Leveraging the mechanism of action (MOA) of xevinapant, an IAP inhibitor, for phase 3 dosing (RP3D) strategies in combination with radiation (RT) and chemoradiotherapy (CRT) in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Vugmeyster Yulia , Ravula Abhigyan , Rouits Elisabeth , Ferretti Roberta , Glaeser Kathrin , Esdar Christina , Schröder Andreas , Koenig Andre , Venkatakrishnan Karthik , Goteti Kosalaram 
Published: June 2023

e18001 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, thereby enhancing the efficacy of RT and CRT. Xevinapant 200 mg/d (d1-14, Q3W) + CRT showed clinical benefit vs placebo + CRT in a phase (ph) 2 study of patients (pts) with LA SCCHN (NCT02022098). Exposure-response (E-R) relationships for efficacy and the composite safety endpoint of mucositis and/or dysphagia (AE_MD, a known RT-associated toxicity) were also identified. Two ph 3 studies of 200 mg/d xevinapant (d1-14, Q3W) + RT (XRay Vision; NCT05386550) or CRT (TrilynX; NCT04459715) followed by xevinapant monotherapy (MT) in pts with LA SCCHN are ongoing. We leverage the MOA of xevinapant to confirm RP3D strategy. Methods: Results from clinical and preclinical studies and quantitative pharmacology modeling were integrated. Results: Updated analyses of NCT02022098 data show an association between complete response (CR) and AE_MD in both treatment arms; AE_MD was the only AE with identified E-R relationship out of 13 AEs tested. In the xevinapant arm, the CR+AE_MD+ group had the highest median AUC but it overlapped with other groups (CR-AE_MD+, CR+AE_MD-, CR-AE_MD-) which all had similar AUCs. These data suggest that AE_MD is related to the RT-enhancing MOA of xevinapant and that decoupling efficacy from AE_MD incidence by exposure modulation is not feasible. Intermittent dosing for xevinapant was designed for recovery from epithelial toxicities considering the turnover of mucosal cells. In a human breast cancer mouse model, cIAP1 degradation with the intermittent regimen (100 mg/kg Q3D) at the end of the dosing interval was ~50% compared with the continuous one (30 mg/kg QD) expected to maintain maximal (max) cIAP1 degradation, but showed similar efficacy. This suggests continuous max cIAP1 degradation may not be required for efficacy, consistent with RT-enhancing MOA. Based on population PKPD modeling, at the RP3D for xevinapant max cIAP1 degradation was achieved during the dosing period; 91% of pts had at least 50% suppression at the end of the cycle. Xevinapant MT cycles are supported by enhanced anti-tumor activity with extended MT dosing following xevinapant/ RT cycles in MC38 syngeneic mouse model. Food-agnostic dosing is supported by similar AUCs observed in fed and fasted conditions. A human ADME study showed that urinary excretion is a minor elimination pathway, supporting no dose adjustment for pts with moderate renal impairment. Conclusions: Integrated assessment of all available clinical and nonclinical data supports the proposed RP3D strategy for xevinapant combined with RT or CRT, selected to maximize efficacy while minimizing potential adverse events and cumulative toxicity. Clinical trial information: NCT02022098 .