Immune checkpoint inhibitor use in head and neck squamous cell carcinoma: the current landscape and future perspectives

Abstract

Immune checkpoint inhibitors are licensed for use in patients with unresectable, recurrent or metastatic head and neck squamous cell carcinoma. Multiple published and ongoing trials are assessing efficacy in the curative management of patients in the concomitant, neoadjuvant and/or adjuvant settings, as well as part of multimodality treatment in patients with metastatic disease. This review evaluates the evidence for use of immune checkpoint inhibitors in all stages of head and neck squamous cell carcinoma and considers future approaches.

Article highlights

Immune checkpoint inhibitors

• Immune checkpoint inhibitor (ICI) therapies most commonly target PD-1, PD-L1 or CTLA-4, but novel targets include TIGIT, TIM3 and OX-40.

• Head and neck squamous cell carcinomas (HNSCCs) can utilise immune escape mechanisms rendering them resistant to ICI therapy.

Tumour microenvironment

• HNSCCs frequently over-express VEGF and EGFR.

• The tumour microenvironment is complex and further characterisation of the signalling pathways will help to ascertain and potentially overcome various resistance mechanisms exhibited by cancer cells.

Current landscape in head & neck squamous cell carcinoma

• For patients with unresectable, recurrent or metastatic HNSCC, ICI therapy with either pembrolizumab or nivolumab has offered the possibility of long-term control of their disease.

• In the KEYNOTE-048 study, initially patients treated with chemotherapy and cetuximab have an improved overall survival compared with pembrolizumab alone, and possible explanations for this include favourable objective response rates to chemotherapy and cetuximab, primary resistance to ICI therapy or hyperprogression as a response to pembrolizumab treatment.

Unresectable recurrent &/or metastatic setting

• Dual checkpoint inhibition has to date shown no overall survival benefit compared with ICI monotherapy.

• Differences in radiotherapy dose and fractionation can cause radiation treatment to be either immunogenic or immunosuppressive and trials are ongoing to ascertain the ideal regime to achieve the desired response by modulating the tumour microenvironment.

• The addition of cetuximab in combination with ICI therapy has shown favourable objective response rates and overall survival in phase II trials.

• The addition of other systemic treatments combined with ICI therapy, with or without radiotherapy, are being investigated in this setting.

Operable recurrent disease

• Neoadjuvant ICI therapy has been assessed in operable recurrent disease and results appear promising.

Locally advanced disease

• The sequence of ICI therapy is likely to be very important in order to improve outcomes for patients with locally advanced disease, as multiple trials have failed to show a survival benefit with the addition of concomitant ICI therapy alongside radical radiotherapy, or in the neoadjuvant or adjuvant settings.

• Preclinical data has revealed that sublethal radiotherapy doses improve immunogenicity, which may prove beneficial in combination with ICI therapy in the future.

• Neoadjuvant ICI therapy prior to surgery has been shown to have promising objective response rates, and adjuvant ICI therapy studies are underway.

Early stage disease

• Trials are ongoing to assess the use of ICI therapy concurrently with de-intensified radiotherapy.

Challenges

• Further research is required to discover effective combination therapies and the sequencing of treatments, to allow for increased tumor neoantigen presentation and hopefully subsequent improved responses to immune checkpoint blockade in all stages of HNSCC.

• The length of ICI therapy use in future trials needs to be considered, as prolonged adjuvant treatments expose patients to increased risks of life-long toxicities, as well as there being a significant financial implication.

Future perspective

• Biomarkers currently used in HNSCC include PD-L1 and HPV status, but better predictive biomarkers will allow for improved patient selection, further improving the benefit risk ratio for patients offered ICI therapy.

• Next generation sequencing of tumor DNA allows for better characterization of the tumor mutational burden, and may improve response predictions.

• Developing trials supported by preclinical data and taking into account previous negative studies is necessary.

Keywords: :

• head and neck squamous cell carcinoma
• immune checkpoint inhibitors
• immunotherapy

Author contributions

E Gatfield – Collected the data/information (via literature search); performed the analysis and interpretation of results; wrote the article. J Tadross – Performed the analysis and interpretation of results; revised the draft manuscript. W Ince – Conceived and devised the project; performed the analysis and interpretation of results; revised the draft manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilised in the production of this manuscript.