Durvalumab Does Not Improve Outcomes Vs Cetuximab in Head and Neck Cancer

For patients with head and neck squamous cell carcinoma and contraindications to cisplatin, durvalumab yielded worse PFS vs cetuximab.

For patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy with contraindications to cisplatin, durvalumab (Imfinzi) did not improve outcomes compared with cetuximab (Erbitux), according to data from the phase 2/3 NRG-HN004 trial (NCT03258554) published in Lancet Oncology.

At the time of post-hoc extended analysis, with a median follow-up of 2.3 years (IQR, 1.9-3.1), 2-year progression-free survival (PFS) was 50.6% in the durvalumab group (95% CI, 41.5%-59.8%) and 63.7% in the cetuximab group (95% CI, 51.3%-76.1%). Post hoc 2-year overall survival (OS) estimates were 69.3% (95% CI, 60.8%-77.8%) in the durvalumab group and 77.5% (95% CI, 66.7%-88.3%) in the cetuximab group.

At the time of protocol-specified analysis, 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). Also, 2-year PFS estimates were 51.0% (95% CI, 40.7%-61.2%) in the durvalumab group and 66.4% (95% CI, 52.8%-80.1%) in the cetuximab group.

The interim futility analysis had a median follow-up of 6.4 months (IQR, 2.2-14.2). A PFS event was observed in 37 patients, 25 (22%) of which were in the durvalumab group and 12 (21%) were in the cetuximab group. Treatment effect HR was 1.05 (95% CI, 0.53-2.09); this crossed the protocol-specified futility boundary (HR = 1) and, as a result, the NRG Oncology Data Monitoring Committee recommended permanent accrual closure for the trial.

“The NRG-HN004 phase 2/3 trial was stopped after a planned interim futility analysis suggested that PD-L1 inhibition with durvalumab and radiotherapy was unlikely to improve outcomes over standard cetuximab with radiotherapy for patients with HNSCC and a contraindication to cisplatin,” lead study author Loren K. Mell, MD, chief of the head and neck malignancy service and radiation oncologist at University of California San Diego Health, and coauthors wrote. “The final phase 2 results did not show a statistically significant signal of efficacy of durvalumab and radiotherapy.”

A total of 190 patients were enrolled, with 186 randomly assigned in a 2:1 ratio by permuted block randomization via multiples of 6 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 and comorbidity, and primary site and p16 status.

Radiotherapy was intensity-modulated and given at 70 Gy in 35 daily fractions over 7 weeks. Then, depending on the group, patients were given 1500 mg of durvalumab intravenously starting 2 weeks before radiotherapy, then every 4 weeks starting on week 2 of radiotherapy for up to 7 cycles; or 400 mg/m² of cetuximab intravenously 1 week before radiotherapy then 250 mg/m² weekly starting week 1 of radiotherapy for up to 8 cycles.

Patients were aged 18 years or older, had stage III to IVB p16-negative squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or unknown HNSCC, or unfavorable risk p16-positive squamous cell carcinoma of the oropharynx, with a contraindication to cisplatin. Contraindications to cisplatin were considered to be an ECOG performance status of 2, hearing impairment, renal impairment, grade 1 or higher peripheral neuropathy, or vulnerability to cisplatin.

Patients were excluded from participation if they had distant metastasis; an ECOG performance status of 3 or higher; a bodyweight of 30 kg or lower; pregnancy; inadequate major organ function; previous immunotherapy, systemic therapy, or radiotherapy to the head or neck region; and a previous invasive malignancy within 3 years of treatment.

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

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

Treatment-related serious AEs occurred in 29 patients (24%) in the durvalumab group and 15 patients (25%) in the cetuximab group; aspiration, dehydration, dyspnea, laryngeal edema, and lung infection were the most common.

Four patients in the durvalumab group and 1 patient in the cetuximab group died from treatment-related AEs.

Reference

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