Durvalumab combined with weekly carboplatin/paclitaxel as first-line treatment of patients with recurrent and/or metastatic HNSCC not eligible for cisplatin-based chemotherapies: results of the multicenter prospective study FRAIL-IMMUNE

Background Pembrolizumab, combined with platinum-5-FU or as a monotherapy, is the standard treatment of patients with recurrent and/or metastatic (R/M) head and neck squamous-cell carcinoma (HNSCC). This treatment is used exclusively in programmed death-ligand 1 (PD-L1)-positive patients in Europe, whereas it is used in the USA regardless of PD-L1 status. However, substantial toxicities, notably those related to cisplatin-based chemotherapy, preclude the use of combination therapy in fragile patients. We investigated the efficacy and tolerance of first-line durvalumab combined with weekly carboplatin/paclitaxel in R/M HNSCC patients who were ineligible for cisplatin. Patients and methods This prospective multicenter single-arm phase II study assessed tolerance in R/M HNSCC patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-1 (run-in phase study feasibility, then cohort A) and ECOG-PS 2 (cohort B), frail, not eligible for standard cisplatin-based chemotherapy. In the first-line, patients received four 28-day chemotherapy cycles (carboplatin AUC2; paclitaxel 80 mg/m 2 day 1, 8, and 15) combined with durvalumab 1500 mg every 4 weeks for 12 months maximum. The primary endpoint was 12-month overall survival (OS) rate based on a Fleming A'Hern design: cohort A, P 0 inefficacy boundary 47%, P 1 target efficacy 65%, at least 38 successes among 64 patients assessable were required for further investigations; cohort B: P 0 15%; P 1 35%, at least 10 successes needed among 38 patients to reject the null hypothesis. Results From 16 May 2019 to 4 March 2021, 64 patients with an ECOG-PS of 1 (cohort A) from 13 French authorized centers (hospital, cancer centers) were included and received study treatments. Cohort B enrolled 40 patients with an ECOG-PS of 2 from 25 Aug 2021 and 9 March 2023 and 39 were assessable. With 40 patients with an ECOG-PS of 0-1 [62.5%, unilateral 95% confidence interval (CI) 51.5%-∞], and 20 patients with an ECOG-PS of 2 (51.3%, unilateral 95% CI 37.1%-∞) alive at 12 months, the study met its primary endpoints. Conclusions The promising results in frail patients with an ECOG-PS of 0-1 and 2 encourages further investigation of durvalumab with weekly carboplatin/paclitaxel in first-line R/M HNSCC patients in a comparative phase III clinical trial.