No Improvement With Durvalumab vs Cetuximab in Advanced HNSCC

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Treatment with durvalumab (Imfinzi) did not improve outcomes over cetuximab (Erbitux) when given to patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy with contraindications to cisplatin, according to findings from the phase 2/3 NRG-HN004 trial (NCT03258554).¹

In a post-hoc extended analysis published in The Lancet Oncology, with a median follow-up of 2.3 years (IQR, 1.9-3.1), the 2-year progression-free survival (PFS) was 50.6% for those treated with durvalumab (95% CI, 41.5%-59.8%) and 63.7% for those given cetuximab (95% CI, 51.3%-76.1%). The median PFS was 2.2 years (95% CI, 1.2-not reached [NR]) in the durvalumab group and 2.7 years (95% CI, 2.7-NR) in the cetuximab group (HR, 1.47; 95% CI, 0.86-2.52; P = .92) at the protocol-specified analysis. Two-year PFS estimates were 51.0% (95% CI, 40.7%-61.2%) for durvalumab and 66.4% (95% CI, 52.8%-80.1%) for cetuximab.

Similarly, 2-year overall survival (OS) estimates were 69.3% (95% CI, 60.8%-77.8%) and 77.5% (95% CI, 66.7%-88.3%) in the durvalumab and cetuximab groups, respectively.

During an interim futility analysis with a median follow-up of 6.4 months (IQR, 2.2-14.2), PFS events occurred in 25 patients (22%) in the durvalumab group and 12 patients (21%) in the cetuximab group. The treatment effect hazard ratio was 1.05 (95% CI, 0.53-2.09), crossing the protocol-specified futility boundary (HR = 1). Consequently, the NRG Oncology Data Monitoring Committee recommended permanent closure of trial accrual.

At the extended follow-up, 41 patients (33%) in the durvalumab group and 17 patients (27%) in the cetuximab group had died.

In terms of safety, dysphagia, lymphopenia, and oral mucositis were the most common grade 3 or 4 adverse events (AEs). Deaths from AEs regardless of treatment relationship occurred in 11 patients (9%) in the durvalumab group and 1 patient (2%) in the cetuximab group.

Treatment-related serious AEs were seen in 29 patients (24%) in the durvalumab arm and 15 patients (25%) in the cetuximab arm. The most common included aspiration, dehydration, dyspnea, laryngeal edema, and lung infection. Treatment-related deaths were reported in 4 patients (3%) in the durvalumab group and 1 patient (2%) in the cetuximab group.

About the NRG-HN004 Trial

The NRG-HN004 trial enrolled 190 patients, with 186 randomly assigned in a 2:1 ratio by permuted block randomization to either a radiotherapy with durvalumab group (n = 123) or a radiotherapy with cetuximab group (n = 63). Patients were stratified by disease stage, performance status, comorbidity, primary site, and p16 status.²

Radiotherapy was delivered as intensity-modulated radiation therapy at 70 Gy in 35 daily fractions over 7 weeks. Durvalumab was administered at 1500 mg intravenously starting 2 weeks before radiotherapy, and then every 4 weeks during radiotherapy for up to 7 cycles. Cetuximab was administered at 400 mg/m² intravenously 1 week before radiotherapy, followed by 250 mg/m² weekly during radiotherapy for up to 8 cycles.

Eligible patients were aged 18 years or older with stage III to IVB p16-negative squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or unknown primary HNSCC, or unfavorable risk p16-positive oropharyngeal carcinoma. All had contraindications to cisplatin, such as ECOG performance status of 2, hearing or renal impairment, grade ≥1 peripheral neuropathy, or other vulnerabilities to cisplatin.

The median age of those enrolled was 72 years (interquartile range, 64-77). Thirty (16%) patients were women and 156 (84%) were men.

Accrual for the phase 2 portion of the trial was halted on July 30, 2021, after an interim futility analysis, and the study was permanently closed on September 1, 2022. The phase 3 segment of the trial was not carried out.

Overall, the NRG-HN004 trial showed that durvalumab did not improve outcomes vs cetuximab in this patient population, leading to early trial closure.¹ These findings underscore the need for alternative therapeutic strategies and further investigation to define this population's standard of care.

REFERENCE

1. Mell LK, Torres-Saavedra PA, Wong SJ, et al. 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. Lancet Oncol. Published online November 14, 2024. doi:10.1016/S1470-2045(24)00507-2

2. Radiation therapy with durvalumab or cetuximab in treating patients with locoregionally advanced head and neck cancer who cannot take cisplatin. ClinicalTrials.gov. Updated November 13, 2024. Accessed January 3, 2025. https://clinicaltrials.gov/study/NCT03258554