Pembrolizumab: the value of PDL1 biomarker in head and neck cancer

Head and neck cancer is the fifth most common cancer worldwide and despite advances in first-line and secondline treatments, it has still a poor prognosis due to its high incidence and occurrence in sites not amenable to surgery [1,2]. Once the disease has relapsed or becomes metastatic, patients’ median survival time is about 9 months [3], and there are few treatment options. While therapeutic strategies such as surgery, radiation and chemotherapy when applied alone or in combination are useful for managing the disease [4], in most cases, they fail to obtain a cure. The most commonly used treatments for head and neck cancers are platinum agents, taxanes, 5-fluorouracil, methotrexate and cetuximab. The immune system plays an important role in the development and progression of head and neck cancers, as the development of such tumors strongly depends on their ability to escape immune surveillance. Head and neck cancer tissue contains inflammatory T cells that highly express PD-L1 receptors in both human papillomavirus (HPV)-positive and HPVnegative tumors. Moreover, the therapeutic strategy of creating an immune checkpoint blockade has recently been shown to enable the effective treatment of a variety of tumors [5]. Increased PD-L1 expression has been demonstrated in cases of actinic cheilitis, a premalignant condition of the oral cavity, as well as in respiratory HPV infections, which can produce lesions that progress to laryngeal cancers [6]. Immunosuppressed patients are more likely to develop head and neck cancers [7] and the tumors that occur in these individuals tend to have a poor response to treatment. Moreover, in some instances, the expression levels of immune checkpoint ligands and their receptors have been associated with the clinical prognosis of head and neck cancer patients [8]; however, the overall data are conflicting. Recent evidence suggests that oral squamous cell carcinoma patients who exhibit high levels of PD-L1 expression are more likely to have a poor clinical outcome and that PD-L1 expression, as determined by immunohistochemical staining, may serve as an independent prognostic marker for a subset of these patients who are male or have a smoking habit [9]. Pembrolizumab (formerly known as lambrolizumab and MK 3575) is a highly selective, humanized, IgG4 monoclonal antibody against PD-1. Pembrolizumab blocks interactions between the PD-1 receptor and its ligands (PD-L1 and PD-L2) and may, thereby, reactivate immune surveillance and elicit antitumor activity (Table 1) [10]. In September 2014, pembrolizumab became the first drug with an anti-PD-1 mechanism of action to be approved by the US Food and Drug Administration for treatment of melanoma and it is currently approved worldwide as monotherapy for advanced (nonresectable or metastatic) melanoma in adults. Moreover, results of the Keynote clinical trial [11] were used to support the accelerated approval of pembrolizumab in the United States for treatment of patients with metastatic non-small-cell lung cancer and patients whose PD-L1-expressing tumors progress during or after platinum-based chemotherapy [12]. The first data concerning the use of pembrolizumab to treat patients with head and neck cancers were presented by Seiwert et al. [13] at the 2014 American Society of Clinical Oncology meeting. The data from the multicenter, non-randomized Phase Ib head and neck squamous cell carcinoma (HNSCC) Keynote 012 study showed that 78% of patients with recurrent metastatic HNSCC expressed PD-L1 in their tumor stroma, regardless of whether HPV was detected. The majority of those patients had previously been treated for their disease and 35.7% had received more than three lines of therapy. Their treatment was continued for 24 months or until disease progression or a drug-related intolerable toxicity occurred [13]. Tumor shrinkage was observed in 26 (51%) of 51 patients, and the best overall response rate (ORR) (19.6%) was observed when pembrolizuamb was given at a dose of 10 mg/kg every 2 weeks to patients who had either HPV infection-associated or non-HPV-associated tumors. Among those patients, 28.7% achieved stable disease and the disease control rate was 61.5%. Furthermore, the responses were durable, as more than 50% of the patients continued to receive treatment after the data cutoff point of the clinical trial. Pembrolizumab appears to be well tolerated in patients with HNSCC. To date, a low rate of serious drug-related adverse events has been reported and only 16.7% of grade 3–5 adverse events have been drug related. The most common adverse events are fatigue, pruritus, rash and nausea.