Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase 2 study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1‐14 of a 3‐week cycle. To confirm 200 mg/day as the recommended phase 3 dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure‐response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100‐200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure‐response analyses of data from 62 patients in the phase 2 study showed exposure‐related increases in probabilities of locoregional control at 18 months (primary endpoint), overall response, complete response, and the radiosensitization mechanism‐related composite safety endpoint “mucositis and/or dysphagia” (p<0.05). Exposure‐response relationships were not discernible for 12 of 13 evaluated safety endpoints, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model‐derived target inhibition profiles, positive exposure‐efficacy relationships, and lack of discernible exposure‐safety relationships for most safety endpoints, supports selection of xevinapant 200 mg/day on days 1‐14 of a 3‐week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.