Phase 1/2a trial of BMS-986148, an anti-mesothelin antibody-drug conjugate, alone or in combination with nivolumab in patients with advanced solid tumors.

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) {plus minus} nivolumab in patients with selected tumors. Experimental design: In an international phase 1/2a study (NCT02341625 [CA008-002]), patients received BMS-986148 monotherapy (0.1-1.6 mg/kg IV Q3W or 0.4 or 0.6 mg/kg IV QW; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg IV Q3W (n = 30). The primary endpoint was safety and tolerability. Results: In CA008-002, the most common ({greater than or equal to} 10%) treatment-related adverse events (TRAEs) included increased AST, ALT, and ALP. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 Q3W monotherapy, 3 (25%) receiving BMS-986148 QW monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab Q3W. Overall, 17 of 126 patients (13%) discontinued due to a TRAE. The maximum tolerated dose of BMS-986148 was 1.2 mg/kg IV Q3W.The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (Q3W and QW). Preliminary clinical activity was observed with BMS-986148 {plus minus} nivolumab. No association between mesothelin expression and response was detected. Conclusions: BMS-986148 {plus minus} nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.