Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study

Abstract

PURPOSE Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC. PATIENTS AND METHODS Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS). RESULTS The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m2. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively. CONCLUSION Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

“…39 This effect was also found in a recent phase IB trial when radiochemotherapy was combined with pembrolizumab in locally advanced HNSCC. 3 In the CheckRad-CD8 trial, p16 positive tumors had a higher CD8+ cell density and higher PD-L1 immune cell area compared with p16 negative tumors. Increased densities of tumor-infiltrating immune cells in p16-positive tumors have also been reported previously.…”

<p>Suppressing UVRAG Induces Radiosensitivity by Triggering Lysosomal Membrane Permeabilization in Hypopharyngeal Squamous Cell Carcinoma</p>

“…Hypopharyngeal squamous cell carcinoma (HSCC) is one of the most malignant head and neck cancers. 25 Although there is a comprehensive treatment including surgical excision, chemotherapy and radiotherapy, the prognosis of patients with HSCC remains poor. 26 Radioresistance is one of the most important factors leading to treatment failure of HSCC.…”

Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma

“…Similar results were obtained by another small phase II trial [ 133 ], while other studies have evaluated the combination of immune checkpoint inhibition, radiotherapy and cisplatin. Taken together, there appears no major concerns of safety problems with this approach [ 134 , 135 , 136 ].…”