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
Author(s): ,
Rakesh Popat
Affiliations:
NIHR/University College London Hospital Clinical Research Facility,London,United Kingdom
,
Nikoletta Lendvai
Affiliations:
Memorial Sloan Kettering Cancer Hematology Oncology.,Memorial Sloan Kettering Cancer Hematology Oncology.,New York,United States
,
Suzanne Trudel
Affiliations:
Princess Margaret Cancer Centre,University Health Network,Ontario,Canada
,
Peter M. Voorhees
Affiliations:
Levine Cancer Institute,,Atrium Health,Charlotte,United States
,
Brandi Reeves
Affiliations:
UNC Hospitals Adult Oncology Clinics,UNC Hospitals Adult Oncology Clinics,Chapel Hill, NC,United States
,
Edward N. Libby
Affiliations:
Department of Medicine,University of Washington,Seattle,United States
,
Paul G. Richardson
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Larry D. Anderson Jr
Affiliations:
University of Texas Southwestern,Dallas,United States
,
Heather J. Sutherland
Affiliations:
Vancouver General Hospital,Vancouver,Canada
,
Kwee Yong
Affiliations:
UCL Cancer Institute,NIHR/University College London Hospital Clinical Research Facility,London,United Kingdom
,
Axel Hoos
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Michele M. Gorczyca
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Zangdong He
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Roxanne C. Jewell
Affiliations:
GlaxoSmithKline,Research Triangle Park,United States
,
E. J. Dettman
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Fabio Rigat
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Ira Gupta
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Veronique Bragulat
Affiliations:
GlaxoSmithKline,Philadelphia,United States
,
Joanna B. Opalinska
Affiliations:
GlaxoSmithKline,Philadelphia,United States
Adam D. Cohen
Affiliations:
Abrahmson Cancer Center,University of Pennsylvania,Philadelphia,United States
EHA Library. Popat R. Jun 15, 2019; 266989; PS1372
Rakesh Popat
Rakesh Popat
Contributions
Abstract

Abstract: PS1372

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

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.

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.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Clinical trial, Multiple myeloma

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