Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER)

Autor: Gerald Steven Falchook, Antoni Ribas, Diwakar Davar, Zeynep Eroglu, Judy S. Wang, Jason J. Luke, Erika P. Hamilton, Brian Di Pace, Tianli Wang, Srimoyee Ghosh, Arindam Dhar, Theo Borgovan, Angela Waszak, Patricia LoRusso
Rok vydání: 2022
Předmět:
Zdroj: Journal of Clinical Oncology. 40:2504-2504
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2022.40.16_suppl.2504
Popis: 2504 Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]
Databáze: OpenAIRE
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