Cancer chemotherapy and pharmacology · 2025
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.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Desai Jayesh, Deva Sanjeev, Gao Bo, Yang Kunyu, O'Byrne Kenneth J, Sun Meili, Liu Tianshu, Meniawy Tarek, Yu Xinmin, Voskoboynik Mark, Davar Diwakar, Matos Marco, Leaw Shiangjiin, Rahman Tahmina, Qu Xiaofei, Giovinazzo Hugh, Chen Xin, Dong Yan, Day Daphne
Аннотация
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.
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.