Xevinapant Plus Standard Chemoradiotherapy Demonstrates Sustained Benefit in Locally Advanced HNSCC

Jean Bourhis, MD, PhD

The addition of xevinapant (Debio 1143) to standard-of-care (SOC) chemoradiotherapy elicited continued 5-year overall survival (OS) and 3-year duration of response (DOR) benefits in patients with unresected locally advanced head and neck squamous cell carcinoma (HNSCC), according to 5-year results of a phase 2 trial (NCT02022098).¹

A notable 53% (HR, 0.47; 95% CI, 0.27-0.84; P = .010) reduction in the risk of death with xevinapant vs placebo was reported in a presentation at the 2022 ESMO Congress by lead investigator Jean Bourhis, MD, PhD.

“Adding xevinapant to SOC chemoradiotherapy markedly improved efficacy outcomes without increasing toxicity,” Bourhis, chief of the Radiation Oncology Service at Lausanne University Hospital in Switzerland, said in a presentation of the data. “This is the first study in decades to improve the cure rate by adding a new treatment to the SOC of cisplatin and radiotherapy.”

Previous findings that were reported in 2020 indicated that the double-blind, randomized trial met its primary end point of superior locoregional control at 18 months (OR, 2.74; 95% CI, 1.15-6.53; P = .0232) and improved progression-free survival (HR, 0.33; 95% CI, 0.17-0.67; P = .0019) with the experimental regimen vs control therapy.^2,3

The potent, oral, first-in-class small-molecule inhibitor of apoptosis was investigated in patients with stage III or IVA/B unresectable locally advanced squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx (≥T2/N0-3/M0) and more than a 10 pack-year smoking history (n = 96). Factors for stratification included nodal status and primary tumor site.

Those receiving xevinapant (n = 48) did so at 200 mg daily on days 1 through 14 of every 3-week cycle for 3 cycles plus intravenous cisplatin at 100 mg/m² every 3 weeks for 3 cycles and intensity-modulated radiotherapy at a total of 70 Gy (2 Gy per day/5 days per week/7 weeks). Treatment on a placebo arm consisted of the same regimen with matched placebo in place of xevinapant (n = 48).

At the 5-year analysis, median OS was not reached with xevinapant vs 36.1 months with placebo; median follow-up in each arm was 60.1 months (range, 7.1-70.5) and 39.2 months (4.8-71.2), respectively. OS rates at the 5-year mark were 53% with xevinapant and 28% with placebo. Bourhis noted that the benefit of xevinapant was consistent across subgroups stratified by human papillomavirus status, tumor site, tumor stage, and smoking status.

DOR was longer in those receiving xevinapant after 3 years of treatment, with the median not reached vs 17.3 months in the placebo arm; those still in response at 3 years accounted for 79% and 36% of each respective arm (HR, 0.21; 95% CI, 0.08-0.54; P = .0011). In total, there were 31 complete responses (CRs) and 6 partial responses (PRs) with xevinapant vs 26 CRs and 9 PRs with placebo.

Receipt of subsequent anticancer therapy was consistent with SOC treatment in the xevinapant and control arms and accounted for 33.3% (n = 16) and 40.4% (n = 19) of treated patients, respectively. The most common type of subsequent therapy was systemic therapy (75.0% vs 84.2%) followed by radiotherapy (37.5% vs 21.1%) and surgery (31.3% vs 31.6%).

Occurrence of adverse effects (AEs) was similar between arms, with any-grade, late-onset toxicities arising in 81.3% of patients in the xevinapant arm and 70.2% in the control arm. There were no deaths due to treatment-emergent AEs in the xevinapant arm vs 2 in the placebo arm. Premature treatment discontinuation occurred in 8 patients (16.7%) in the experimental arm and 7 (14.6%) in the placebo arm.

Bourhis concluded by stating that the phase 3 TrilynX trial (NCT04459715) of xevinapant plus chemoradiotherapy vs match placebo is recruiting patients with locally advanced HNSCC.

References

1. Bourhis J, Le Tourneau C, Calderon B, et al. 5-year overall survival (OS) in patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase II study. Ann Oncol. 2022;33(suppl 7):LBA33. doi:10.1016/annonc/annonc1089
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. 2020;21(9):1173-1187. doi:10.1016/S1470-2045(20)30327-2
3. Bourhis J, Sun X, Le Tourneau C, et al. 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. Ann Oncol. 2020;31(suppl 4):LBA39. doi:10.1016/j.annonc.2020.08.2269