The first-in-class agent xevinapant (also known as Debio 1143), given with chemotherapy and radiotherapy, significantly improved overall survival in a phase II study of 96 patients with locally advanced squamous cell carcinoma of the head and neck.1 “This is the first study in decades to improve the cure rate by adding a new treatment to the standard of care, cisplatin plus radiotherapy,” said Jean Bourhis, MD, PhD, of the Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, who reported the results at the European Society for Medical Oncology (ESMO) Congress 2022.
Jean Bourhis, MD, PhD
Xevinapant is a first-in-class, orally available antagonist of inhibitor of apoptosis proteins (IAP) with the potential to enhance the antitumor activity of cisplatin and radiotherapy. The addition of this IAP inhibitor to standard-of-care chemoradiotherapy improved efficacy outcomes without increasing toxicity: at 5 years, deaths were reduced by 53%, and at 3 years, the odds of death or disease progression were reduced by 79%, Dr. Bourhis reported.
About the Study
The study was a double-blind trial of 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (T ≥ 2, N0–3, M0) and a smoking history of at least 10 pack-years. Patients were randomly assigned (1:1) to receive xevinapant at 200 mg once daily (days 1–14 of a 3-week cycle) every 3 weeks for three cycles plus chemoradiotherapy. The chemoradiotherapy regimen included cisplatin at 100 mg/m2 on day 2 every 3 weeks for three cycles plus intensity-modulated radiotherapy at 70 Gy for 7 weeks or placebo plus the same regimen for three cycles.
Patients were followed until July 2020; survival data were collected until April 2022, which was 5 years after the last patient was randomly assigned to treatment. The primary endpoint was locoregional tumor control rate at 18 months from the end of chemoradiotherapy.
Updated Findings: Near Doubling of Overall Survival
The investigators previously reported that 3 years after the last patient ended treatment, the xevinapant regimen met the primary endpoint, achieving an odds ratio for locoregional tumor control of 2.74 (P = .0232).2 The secondary endpoint of progression-free survival was also significantly improved, with the median not reached with xevinapant vs 16.9 months with placebo (hazard ratio [HR] = 0.33; P = .0019). At 3 years, 72% vs 36% of patients, respectively, were progression-free.
At the ESMO Congress 2022, Dr. Bourhis reported updated findings on the duration of response at 3 years and overall survival after 5 years. The 5-year analysis was based on a median follow-up of 60 months in the experimental arm and 39 months in the control arm.
“The addition of xevinapant to chemoradiotherapy nearly doubled the 5-year overall survival…. The risk of death was more than halved,” he said. “Xevinapant improved overall survival across all prespecified subgroups.”
At a median follow-up of 60.1 months for the experimental arm and 39.2 months for the control arm, median overall survival was not reached for patients receiving xevinapant and was 36.1 month for those treated with chemoradiotherapy alone (HR = 0.47; P = .0101), with 53% vs 28% of patients, respectively, alive. The risk of death or disease progression after an initial response—ie, the duration of response at 3 years—was reduced by 79% in the xevinapant arm vs the placebo arm (HR = 0.21; P = .0011), based on a median duration of response that was not reached with xevinapant compared with 17.3 months with chemoradiotherapy.
Receipt of subsequent anticancer therapy was comparable between the arms, and safety (including treatment discontinuations) was also similar. A confirmatory phase III trial—TrilynX—is currently recruiting patients.
DISCLOSURE: The study was funded by Debiopharm. Dr. Bourhis reported financial relationships with AstraZeneca, Bristol Myers Squibb, Debiopharm, Merck, MSD, Nanobiotix, and Roche.
REFERENCES
1. Bourhis J, Le Tourneau C, Calderon B, et al: 5-year overall survival in patients with locally advanced squamous cell carcinoma of the head and neck treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase II study. ESMO Congress 2022. Abstract LBA33. Presented September 10, 2022.
2. Sun XS, Tao Y, Le Tourneau C, et al: Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: A double-blind, multicentre, randomised, phase 2 study. Lancet Oncol 21:1173-1187, 2020.
