Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

• Published in: The lancet oncology 2024-12, Vol.25 (12), p.1576-1588
• Main Authors: Mell, Loren K, Torres-Saavedra, Pedro A, Wong, Stuart J, Kish, Julie A, Chang, Steven S, Jordan, Richard C, Liu, Tian, Truong, Minh Tam, Winquist, Eric W, Takiar, Vinita, Wise-Draper, Trisha, Robbins, Jared R, Rodriguez, Cristina P, Awan, Musaddiq J, Beadle, Beth M, Henson, Christina, Narayan, Samir, Spencer, Sharon A, Powell, Steven, Dunlap, Neal, Sacco, Assuntina G, Hu, Kenneth Shung, Park, Henry S, Bauman, Julie E, Harris, Jonathan, Yom, Sue S, Le, Quynh-Thu
• Format: Article
• Language: English
• Subjects: Adult; Adverse events; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - therapeutic use; Bronchopulmonary infection; Cancer therapies; Cetuximab - administration & dosage; Cetuximab - adverse effects; Cetuximab - therapeutic use; Chemoradiotherapy - adverse effects; Chemoradiotherapy - mortality; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Clinical trials; Comorbidity; Contraindications; Dysphagia; Edema; Female; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - therapy; Hearing loss; Humans; Immunotherapy; Intravenous administration; Lymphopenia; Male; Middle Aged; Mucositis; Oncology; Oropharyngolaryngeal carcinoma; Patients; Peripheral neuropathy; Progression-Free Survival; Radiation therapy; Review boards; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - mortality; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - therapy; Toxicity
• ISSN: 1470-2045; 1474-5488; 1474-5488
• DOI: 10.1016/S1470-2045(24)00507-2

Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended fo