Immune checkpoint inhibitors exert their anti-tumor effects by reinvigorating T-cell functions, resulting in long-term survival potential. They are also indicated for non-small cell lung cancer, small cell lung cancer, and esophageal cancer in the tracheoesophageal region, with the range of indications extending not only to advanced stages but also to the perioperative period. Understanding the me chanisms of anti-tumor T-cell immunity is necessary for appropriate treatment selection and management of immune-related adverse events, to maximize therapeutic efficacy.

In the treatment of head and neck cancer and esophageal cancer, multidisciplinary treatment using surgery, chemotherapy, and radiation therapy has been used in the past. Recently, immune checkpoint inhibitors (ICIs) have become the mainstay of the new standard treatment options. While some patients have achieved long-term survival with the use of ICIs, a low response rate has been a problem, and trials of various combination therapies using ICIs are currently underway to improve the response rate. Not much is known about the type of patients who will benefit from the therapy, and the search for biomarkers as predictors of therapeutic efficacy has been intense. In addition to PD-L1 (programmed death-ligand 1) and MSI (microsatellite instability), TMB (tumor mutational burden) has recently been approved. Rapid advances in gut microbiome analysis have led to reports that gut bacteria and their metabolites, short-chain fatty acids, influence anti-tumor immunity, and that fecal microbiota transplantation increases the efficacy of ICI therapy. In the future, as treatment options for cancer therapy become more complex, immune-related adverse events (irAEs) will also become more complex, and appropriate management of these events is desirable. At the same time, more treatment options may provide an opportunity to increase the efficacy of anti-tumor immunity and long-term prognosis, and thus further research is warranted.

Although recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains difficult to treat, the anti-EGFR antibody cetuximab, cisplatin/carboplatin and 5-fluorouracil (5it-FU) (the EXTREME regimen) significantly improved survival rates compared to reliance on platinum-based chemotherapy plus fluorouracil alone as the first-line treatment of recurrent and/or metastatic (R/M) HNSCC. In 2017, nivolumab, an antiprogrammed cell death-1 (PD-1) antibody, was approved based on the results of CheckMate 141 trial. Subsequently, pembrolizumab was also approved for the treatment of recurrent metastatic head and neck cancer in 2019, and it is now being used in the clinical setting. This review describes the current status of immune checkpoint inhibitors in the treatment of recurrent and/or head and neck cancer including the laryngeal and pharyngeal region.

Immune checkpoint inhibitors (ICIs) are one conceivable choice for treatment of lung cancer in any scenario. Originally starting from stage IV treatment, durvalumab has subsequently been used as consolidation therapy after chemoradiotherapy for stage III non-small cell lung cancer. Today, the therapeutic possibilities of ICIs are being expanded to neoadjuvant and adjuvant therapies, and in the future most patients will have experience with ICIs. In view of these rapid changes in ICI treatments, here we present the history of ICI therapies and the clinical trials that marked milestones in the field. Organizing information based on clinical evidence in each usage will help to deepen understanding.

Immune checkpoint inhibitor(s) have been developed for various stages of esophageal cancer in recent years. The efficacy of nivolumab and pembrolizumab as second-line therapies for unresectable advanced or recurrent esophageal cancer was reported in the ATTRACTION-3 trial and KEYNOTE-181 trial, respectively, in 2019. In 2020, the efficacy of pembrolizumab plus doublet chemotherapy as first-line treatment was reported in the KEYNOTE-590 trial. In 2021, the efficacy of nivolumab plus doublet combination chemotherapy and nivolumab plus ipilimumab was demonstrated as first-line therapies in the CheckMate 648 trial. In China, where esophageal squamous cell carcinoma frequently occurs, several clinical trials have also been conducted using novel immune checkpoint inhibitor(s), showing the efficacy of combination therapy with immune checkpoint inhibitor(s) and chemotherapy as first-line treatment in the ESCORT-1st trial, JUPITER-6 trial and ORIENT-15 trial. Currently, a combination treatment of immune checkpoint inhibitor(s) and chemotherapy, plus molecular targeting agents, is being developed for advanced esophageal squamous cell carcinoma in the LEAP-014 trial and the SKYSCRAPER-08 trial. In the perioperative setting, the efficacy of postoperative nivolumab therapy was demonstrated in esophageal cancer patients who failed to achieve a pathologic complete response after preoperative chemoradiation and surgery in the CheckMate 577 trial. In addition, the development of therapies that include immune checkpoint inhibitor(s) as preoperative treatment is ongoing in the FRONTiER trial. As these various developments indicate, immune checkpoint inhibitor(s) are increasing in importance for treatment of esophageal cancer.