the future.

Research perspectives

Novel combination strategies to potentiate and prolong the anti-tumor activity of ICI are being evaluated currently. Gaps in knowledge exist on some important issues such as predictive biomarkers, and about the identification of patients who will benefit from immunotherapy based on biomarker assessment. Future studies should focus on these issues.