A first-in-human phase 1 study of the SHP2 inhibitor BBP-398 in patients with advanced solid tumors.

BBP-398 is a selective allosteric SHP2 inhibitor designed to inhibit mitogen-activated protein kinase (MAPK) pathway-driven tumors. We performed the first-in-human phase 1 trial described herein to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of BBP-398 in patients with advanced solid tumors harboring MAPK pathway mutations. Once-daily BBP-398 was administered at 350-550 mg in the dose-escalation phase (1a; n = 35) followed by a dose-expansion phase (1b; n = 37). The study endpoints were dose-limiting toxicities, treatment-emergent adverse events, pharmacokinetics, target engagement, disease control rate, progression-free survival, and overall survival. In phase 1a, 26% of the 23 evaluable patients had stable disease, with a median progression-free survival duration of 1.8 months (range, 1.7-4.1 months). In phase 1b, 30% of the 27 evaluable patients had stable disease (31% at 350 mg, 27% at 450 mg), with median progression-free survival of 2.2 months and 1.9 months at 350 mg and 450 mg, respectively. We halted dose escalation at 550 mg owing to an increased rate of thrombocytopenia and edema. At daily doses of up to 450 mg, BBP-398 exhibited an acceptable safety profile and produced disease stabilization in nearly 30% of heavily pretreated patients.