PS1372 B‐CELL MATURATION ANTIGEN ANTIBODY‐DRUG CONJUGATE (ADC), GSK2857916, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): FINAL SAFETY, EFFICACY AND PHARMACOKINETIC (PK) ANALYSES FROM A PHASE I STUDY
Authors: Popat R. , Lendvai N. , Trudel S. , Voorhees P.M. , Reeves B. , Libby E.N. , Richardson P.G. , Jr L.D. Anderson , Sutherland H.J. , Yong K. , Hoos A. , Gorczyca M.M. , He Z. , Jewell R.C. , Dettman E.J. , Rigat F. , Gupta I. , Bragulat V. , Opalinska J.B. , Cohen A.D. 
Published: June 2019

Please indicate where the abstract has been published before: A portion of these data have been submitted for publication in Blood Cancer Journal, of which interim data have been published in The Lancet Oncology.Background:Outcomes remain poor for patients with RRMM. The tumor necrosis superfamily cell‐surface receptor, B‐cell maturation antigen (BCMA), is expressed on MM cells and associated with reduced survival. Therefore, BCMA is a potential therapeutic target in MM. Interim analysis (after approximately 4 months of follow‐up) of a first‐in‐human study of a novel anti‐BCMA antibody conjugated to the microtubule‐disrupting agent monomethyl auristatin F (GSK2857916) reported 60% (95% CI 42.1–76.1) overall response rate at the recommended phase 2 dose, and 7.9 months (95% CI 3.1–not estimable) progression‐free survival (PFS) in patients with RRMM.Aims:Final analyses, a further 14 months after interim analysis, of the efficacy, safety and PK of GSK2857916 in patients with RRMM are reported here.Methods:This open‐label, 2‐part Phase I study was conducted in 9 centers in the USA, Canada, and UK in adults with MM and progressive disease after stem cell transplantation (or considered transplant ineligible), alkylators, proteasome inhibitors, and immunomodulators. In Part 1 (dose escalation), patients received GSK2857916 (0.03–4.60 mg/kg) via 1 h intravenous infusions once every 3 weeks (Q3W). In Part 2 (dose expansion), patients received the selected dose of 3.4 mg/kg Q3W for up to 16 cycles. Primary endpoints were safety, maximum tolerated dose and recommended Part 2 dose; secondary endpoints included clinical activity (percentage of patients achieving at least a partial response [overall response]) and PK parameters. MM biomarkers were assessed, including myeloma BCMA expression by immunohistochemistry, and circulating free soluble BCMA (sBMCA) by immunoassay in serum pre‐ and post‐infusion. Safety and tolerability were assessed using adverse event (AE) reporting.Results:In Part 1, 38 patients were enrolled and analyzed, with a mean (range) age of 59 (39–79) years. In Part 2, the 35 patients enrolled had a mean age of 61 (46–75) years; patients completed a median of 12.5 (0.7–23.2) months of follow‐up. The most frequently reported AEs in Part 2 were corneal events (24/35; 69%) and thrombocytopenia (22/35; 63%). Treatment‐related serious AEs were experienced by 7/35 (20%) patients; infusion‐related reaction (2/35; 6.0%) was the most common. In Part 2, 60% of patients achieved an overall response (95% CI 42.1–76.1). Median PFS was 12.0 (95% CI 3.1–not estimable) months and median duration of response was 14.3 (95% CI 10.6–not estimable) months. Combining all dose levels in Part 1, geometric mean clearance was 18 mL/h, steady‐state volume of distribution was 4.1 L, and half‐life was 6.7 days for the antibody drug conjugate (ADC) (n = 18). Plasma exposures of ADC, total mAb, and cys‐mcMMAF appeared to increase proportionally with dose.In Part 2, all patients were positive for BCMA expression on MM cells with no relation to response. Median baseline sBCMA was 45 ng/mL in responders (n = 20) and 89 ng/mL in non‐responders (n = 11); responders were identified with high levels of baseline sBCMA, ranging from <10 ng/mL up to 262 ng/mL. GSK2857916 dose‐dependently engaged sBCMA, as measured by reduced free sBCMA from baseline to end of infusion, with >90.0% binding at doses of GSK2857916 >1.9 mg/kg.Summary/Conclusion:GSK2857916 was well tolerated and demonstrated deep and durable responses in heavily pre‐treated patients with RRMM. The PK profile was characterized by slow clearance, a small volume of distribution, and half‐life of 6.7 days. Further investigations are needed to understand the value of BCMA expression on MM cells and circulating free sBCMA as biomarkers for response to GSK2857916.