Immunotherapy for head and neck cancer: Recent advances and future directions

Abstract

Three randomized phase III trials have now conclusively proven that exposure to a PD-1 inhibitor prolongs survival in recurrent/metastatic (R/M) HNSCC, and it is clear that such agents should be used in the management of all patients who do not have contraindications to their use. Two of these phase III randomized trials showed that the anti-PD1 antibodies nivolumab and pembrolizumab were superior to investigators' choice chemotherapy in second-line platinum-refractory R/M HNSCC. Recently, a third phase III randomized trial, KEYNOTE-048, showed that pembrolizumab with chemotherapy was superior to the EXTREME regimen (cis- or carboplatin, 5-fluorouracil (5-FU) and cetuximab) in all patients, and pembrolizumab monotherapy was superior in patients whose tumors express PD-L1 in first-line R/M HNSCC. Pembrolizumab is now approved as monotherapy in PD-L1 expressing disease (combined positive score ≥1) or in combination with chemotherapy for all patients with R/M HNSCC. Thus, PD-L1 biomarker testing will be routinely used in R/M HNSCC, and this employs a scoring system that incorporates immune cell staining, referred to as the combined positive score (CPS). Additionally, for the 85% of patients with PD-L1 CPS ≥1, clinical judgment will guide the choice of pembrolizumab monotherapy or pembrolizumab plus chemotherapy, until more detailed clinical data are forthcoming to better inform this decision. In this article we discuss the clinical trials leading to these therapeutic advances and we will review initial results from clinical trials in previously untreated, locally advanced disease, and those using novel combinations of checkpoint inhibitors, co-stimulatory agonists, and therapeutic vaccines.

Keywords: Head and neck cancer; Head and neck squamous cell carcinoma; Immune checkpoint inhibitor; Immunotherapy; Nivolumab; Pembrolizumab.

Fig. 1.

Algorithm for management of recurrent or metastatic HNSCC. Abbreviations: DFI = disease free interval, CPS = combined proportion score.

Fig. 2.

Mechanisms of combination immunotherapy and chemotherapy in HNSCC. A. Molecular mechanism of action of anti-PD1 therapy and chemotherapy. B. Depiction of response rate to anti-PD1 therapy and chemotherapy. Response rates will vary based on the specific chemotherapy regimen used. Each person represents approximately 2%. Red colored persons represent those that respond to anti-PD1 therapy and blue colored persons represent those that respond to combination chemotherapy. C. Depiction of overall survival curves observed in HNSCC with anti-PD1 immunotherapy and chemotherapy. Anti-PD1 therapy produces a dramatically improved duration of response (i.e. tail of the curve) that has powered the overall survival benefit with this therapy despite a modest response rate. The images in part A are a derivative of cell_membrane, antibody, receptor, nucleus and dimeric receptor by Idoya Lahortiga & Luk Cox (https://www.somersault1824.com/) used under Creative Commons BY-NC-SA 4.0 https://creativecommons.org/licenses/by-nc-sa/4.0/.