TrilynX: A phase 3 trial of xevinapant and concurrent chemoradiation for locally advanced head and neck cancer.

Abstract

TPS6091 Background: Concurrent chemoradiotherapy (CRT) is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinomas of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements of xevinapant versus placebo in addition to standard chemoradiation (CRT) for locoregional control (LRC) rate at 18 months, PFS and OS. The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Methods: TrilynX is a multinational, Phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-HNSCC. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharynx, larynx and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ̃90% power to detect the expected hazard ratio benefit of 0.73. Secondary end-points include OS, PFS, LRC, ORR, HRQL, and safety. Data driven design, patients will be followed up for a minimum of 60-months. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and it is ongoing. References: [1] X. Sun et. al, Lancet Oncol; 21(9): 1173-1187, 2020. [2] J. Bourhis et\xa0al., Ann Oncol; 31 (suppl 4): LBA39, 2020. Clinical trial information: NCT04459715.