Xevinapant plus avelumab in advanced solid tumours, with a dose expansion in advanced non-small-cell lung cancer: exploratory biomarker, safety and efficacy analyses from an open-label, nonrandomised phase Ib study.
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BACKGROUND: Xevinapant, an inhibitor of apoptosis protein (IAP) inhibitor, has shown promising activity in combination with anticancer agents, including radiotherapy, and, in preclinical studies, anti-PD-(L)1 antibodies. This, in part, is due to its ability to restore apoptosis and increase antitumour immunity. OBJECTIVES: We report efficacy, safety and exploratory biomarker analyses of xevinapant plus avelumab (anti-PD-L1) in a two-part, open-label, nonrandomised, phase Ib study. DESIGN: Part A assessed patients with advanced solid tumours who received xevinapant (100, 150, 200 or 250 mg/day, with no random allocation, on Days 1-10 and 15-24) in combination with avelumab (10 mg/kg) on Days 1 and 15 in 28-day cycle. Part B assessed patients with advanced non-small-cell lung cancer (NSCLC) who received xevinapant at the recommended phase II dose (RP2D) plus avelumab (maximum 26 cycles). METHODS: Part A assessed the safety and tolerability of the combination and established the maximum tolerated dose (MTD) and RP2D of xevinapant. Part B assessed the antitumour activity of xevinapant at the RP2D combined with avelumab compared with a historical control (avelumab alone). Exploratory biomarker analyses were also conducted. RESULTS: In part A (n = 16), xevinapant 200 mg/day was established as the RP2D with avelumab and the MTD was not reached. The most common treatment-emergent adverse events (TEAEs) irrespective of xevinapant dose were nausea and fatigue (n = 11 (68.8%) each). In part B (n = 38; four patients received prior anti-PD-(L)1 antibody), the objective response rate (ORR) was 10.5% (95% confidence interval (CI), 2.9-24.8; partial response, n = 4) and the most common TEAE was decreased appetite (n = 13 (34.2%)). Levels of plasma IL-10, IL-1β, IL-13 and CD8+ T cells increased during the study, and circulating levels of CD4+ T cells and Tregs increased during cycle 1. Macrophage-related gene expression signatures increased in patients with a partial response or stable disease. Low baseline Ki-67 expression in tumour samples correlated with a partial response. CONCLUSION: The RP2D of xevinapant with avelumab was established; however, the ORR was not superior to the historical control (avelumab alone). The combination had a manageable safety profile in both study parts. Biomarker analyses provide insights into drivers associated with efficacy in patients with NSCLC receiving xevinapant plus avelumab. TRIAL REGISTRATION: NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017.
