Durvalumab Is Not Statistically Significant Vs Cetuximab in HNSCC

For patients with head and neck squamous cell carcinoma who have a contraindication to cisplatin, radiotherapy plus durvalumab (Imfinzi) did not improve survival vs radiotherapy plus cetuximab (Erbitux), according to results from the phase 2/3 NRG-HN004 trial (NCT03258554) published in The Lancet Oncology.

The median follow-up was 2.3 years. The 2-year progression-free survival (PFS) was 50.6% (95% CI, 41.5%-59.8%) in the durvalumab arm vs 63.7% (95% CI, 51.3%-76.1%) in the cetuximab arm (HR, 1.33; 95% CI, 0.84-2.12; P = .89).

At the interim futility analysis, the median follow-up was 6.4 months, with 37 patients having a PFS event including 22% in the durvalumab group and 21% in the cetuximab group. The 2-year PFS for patients with p16 status and treatment group interaction were not statistically significant (P = .22).

The protocol-specified analysis had a median follow-up of 1.2 years with 42% of patients in the durvalumab group having a PFS event vs 29% in the cetuximab group. The median PFS was 2.2 years (95% CI, 1.2-not reached [NR]) vs 2.7 years (95% CI, 2.7-NR) in either arm (HR, 1.47; 95% CI, 0.86-2.52; P = .92). The 2-year PFS estimates were 51.0% (95% CI, 40.7%-61.2%) vs 66.4% (95% CI, 52.8%-80.1%).

The HR for treatment effect was 1.05 (95% CI, 0.53-2.09) which crossed the protocol-specified boundary of 1. Because of the results with similar distribution of disease-specific events that led to the PFS end point, the NRG Oncology Data Monitoring Committee recommended permanent accrual closure. Additionally, with any additional follow-up, 69 PFS events were required for the phase 2 primary end point analysis.

The null hypothesis for this trial was that no difference in PFS would be observed between either arm.

“The trial was intended to go a lot longer than it did, and the goal was to recruit a lot more patients than it ended up recruiting. The reason that it didn’t is because it closed early, because the planned analysis of the data at that point showed that the experimental arm was not performing as well as the control arm,” study author Christina E. Henson, MD, Residency Program Director for Radiation Oncology at OU Health, said in an interview with CancerNetwork®. “What we saw [after] following the patients for 2 years after they received treatment, was that the cure rate was about 13% lower actually in the experimental arm, which is a pretty big difference.”

In the phase 2 portion of the trial that took place from March 12, 2019, to July 30, 2021, a total of 190 patients were enrolled and 186 were randomly assigned to either the durvalumab arm (n = 123) or the cetuximab arm (n = 63). The median age was 72 years old, with 59% being 70 years or older. Overall, the majority were men (84%), White (83%), and had p16-positive oropharyngeal or unknown primary disease (47%).

Contraindications to cisplatin included hearing loss (49%), renal insufficiency (28%), grade 1 or higher peripheral neuropathy (21%), and an ECOG performance status of 2 (12%). For those who did not have contraindications, they were 70 years or older with a moderate or severe comorbidity (9%), or younger than 70 years with a severe comorbidity (8%). The median number of comorbidities was 5.

During extended follow-up, 58 patients had died. The post-hoc median overall survival was not reached in either arm (HR, 1.30; 95% CI, 0.74-2.28; P = .82). Similar results were observed when adjusted for stratification factors, except for p16 status (P = .0092).

The post-hoc 2-year OS estimated were 69.3% (95% CI, 60.8%-77.8%) in the durvalumab arm vs 77.5% (95% CI, 66.7%-88.3%) in the cetuximab arm.

Locoregional failure was observed in 31% of patients in the durvalumab arm and 19% in the cetuximab arm, with 11% vs 14% having distant metastasis events. Competing mortality events between either arm were observed in 9% vs 6% of patients.

The most common grade 3/4 adverse effects (AEs) included dysphagia (22% vs 30%), lymphopenia (28% vs 33%), and oral mucositis (11% vs 18%) between the durvalumab and cetuximab arms, respectively. In the durvalumab group, 9% of patients died vs 2% in the cetuximab group due to AEs.

Treatment-related serious AEs that were most common included aspiration (3% vs 3%), dehydration (4% vs 7%), dysphagia (3% vs 7%), dyspnea (3% vs 2%), and laryngeal edema (3% vs 0%). Death from treatment-related serious AEs was noted in 3% of patients in the durvalumab group vs 2% in the cetuximab group

One year after the end of radiotherapy, 19.0% (95% CI, 12.1%-28.7%) of patients in the durvalumab group vs 16.3% (95% CI, 8.1%-30.0%) in the cetuximab group had a feeding tube (P = .70).

“It’s always disappointing when we have a trial that comes out to be negative and that we didn’t find something that benefits our patients, but it also can show us the importance of a good trial design, and help us to better design future trials,” Henson concluded.

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. 2024;25(12):1576-1588. doi:10.1016/S1470-2045(24)00507-2