A phase I study of the OX40 agonist BGB-A445 with or without tislelizumab, an anti–PD-1 monoclonal antibody, in patients with advanced solid tumors: dose-escalation results

Purpose: OX40 may stimulate T-cell activation, potentially enhanced with checkpointinhibition. Results are from the dose-escalation part of an ongoing, multicenter, open-label study (NCT04215978, registered 30 December 2019) investigating OX40 agonist BGB-A445 alone or with anti-PD-1 antibody tislelizumab in patients with advanced solid tumors. Methods: Adults ≥18 years with previously treated advanced solid tumors, measurable by RECIST v1.1, enrolled. Dose-escalation A: 8 cohorts received increasing doses of IV BGB-A445 as monotherapy (20, 60, 150, 300, 600, 1200, 2400, 3600 mg); dose-escalation B: 6 cohorts received increasing doses of IV BGB-A445 (150, 300, 600, 1200, 2400, 3600 mg) + IV tislelizumab 200 mg. Primary objectives were safety and tolerability; secondary objectives included overall response rate (ORR) and pharmacokinetics. Results: 112 patients were treated (A, n=63; B, n=49); 34/112 (30.4%) previously received checkpoint inhibitors. Treatment-related adverse events occurred in 36 (57.1%) (A) and 37 (75.5%) (B) patients, were grade ≥3 in 4 (6.3%) and 9 (18.4%), and caused treatment discontinuations in 1 (1.6%) and 1 (2.0%), respectively. Immune-mediated adverse events occurred in 8 (12.7%) (A) and 18 (36.7%) (B) patients, and infusion-related reactions in 9 (14.3%) (A) and 9 (18.4%) (B). No dose-limiting toxicities occurred. Unconfirmed ORR was 3.3% (unconfirmed partial response [PR], n=2) (A); confirmed was 21.3% (including PR, n=10) (B). BGB-A445 exposure increased dose-proportionally with a half-life of 8–13 days. OX40 receptor occupancy was saturated at ≥300 mg BGB-A445 in all cohorts. Conclusion: BGB-A445 was well tolerated and demonstrated on-target immune activation at clinically relevant doses. Antitumor activity was observed across cohorts.