BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.

Abstract

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.