Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study

• DOI: 10.1016/j.annonc.2022.12.008
• Publication Date: 2022-12-16T07:59:55Z
• Authors: A. Psyrri; J. Fayette; K. Harrington; M. Gillison; M.-J. Ahn; S. Takahashi; J. Weiss; J.-P. Machiels; S. Baxi; A. Vasilyev; A. Karpenko; M. Dvorkin; C.-Y. Hsieh; S.C. Thungappa; P.P. Segura; I. Vynnychenko; R. Haddad; S. Kasper; P.-S. Mauz; V. Baker; P. He; B. Evans; S. Wildsmith; R.F. Olsson; A. Yovine; J.F. Kurland; N. Morsli; T.Y. Seiwert
• Keywords: programmed death-ligand 1; durvalumab; Medizin; 610; head and neck squamous cell carcinoma; B7-H1 Antigen; 03 medical and health sciences; tremelimumab; 0302 clinical medicine; 616; Antineoplastic Combined Chemotherapy Protocols; Humans; programmed cell death ligand-1; kestrel; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Oncology and carcinogenesis; Hematology; phase III study; 3. Good health; Pharmacology and pharmaceutical sciences; Neoplasm Recurrence; Local; Squamous Cell; Oncology; Head and Neck Neoplasms; randomized; Carcinoma, Squamous Cell; immune checkpoint inhibition; Durvalumab; Neoplasm Recurrence, Local

Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC.Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed.Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively.In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.