A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors

TPS2654 Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177. © 2019 by American Society of Clinical Oncolog