Background: The current standard of care for patients with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For patients at high risk of disease recurrence who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant is a first-in-class, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in patients with unresected LA SCCHN, treatment with xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and reduced the risk of death or disease progression by 67% after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant and RT in cisplatin-ineligible patients with LA SCCHN. Methods: XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo in combination with intensity-modulated RT (IMRT) in patients with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible patients must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4 to 8 weeks before the start of treatment; high risk of relapse; no residual disease by computed tomography scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: estimated glomerular filtration rate <60 mL/min/1.73 m²; hearing loss [grade ≥2 audiometric hearing loss or grade ≥2 tinnitus]; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14]). Other eligibility criteria include ECOG performance status of 0 or 1 and adequate hematologic and hepatic function. Approximately 700 eligible patients will be randomized to oral xevinapant (200 mg/day on days 1-14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy per fraction, 5 days per week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Patients will be followed up for a minimum of 60 months. Enrollment is planned in 27 countries, including the US, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Clinical trial information: NCT05386550.