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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: GlaxoSmithKline.

Figure 1.. CONSORT diagram

(A) Part 1 (Dose Escalation) and (B) Part 2 (Expansion Cohort)

Figure 2.. Best responses to GSK2857916 (Part 2; 3∙4 mg/kg dose)

(A) Maximum percentage change of serum/urine M-protein or free light chain as compared with baseline values. For patients with measurable serum M-protein, serum values are depicted; for patients who are followed by urine M-protein, the urine values are depicted; and for patients who did not have measurable serum or urine M-protein and were followed by free light chains, the values for free light chain are depicted. (B) Forest plot of overall response rate by patient subgroup (Part 2). Patients with any of the following genetic abnormalities were considered high risk: t(4:14), del17p, t(14:16).

Figure 3.. Response durations and effect of dose modifications

(A) Duration of study treatment by response in Part 2 (3∙4 mg/kg dose). Treatment duration counts the time difference between first dosing date and dosing end date without accounting for dosing interruptions. Triangles indicate ongoing patients. (B) Dose modifications in responding patients in Part 2. For each of the 21 responding patients, indicated in green font is initial response (PR or better); blue font, best response; red font, progressive disease; the numbers indicate dose for each infusion. CR: complete response, MR: minimal response, NE: not evaluable, PD: progressive disease, PR: partial response, sCR: stringent complete response, SD: stable disease, VGPR: very good partial response.

Figure 4.. Kaplan–Meier curves for progression-free survival and duration of response

Progression-free survival (A) and duration of response (B) from Part 2 (dose expansion phase; 3∙4 mg/kg dose) are shown. The median progression-free survival was 7·9 months and the median duration of response was not estimable. Tick marks indicate censored data.