Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody-drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors

Sylvie Rottey, Jeffrey Clarke, Kyaw Aung, Jean-Pascal Machiels, Ben Markman, Kimberley M Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul de Souza, Matteo Duca, Giuseppe Curigliano, Armando Santoro, Takafumi Koyama, Michelle Brown, Heather Vezina, Chunsheng He, Quincy Siu-Chung Chu, Sylvie Rottey, Jeffrey Clarke, Kyaw Aung, Jean-Pascal Machiels, Ben Markman, Kimberley M Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul de Souza, Matteo Duca, Giuseppe Curigliano, Armando Santoro, Takafumi Koyama, Michelle Brown, Heather Vezina, Chunsheng He, Quincy Siu-Chung Chu

Abstract

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) ± nivolumab, in patients with selected tumors.

Patients and methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability.

Results: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. 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 (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected.

Conclusions: BMS-986148 ± 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.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Association between mesothelin expression level at the plasma membrane and response to BMS-986148 in mesothelioma and ovarian cancer. Response was evaluated using RECIST 1.1 or modified RECIST for malignant pleural mesothelioma; these data include all patients enrolled across dose levels and treatment cohorts in study CA008-002.

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