BCMA-Targeting Antibody Associated With Clinical Activity in Previously Treated Myeloma

In a first-in-human trial published in Lancet Oncology, the anti–B-cell maturation antigen (BCMA) antibody GSK2857916 was associated with clinical activity and was reasonably well tolerated in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM). According to the researchers, the interim findings from this study suggest that GSK2857916, at its recommended phase II dose of 3.4 mg/kg once every three weeks, may be a helpful treatment approach for patients with RRMM.

“There is a clear need for further treatment options in these patients, especially for those who are refractory to both proteasome inhibitors and immunomodulatory drugs, as the prognosis in those patients is particularly bleak,” study author Suzanne Trudel, MD, of the Princess Margaret Cancer Centre in Toronto, told ASH Clinical News. “The single-agent clinical activity, demonstrating an overall response rate of 60 percent (including high-quality responses) and preliminary progression free survival (PFS) of 7.9 months, is highly significant in this patient population.”

This international, open-label trial enrolled individuals with RRMM. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 to 1, as well as progressive disease following hematopoietic cell transplantation, alkylators, proteasome inhibitors, and immunomodulatory drugs.

The study was conducted in two parts: In the doseescalation phase (part 1), 38 patients received GSK2857916 0.03 to 4.6 mg/kg in one-hour infusions once every three weeks; in the dose-expansion phase (part 2), 35 patients received GSK2857916 3.4 mg/kg (the recommended phase II dose) once every three weeks.

Median age in each cohort was 60 years (range = 39-79 years), and the majority of patients received five or more prior therapies (76% in part 1 and 57% in part 2).

There were no dose-limiting toxicities and no maximum tolerated dose identified in the dose-escalation phase.

The most common grade 3 or 4 adverse events (AEs) were thrombocytopenia (n=13; 34%) and anemia (n=6; 16%). One patient died in the 4.6-mg/kg cohort, but this was attributed to disease progression. There were four ongoing responses at the time of data cutoff (June 26, 2017), with response durations ranging from 7.98 to 13.08 months. Corneal events occurred in 20 patients in part 1 (53%) but were mostly mild, with 18 patients experiencing grade 1/2 events (47%), and resulted in only two treatment discontinuations Based on the overall response and tolerability results in part 1, the researchers selected 3.4 mg/kg for the dose-expansion cohort.

In part 2, patients had a median follow-up of 6.6 months (interquartile range = 4.7-8.1 months) and had received a median of five treatment infusions (range = 1-13 infusions) at time of data cutoff (June 26, 2017). All patients in part 2 experienced at least one AE, and the most common grade 1/2 treatment-emergent AEs were corneal events, which included but were not limited to blurred vision (n=16; 46%) and dry eyes (n=11; 31%). Hematologic AEs included thrombocytopenia (grade 1/2, 23%; grade 3, 26%) and anemia (grade 1/2, 14%; grade 3, 14%).

Two-thirds of patients in part 2 experienced AEs that led to dose reductions (most commonly blurred vision and thrombocytopenia), and 25 (71%) had AEs that led to dose interruptions or delays. Two patients discontinued treatment because of AEs, again because of thrombocytopenia. Three patients died during follow-up, all of which were attributed to progressive disease.

Twenty-one of 35 patients (60%) in part 2 had a confirmed overall response, including: one stringent complete response (3%). two complete responses (6%), 15 very good partial responses (43%), and three partial responses (9%).

The median time to first response was 1.4 months (range = 0.8-2.0 months). Over time, most responses to therapy were maintained and sometimes deepened, the authors reported. The median PFS was 7.9 months (range = 3.1 to not estimable), yet the median duration of response was not estimable. Data on overall survival were considered immature and were not assessed.

“Our preliminary findings demonstrated longer PFS than many other approved single-agent therapies for MM.”

—Suzanne Trudel, MD

“Our preliminary findings demonstrated longer PFS than many other approved single-agent therapies for MM and a promising overall response, with around half of the patients achieving at least a very good partial response,” Dr. Trudel explained. “Other therapeutic options that target BCMA, such as BCMA chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BITEs), also have shown promising efficacy data.”

However, GSK2857916 is an off-the-shelf product and does not have the risks of cytokine-release syndrome or neurotoxicity present with BCMA CAR T cells or BITEs, she added. While substantially less toxic, PFS appears somewhat shorter than early results from trials of CAR T-cell therapies.

The “necessarily small sample size” represents an inherent limitation of this analysis, the researchers wrote. In addition, the lack of a comparator control, such as placebo, and the lack of randomization are additional limitations of this initial study. Corneal toxicity may be problematic in some patients.

“As these data are based on interim analyses of a phase I study, we’re looking forward to the final analyses after longer follow-up,” Dr. Trudel added. “Larger-scale and later-phase clinical trials that explore the role of GSK2857916 as part of combination therapy for RRMM are also greatly anticipated.”

The authors report relationships with GlaxoSmithKline, which supported the study.

Reference

Trudel S, Lendvai N, Popat R, et al. 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. Lancet Oncol. 2018;19:1641-53.

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