Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study

Abstract

Purpose: TrilynX was a randomized, double-blind, phase III study evaluating the addition of xevinapant (an inhibitor of apoptosis proteins inhibitor) or placebo to chemoradiotherapy (CRT) in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

Methods: Patients with unresected LA SCCHN (oropharynx [p16-negative only], hypopharynx, or larynx) were randomly assigned 1:1 to six cycles of oral xevinapant 200 mg/day or matched placebo (once daily on Days 1-14 of a 21-day cycle) plus CRT for the first three cycles (cisplatin [100 mg/m² once on Day 2 of every cycle] plus intensity-modulated radiotherapy [70 Gy; 35 fractions of 2 Gy/day, 5 days/week]). The primary end point was event-free survival (EFS) assessed by the blinded independent review committee. Progression-free survival, overall survival (OS), and safety were secondary end points.

Results: Between September 20, 2020, and February 27, 2023, 730 patients were randomly assigned to xevinapant plus CRT (n = 364) or placebo plus CRT (n = 366). The median (95% CI) EFS was 19.4 months (14.5 to not estimable) with xevinapant and 33.1 months (21.0 to not estimable) with placebo (hazard ratio [HR], 1.33 [95% CI, 1.05 to 1.67]; P = .9919). OS was worse in the xevinapant arm (HR, 1.39 [95% CI, 1.04 to 1.86]). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 320 (87.9%; xevinapant) and 286 (80.3%; placebo) patients; anemia (78 [21.4%] v 51 [14.3%]) and neutropenia (71 [19.5%] v 69 [19.4%]) were the most common. Serious TEAEs occurred in 194 (53.3%; xevinapant) and 129 (36.2%; placebo) patients. TEAEs leading to death occurred in 22 (6.0%; xevinapant) and 13 (3.7%; placebo) patients.

Conclusion: Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN.

Trial registration: ClinicalTrials.gov NCT04459715.

FIG 1.

Patient disposition (CONSORT diagram). ^aTwo patients assigned to the placebo arm erroneously received xevinapant treatment because of error at the site and were therefore reassigned to the xevinapant arm for safety analyses. CRT, chemoradiotherapy; EFS, event-free survival.

FIG 2.

EFS in the intention-to-treat population: (A) Kaplan-Meier estimates of EFS by BIRC in the overall population and (B) forest plot of EFS in prespecified subgroups. BIRC, blinded independent review committee; CRT, chemoradiotherapy; EFS, event-free survival; HR, hazard ratio; NE, not estimable; NR, not reported; P, placebo; X, xevinapant.

FIG 3.

Efficacy in the intention-to-treat population. (A) Kaplan-Meier estimates of PFS by BIRC, (B) Kaplan-Meier estimates of OS, (C) Kaplan-Meier estimates of LRC, (D) competing risk analysis of locoregional failure, and (E) competing risk analysis of distant failure. BIRC, blinded independent review committee; CRT, chemoradiotherapy; HR, hazard ratio; LRC, locoregional control; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival.