Xevinapant Fails to Improve EFS in Patients with Head and Neck Cancer

Results from a phase 3 study (NCT04459715)¹ revealed that the treatment combination of xevinapant (Debio 1143)¹, an inhibitor of apoptosis proteins inhibitor (IAP), plus chemoradiotherapy (CRT) did not improve event-free survival (EFS) and demonstrated an unfavorable safety profile in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).²

The study was conducted between September 2020 and February 2023 with 730 patients randomly assigned to 1 of 2 groups, either xevinapantplus CRT (n=364) or placebo plus CRT (n=366). The median (95% CI) EFS was 19.4 months (range, 14.5–not estimable [NE]) with xevinapant and 33.1 months (range, 21.0–NE) with placebo (HR, 1.33; 95% CI, 1.05–1.67]; P =.9919). The primary endpoint was EFS, which was not reached. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. OS fared worse in patients in the xevinapant group (HR, 1.39; 95% CI, 1.04–1.86). Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 320 (xevinapant , 87.9%) and 286 (placebo, 80.3% patients. These included anemia and neutropenia. Serious TEAEs occurred in 194 (xevinapant, 53.3%) and 129 (placebo, 36.2%) patients. TEAEs leading to death occurred in 22 (xevinapant, 6.0%) and 13 (placebo, 3.7%) patients.^1,2

“To our knowledge, TrilynX was the first randomized phase [3] study of an IAP inhibitor in any tumor type,” said the authors of the study.² “Historically, apoptosis has been considered an immune-silent or immunosuppressive form of cell death. Given that xevinapantpredominantly rewires cell death toward apoptosis, instead of the more immunogenic necroptosis or pyroptosis,xevinapant might have inadvertently reduced the immune-activating CRT effects. It is unknown whether xevinapant would have been better tolerated or resulted in better outcomes if combined with once weekly cisplatin or RT alone. 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 median ages of patients in both groups were 61 (xevinapant) and 60 (placebo). The site of the primary tumor in patients was the larynx in 31.9% and 30.9%, hypopharynx in 28.8% and 25.4%, and oropharynx in 39.3% and 43.7%, respectively; the stage at baseline was III in 28.0% and 24.0%, IVA in 53.8% and 55.7%, and IVB in 18.1% and 20.2%, respectively.^1,2

At the time of data cutoff, April 8, 2024, 106 (xevinapant, 29.1%) and 80 (placebo, 22.5%) patients had died. The most frequent cause of death between both groups was cancer under study (66 [18.1%] and 48 [13.5%] patients). The median treatment duration was 18 weeks in both groups. The median RT dose was 70 Gy (IQR, 70–70) in both arms; more patients in the xevinapant arm received a dose of 50 to <70 Gy (15 [4.1%] vs5 [1.4%]) or ≤50 Gy (26 [7.1%] vs15 [4.2%]). The median cumulative cisplatin dose was 200 mg/m2 (IQR, 200–300 mg/m2) in the xevinapant arm and 275 mg/m2 (IQR, 200-–300 mg/m2) in the placebo arm.In patients who were treated with xevinapant, EFS events because of death, clinical/radiologic disease progression, and primary treatment failure occurred more frequently.^1,2

Xevinapant also performed worse in PFS and OS. The median PFS was 26.8 months (95% CI, 15.9–NE) vs 33.1 months (95% CI, 22.8–NE) months (HR, 1.24; 95% CI, 0.97–1.57). Additionally, the median OS was not reached in either arm (106 vs81 events; HR, 1.39; 95% CI, 1.04–1.86).^1,2

TEAEs of any grade and any cause occurred in 362 (99.5%) patients in the xevinapant group and 351 (98.6%) patients in the placebo group. The most common TEAEs among patients were anemia, stomatitis, and weight loss with xevinapant, and anemia nausea, and stomatitis with placebo.² 

“Xevinapant plus CRT did not improve EFS versus placebo plus CRT in patients with unresected LA-SCCHN,” concluded the authors of the study.² “In fact, a detrimental effect was observed, which was, in part, due to the poor tolerability and unfavorable safety profile of xevinapant when added to CRT, particularly early during treatment. This unexpected toxicity also led to earlier and more frequent cisplatin dose reductions, both of which might have negatively affected efficacy.”

REFERENCES:

1. A Study of Xevinapant (Debio 1143) in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Participants With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX). ClinicalTrials.gov. Updated October 8, 2025. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT04459715 

2. Bourhis J, Licitra L, Burtness B, et al. 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. J Clin Oncol 43, 3209-3220(2025).doi:10.1200/JCO-25-00272