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Clinical Trial
. 2023 Mar;34(3):262-274.
doi: 10.1016/j.annonc.2022.12.008. Epub 2022 Dec 16.

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

A Psyrri  1 , J Fayette  2 , K Harrington  3 , M Gillison  4 , M-J Ahn  5 , S Takahashi  6 , J Weiss  7 , J-P Machiels  8 , S Baxi  9 , A Vasilyev  10 , A Karpenko  11 , M Dvorkin  12 , C-Y Hsieh  13 , S C Thungappa  14 , P P Segura  15 , I Vynnychenko  16 , R Haddad  17 , S Kasper  18 , P-S Mauz  19 , V Baker  20 , P He  21 , B Evans  21 , S Wildsmith  20 , R F Olsson  22 , A Yovine  20 , J F Kurland  23 , N Morsli  20 , T Y Seiwert  24 ; KESTREL Investigators
Affiliations
Free article
Clinical Trial

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

A Psyrri et al. Ann Oncol. 2023 Mar.
Free article

Abstract

Background: 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 and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: durvalumab; head and neck squamous cell carcinoma; immune checkpoint inhibition; phase III study; programmed death-ligand 1; tremelimumab.

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Conflict of interest statement

Disclosure AP has received research funding from Bristol Myers Squibb, DEMO, KURA Oncology, and Roche and consultant/advisory/honoraria fees from AstraZeneca, Bristol Myers Squibb, HPVtRNA, Merck Serono, MSD, Nanobiotics, and Pfizer companies. JF has served in a consulting or advisory role for Bristol Myers Squibb, Innate Pharma, Merck, Merck Sharp & Dohme, Rakuten, and Roche and has received non-financial support from Bristol Myers Squibb and Merck Sharp & Dohme. KH has received research funding from AstraZeneca, Boehringer Ingelheim, MSD, and Replimune, and consultant/advisory/honoraria fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Codiak, Inzen, Merck Serono, Mersana Therapeutics, MSD, Pfizer, and Replimune. MG has received research funding from Agenus, Bristol Myers Squibb, Cullinan Labs, Genentech, Genocea Biosciences Inc., Kura, LaRoche, NRG, and University of Cincinnati. She has received consulting fees from Amgen Inc., Aspyrian Therapeutics, AstraZeneca Pharmaceuticals, Bayer Healthcare Pharmaceutics, Bicara Therapeutics, Bicara, BioNtech AG, Bristol Myers Squibb, Celgene Corp, Coherus Biosciences, Debiopharm, Eisai Medical Research Inc., EMD Serono, Inc., Genocea Biosciences Inc., Gilead Sciences Inc., Ipsen Biopharmaceuticals Inc., Istari Oncology Inc., iTeos Therapeutics, Kura Oncology, LLX Solutions, LLC, Merck & Co, Mirati Therapeutics, Nektar Therapeutics, NewLink Genetics Corp., OncLive Intellisphere, Roche Diagnostics GmbH, Roche, Seagen, Sensei Biotherapeutics Inc., Shattuck Labs Inc., and TRM Oncology. She received honoraria from OncLive and Roche. She has received support for attending meetings and/or travel from AACR, ASCO, and SITC. She reports an issued patent for NGVL4a-Sig/E7(detox)/HSP70 plasmid DNA for a clinical protocol entitled ‘An open-label phase one study of the safety with stage III or IV HPV16-positive head and neck squamous cell carcinoma’ and pending patents for oral HPV infection detection for oral cancer screening and diagnosis, and for HPV mRNA detection on oral cytology specimens for diagnosis and screening for oral cancer. She reports participation on a data safety monitoring board or advisory board for BioMimetix, Kura, NRG, Seagen, Sensei Biotherapeutics Inc., and SQZBiotech. She reports stock options with Sensei. MJA has received honoraria from AstraZeneca, Bristol Myers Squibb, MSD, ONO, and Roche and is a consultant or advisor for AstraZeneca, Bristol Myers Squibb, Takeda, MSD, Novartis, Roche, and Alpha pharmaceutical. ST reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from Eisai, Novartis, Taiho, MSD, Chugai, Bayer, and Daiichi-Sankyo, outside the submitted work. JW has stock and other ownership interests in Achilles Therapeutics, Nektar Therapeutics, Vesselon, Nuvalent, En Fuego Therapeutics, and Lyell Immunopharma. He has a consulting or advisory role with AstraZeneca, EMD Serono, Genentech, G1 Therapeutics, Jounce Therapeutics, AbbVie, Nanobiotix, Azitra, Eli Lilly, Blueprint Medicines, Pfizer, Saatchi Wellness, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron, Genmab, SDP Oncology, and BeiGene. He has received research funding from Mirati Therapeutics, Sumitomo Dainippon Pharma Oncology, Boehringer Ingelheim, and PDS Biotechnology. His institution has received research funding from Amgen, G1 Therapeutics, Immunicum, Inspirna, and Loxo/Lilly. He has had travel, accommodations, or expenses paid by Mirati Therapeutics. JPM is an advisory board member or speaker with honoraria (institution managed) for: Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, and Nektar Therapeutics. He has accepted travel expenses from: Amgen, Bristol Myers Squibb, Pfizer, and MSD. He is on the data safety monitoring board with honoraria for Psioxus. His institutional conflict of interest (funding to institution for research support) includes all companies. He has an uncompensated advisory role with MSD. SB reports owning stock in Roche Holding AG and is an employee of Verana Health. SCT reports receiving grant or research support from AstraZeneca and Eisai and consultant fees from AstraZeneca. RH is an employee of Dana-Farber Cancer Institute and has a leadership role with NCCN. He is a consultant or advisor for Achilles Therapeutics, AstraZeneca, Bayer, BioNTech AG, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus Biosciences, Eisai, EMD Serono, Genentech, Gilead Sciences, GSK, Immunomic Therapeutics, Loxo, Merck, MIRATI, Pfizer, and Vaccinex. His institution has received research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Kura, Merck, and Pfizer. He has other relationships with ISA Pharmaceuticals and Nanobiotix. SK received honoraria from Merck Serono, MSD, Novartis, Bristol Myers Squibb, Amgen, Roche, Sanofi-Aventis, Servier, Incyte, and Lilly; research funding from Merck Serono, Lilly, Bristol Myers Squibb, and Roche. PSM received advisory/lecture honoraria from BMS, KLS Martin Group, and Roche. He has accepted travel expenses from: AstraZeneca, BMS, GSK, KLS Martin Group, MSD, and Roche. VB is a freelance contractor for, and shareholder in, AstraZeneca. PH, BE, SW, RFO, AY, JFK, and NM are or were employees and shareholders of AstraZeneca. SW and NM report published patent WO2021228988A1. TYS has received grants/research funding from AstraZeneca, Bristol Myers Squibb, CUE biopharma, Kura, Merck/MSD, Nanobiotix, Regeneron, and Roche/Genentech, as well as honoraria from Bayer, BioNTech/Syneos, Coherur Biosciences, Cue Biopharma, Innate, KURA, Merck/MSD, Nanobiotix, Sanofi, Vir Biotechnology. All other authors have declared no conflicts of interest.

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