Abstract B057: BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors

Background: Mesothelin, a GPI-anchored cell surface protein, is highly expressed in several tumor types and can be targeted for antibody (ab)-based cancer therapy. BMS-986148 is a fully human IgG1 anti-mesothelin monoclonal ab conjugated to tubulysin to promote selective cytotoxic delivery to tumor cells. In preclinical models, combination of anti–mesothelin-tubulysin with anti–PD-1 promoted a synergistic antitumor response and influx of tumor-infiltrating lymphocytes. Here, we present initial data for BMS-986148 ± nivolumab (NIVO; anti–PD-1) from a phase 1/2a trial in a biomarker-defined population of patients (pts) with select advanced solid tumors (NCT02341625). Methods: During dose escalation (ESC), pts received BMS-986148 0.1 to 1.6 mg/kg IV Q3W, BMS-986148 0.4 or 0.8 mg/kg IV Q1W, or BMS-986148 0.8 mg/kg + NIVO 360 mg IV Q3W. During monotherapy (mono) dose expansion (EXP), pts with mesothelin-selected mesothelioma (ie, H score ≥ 100 for tumor mesothelin expression), non-small cell lung cancer (NSCLC), or ovarian cancer received BMS-986148 1.2 mg/kg mono IV Q3W, and during combination (combo) dose EXP, pts with mesothelin-selected mesothelioma or pancreatic cancer received BMS-986148 0.8 mg/kg + NIVO 360 mg combo IV Q3W. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK) and antitumor activity. Results: As of April 1, 2019, 126 pts have been treated in this trial; 96 pts received BMS-986148 mono (Q3W, n = 84; Q1W, n = 12), and 30 pts received BMS-986148 + NIVO combo. PK analysis in pts treated during ESC demonstrated that total antibody and active ADC exposures increased in a dose-proportional manner. Unconjugated tubulysin concentrations were low but sustained over the dosing interval. The maximum tolerated dose (MTD) for mono was 1.2 mg/kg Q3W, and the 0.8 mg/kg dose was determined to be tolerable for the combo. Across all cohorts, any-grade and grade 3/4 treatment-related AEs (TRAEs) were reported in 87% and 44% of all pts, respectively. Overall, the most common TRAEs (any grade; grade 3-4) reported in ≥ 15% of pts were AST increased (43%; 17%), ALT increased (41%; 16%), fatigue (37%; 5%), nausea (29%; 0%), decreased appetite (22%; 1%), and blood alkaline phosphatase increased (18%; 4%). The frequency of TRAEs and dose-limiting toxicities related to liver function tests increased with increasing dose of BMS-986148. Most TRAEs resolved with dose interruption, dose reduction, or treatment discontinuation. Serious TRAEs were reported in 18% of pts with mono and 23% of pts with combo. Fifteen percent of pts discontinued due to TRAEs, and 1 pt died due to a TRAE (pneumonitis; 1.2 mg/kg Q3W mono). The ORR was 6% (0 CR, 3 PR) with mono in EXP and 20% (0 CR, 6 PR) with the combo in ESC and EXP. Among pts with mesothelioma, the ORR was 4% with mono in EXP and 31% with combo in ESC and EXP. Among pts with ovarian carcinoma, the ORR was 9% with mono in EXP. Of note, durable responses lasting up to ≈ 20 mo in pts with ovarian cancer with mono and ≈ 9 mo in pts with mesothelioma with mono and combo were observed. Conclusions: BMS-986148 ± NIVO was tolerable and demonstrated a clinically manageable safety profile. Preliminary clinical activity was observed with BMS-986148 ± NIVO in select patient populations, including pts with mesothelioma. Citation Format: Jeffrey Clarke, Siu-Chung Chu, Lillian L Siu, Jean-Pascal Machiels, Benjamin Markman, Kimberley Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul de Souza, Giuseppe Curigliano, Armando Santoro, Michelle Brown, Ronald Fleming, Heather Vezina, Chunsheng He, Sylvie Rottey. BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B057. doi:10.1158/1535-7163.TARG-19-B057