TOPLINE:

In a phase 3 trial, the addition of xevinapant to chemoradiotherapy resulted in worse event-free and overall survival and more serious adverse events in patients with unresected locally advanced head and neck cancer.

METHODOLOGY:

• For patients who do not undergo surgery for locally advanced head and neck squamous cell carcinoma, chemoradiotherapy with curative intent is standard of care. However, local and distant recurrence is common. Xevinapant, an oral drug that blocks inhibitor of apoptosis proteins, was shown in a phase 2 trial to improve locoregional control and progression-free survival when added to chemoradiotherapy.
• The TrilynX trial was a multinational, double-blind, phase 3 study involving 730 patients with unresected locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. Patients were randomly assigned to receive either xevinapant or placebo plus chemoradiotherapy.
• Treatment consisted of six cycles of xevinapant (200 mg once daily) or matched placebo on days 1-14 of a 21-day cycle. Both groups received chemoradiotherapy for the first three cycles: 100 mg/m² cisplatin on day 2 of every cycle and intensity-modulated radiotherapy at 70 Gy in 35 fractions, 5 days per week.
• The primary endpoint was event-free survival, with secondary endpoints of overall survival, progression-free survival, locoregional control, overall response rate, and safety. Median follow-up was 18 months.

TAKEAWAY:

• Xevinapant failed to improve event-free survival compared with chemoradiotherapy alone. Median event-free survival was shorter among patients in the xevinapant group, at 19.4 months vs 33.1 months (hazard ratio [HR], 1.33; 95% CI, 1.05-1.67; P = .9919).
• Patients who received xevinapant also had numerically shorter progression-free and overall survival. Median progression-free survival was 26.8 months in the xevinapant group vs 33.1 months in the placebo group (HR, 1.24; 95% CI, 0.97-1.57). Median overall survival was not reached in either treatment group, but xevinapant was associated with worse overall survival (HR, 1.39; 95% CI, 1.04-1.86).
• There was no difference in locoregional control between the groups (HR, 1.05; 95% CI, 0.74-1.50), and the distant failure rate was higher with xevinapant.
• Treatment-emergent adverse events of grade 3 or higher, including anemia and neutropenia, occurred more frequently with xevinapant (87.9% vs 80.3% in the placebo group), as did serious adverse events (53.3% vs 36.2%). Patients who received xevinapant also had a higher rate of infections (9.3% vs 3.7%) — which, along with the higher risk for distant failure, suggests the drug may have had immunosuppressive effects, the authors noted.

IN PRACTICE:

“Given the outcomes of this interim analysis, it was determined that xevinapant cannot be recommended for use in this indication, and TrilynX was terminated on June 24, 2024,” the authors wrote. It is unknown, they added, whether the drug would have been better tolerated or more effective if combined with once-weekly cisplatin or radiotherapy alone. For now, they concluded, locally advanced head and neck squamous cell carcinoma “remains a difficult-to-treat disease with a high unmet need.”

SOURCE:

This study, led by Jean Bourhis, MD, Radiation Oncology Department, Bâtiment Hospitalier, CHUV, Lausanne, Switzerland, was published online in the Journal of Clinical Oncology.

LIMITATIONS:

There were notable differences in baseline demographics and clinical characteristics between patients in this trial and the phase 2 study — particularly in age, performance status, tumor location, and TNM staging. However, no analyzed subgroups benefited from the addition of xevinapant.

DISCLOSURES:

This study was supported by Debiopharm International SA prior to December 2021, and by Merck since then. Bourhis reported receiving honoraria, research funding or served as a consultant or advisory member for AstraZeneca, Bristol Myers Squibb, Debiopharm Group, Merck, MSD, Nanobiotix, and Roche. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.