Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide in head and neck cancer: the CONFRONT phase I-II trial

Background: Inhibition of the programmed cell death protein 1–programmed death-ligand 1 (PD-1–PD-L1) axis results in a modest objective response rate (ORR) in recurrent/metastatic head and neck squamous cell carcinoma. This study aimed to evaluate whether the addition of metronomic chemotherapy and a single fraction of radiotherapy could synergistically operate with anti-PD-L1 treatment. Patients and methods: We conducted a phase I-II study evaluating avelumab (10 mg/kg intravenously every 2 weeks), low-dose cyclophosphamide (50 mg/day, fixed dose, without treatment breaks), and a single fraction of radiotherapy (8 Gy) to one lesion. The phase II portion of the study followed Simon's two-stage optimal design. A total of 6 patients were enrolled in phase I, and 20 patients were accrued and analyzed in phase II before determining progression to the second stage (51 patients). The primary endpoint was ORR. Further, a panel of circulating cytokines was analyzed to explore potential toxicity and/or efficacy markers. Results: Between January 2019 and June 2020, 20 patients were enrolled. In phase I, only one dose-limiting toxicity was observed among the six patients, allowing progression to phase II. At the end of stage I, five objective responses (2 complete responses and 3 partial responses) were recorded, failing to meet the threshold of six responses required to reject the null hypothesis. The median progression-free survival and overall survival were 3.0 and 9.2 months, respectively. Treatment was well tolerated. Low baseline levels of transforming growth factor-beta (TGF-β) and/or interleukin (IL)-4 were associated with a higher risk of immune-related adverse events (irAEs), whereas high baseline levels of IL-6 and vascular endothelial growth factor (VEGF) correlated with poor outcomes. Conclusions: Our results did not achieve the ORR threshold required to reject the null hypothesis in this cohort of unselected patients with relapsed/metastatic head and neck cancer. IL-6 and VEGF were associated with overall survival, whereas TGF-β and IL-4 correlated with irAEs.