Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159
Authors: Trudel Suzanne , Lendvai Nikoletta , Popat Rakesh , Voorhees Peter M. , Reeves Brandi , Libby Edward N. , Richardson Paul G , Anderson Larry , Sutherland Heather , Yong Kwee , Hoos Axel , Gorczyca Michele , Lahiri Soumi , He Zangdong , Jewell Roxanne C , Opalinska Joanna B. , Cohen Adam D. 
Published: April 2021

Abstract
Background
BCMA is a cell surface receptor in the TNF superfamily with expression restricted to B lineage cells at later stages of differentiation, which is required for the survival of long lived plasma cells. BCMA is also expressed on MM cells. GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. Upon binding to BCMA, GSK2857916 is rapidly internalized and active drug released in the cell. GSK2857916 also exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation of the Fc domain, and potentially induces immunogenic cell death. Here we report results from the Part 2 expansion of a Phase 1 study of GSK2857916 in heavily pretreated MM pts.
Methods
BMA117159 (NCT02064387) is a Phase I, first in human, open-label study investigating GSK2857916 in relapsed/refractory MM and other hematologic malignancies expressing BCMA. The primary objective is safety and determination of maximum tolerated dose and recommended Phase 2 dose (RP2D); secondary objectives include pharmacokinetics (PK), antidrug antibody (ADA) incidence, and overall response rate (ORR). Dose escalation (Part 1) and expansion (Part 2) in MM pts is complete, and enrollment into a lymphoma cohort is ongoing. GSK2857916 is dosed once every 3 weeks as a 1-hr intravenous infusion, without required prophylaxis for infusion-related reactions (IRR). Eligible MM pts must have been treated with alkylators, proteasome inhibitors (PI), immunomodulators (IMiDs), and stem cell transplantation (if eligible) and must have documented progression on or within 60 days of last therapy. Pts remain on treatment until progression, unacceptable toxicity, consent withdrawal, or completing 16 treatment cycles. All pts received steroid eye drops for 4 days with each infusion to mitigate corneal events.
Results
Part 1 results (N=38) were previously presented (Blood, 2016 128:1148); no maximum tolerated dose was identified and the RP2D was determined to be 3.4 mg/kg. Part 2 enrolled 35 MM pts treated at the RP2D: median age is 60 years (range 46-75) and 49% are male. Fifty-seven percent received ≥5 prior lines of therapy (range 1- &gt;10). All pts received and 97% were refractory to PI, all pts received and 91% were refractory to IMiDs, 40% received and 37% were refractory to daratumumab, and 89% were double-refractory to PI and IMiDs. Median number of infusions was 5 (range 1-13) and 54% of pts received ≥5 infusions. The ORR for Part 2 was 60% (21/35; 95% CI 42.1-76.1), including 1 sCR, 2 CR, 15 VGPR, and 3 PR. The ORR in pts previously treated with daratumumab was 43% (6/14; 95% CI 17.7-71.1). Median duration of response was not reached, with a median PFS of 7.9 months (95% CI 3.1- NA). All pts had at least 1 adverse event (AE); the most frequent (≥25%) regardless of cause were corneal events (63%), thrombocytopenia/platelet count decreased (57%), anemia (29%), AST increased (29%), and cough (26%). Corneal events (most frequent ≥20%: vision blurred, dry eye, photophobia) were mostly Grade (Gr) 1/2 and were reversible. Gr 3/4 AEs reported in ≥10% of pts were thrombocytopenia/platelet count decreased (34%) and anemia (14%). Serious AEs were reported in 40% (14/35) of pts. With no pre-medication, 8 pts had IRRs (2 Gr 1, 3 Gr 2, 3 Gr 3) that occurred with the first infusion, resolved, and did not recur with subsequent infusions. A total of 18 pts discontinued treatment for disease progression (n=15), AE (n=2; thrombocytopenia, CPK elevation), or pts decision (n=1); 17 pts are ongoing.
Conclusion
GSK2857916 monotherapy demonstrated encouraging single agent activity with an ORR of 60%, and deep (51% ≥VGPR) and durable responses in heavily pre-treated relapsed/refractory MM pts who have limited treatment options. The target and therapeutic mechanisms of action differentiate GSK2857916 from currently approved drugs in MM. Results show a manageable safety profile, with thrombocytopenia/platelet count decreased and low grade corneal events being the most frequently reported AEs and most frequent reason for dose modifications. Detailed safety and clinical activity together with results from correlative analyses will be presented.
Study is funded by GlaxoSmithKline (NCT02064387); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT ® Technology licensed from BioWa.

Disclosures
Trudel: Astellas: Research Funding; Janssen: Research Funding; Takeda: Honoraria; GlaxoSmithKline: Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Lendvai: GlaxoSmithKline: Research Funding. Popat: Celgene: Honoraria, Other: Travel support for meetings; Amgen: Honoraria; Takeda: Honoraria, Other: Travel support for meetings; Janssen: Honoraria, Other: Travel support for meetings. Voorhees: Janssen: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy. Richardson: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson: Celgene, Takeda, and Amgen: Speakers Bureau. Sutherland: Janssen: Honoraria. Yong: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Hoos: Imugene: Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Gorczyca: GlaxoSmithKline: Employment, Equity Ownership. Lahiri: GlaxoSmithKline: Employment, Equity Ownership. He: GlaxoSmithKline: Employment, Equity Ownership. Jewell: GlaxoSmithKline: Employment, Equity Ownership. Opalinska: GlaxoSmithKline: Employment, Equity Ownership. Cohen: Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Janssen: Consultancy.