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

Author(s): Jean Bourhis, MD¹; Lisa F. Licitra, MD²; Barbara Burtness, MD³; Amanda Psyrri, MD⁴; Robert Haddad, MD⁵; Kevin Harrington, PhD⁶; Ezra E.W. Cohen, MD⁷; Yungan Tao, MD⁸; Katsuki Arima Tiscoski, MD⁹; Amiran Matitashvili, MD¹⁰; Makoto Tahara, MD¹¹; Ammar Sukari, MD¹²; Tomasz Rutkowski, MD¹³; Sebastien Salas, MD^14,15; Heidi Nauwelaerts, MD¹⁶; Rudi Scheerlinck, MD¹⁷; Ngoc-Thuy Ha, PhD¹⁸; Andreas Schroeder, MD¹⁸; Almudena Rodriguez-Gutierrez, MD¹⁹; Jonathan D. Schoenfeld, MD²⁰;

Source: DOI: 10.1200/JCO-25-00272

Dr. Maen Hussein's Thoughts

Xevinapant (an inhibitor of apoptosis proteins inhibitor) added to chemoradiotherapy did not improve event-free survival (EFS) or overall survival (OS); in fact, OS was worse in the combination arm.

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.

Author Affiliations

¹Radiation Oncology Department, Bâtiment Hospitalier, CHUV, Lausanne, Switzerland; ²Fondazione IRCCS Istituto Nazionale dei Tumori & University of Milan, Milan, Italy; ³Yale School of Medicine & Yale Cancer Center, New Haven, CT; ⁴Department of Medicine, Section of Medical Oncology, Attikon University Hospital, Athens, Greece; ⁵Dana-Farber Cancer Institute, Boston, MA; ⁶Division of Radiotherapy and Imaging, The Royal Marsden/The Institute of Cancer Research NIHR Biomedical Research Centre, London, United Kingdom; ⁷University of California, San Diego, CA; ⁸Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France; ⁹Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil; ¹⁰LTD Cancer Research Centre, Tbilisi, Georgia; ¹¹National Cancer Center Hospital East, Kashiwa, Japan; ¹²Karmanos Cancer Institute, Wayne State University, Detroit, MI; ¹³Radiation and Clinical Oncology Department of Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland; ¹⁴Department of Medical Oncology, CHU la Timone, AP-HM, Marseille, France; ¹⁵Aix-Marseille University, Marseille, France; ¹⁶Debiopharm International SA, Lausanne, Switzerland; ¹⁷Ares Trading SA, an Affiliate of Merck KGaA, Eysins, Switzerland; ¹⁸Merck Healthcare KGaA, Darmstadt, Germany; ¹⁹Merck, S.L.U., an Affiliate of Merck KGaA, Madrid, Spain; ²⁰Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA

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