Reference Detail

Ref Type

Journal Article

PMID

(30442502)

Authors

Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, Richardson PG, Anderson LD, Sutherland HJ, Yong K, Hoos A, Gorczyca MM, Lahiri S, He Z, Austin DJ, Opalinska JB, Cohen AD

Title

Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Lancet. Oncology	19	12	2018 Dec	1641-1653	Lancet Oncol

URL

Abstract Text

B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma.We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03-4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment.Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1-76·1) of 35 patients achieved an overall response.At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma.GlaxoSmithKline.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
belantamab mafodotin-blmf	belantamab mafodotin-blmf	0	16
belantamab mafodotin-blmf + Bortezomib + Dexamethasone	Bortezomib Dexamethasone belantamab mafodotin-blmf	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
belantamab mafodotin-blmf	Blenrep	anti-BCMA ADC GSK2857916\|J6M0-mcMMAF\|GSK2857916	TNFRSF17 Antibody 18	Blenrep (belantamab mafodotin-blmf) is an antibody-drug conjugate comprising an antibody targeting BCMA linked to monomethyl auristatin F, which delivers the anti-microtubule agent to BCMA-expressing tumor cells, potentially resulting in increased tumor cell death and decreased tumor growth (PMID: 30442502, PMID: 24569262). Blenrep (belantamab mafodotin-blmf) is FDA approved for use in patients with relapse or refractory multiple myeloma who have received 4 or more prior therapies (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References