FDA Grants BCMA Antibody-Drug Conjugate Breakthrough Status for Myeloma

Axel Hoos, MD, PhD

The FDA has granted GSK2857916 a breakthrough therapy designation for patients with relapsed/refractory multiple myeloma, according to GlaxoSmithKline (GSK), the manufacturer of the B-cell maturation antigen (BCMA) antibody-drug conjugate.

GSK2857916 is indicated for patients who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and are refractory to a proteasome inhibitor and an immunomodulatory agent.

GSK also noted in a press release that the European Medicines Agency (EMA) granted PRIME designation to GSK2857916 in October for the treatment of relapsed and refractory multiple myeloma patients whose prior therapy included a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

The breakthrough and PRIME designations will expedite the development and review of GSK2857916 in the United States and European Union, respectively.

“Oncology R&D at GSK is focused on developing medicines with transformational potential for patients and we are pleased that our investigational antibody-drug conjugate is the first BCMA targeting agent to receive breakthrough therapy and PRIME designation,” Axel Hoos, MD, PhD, senior vice-president, Oncology R&D, said in a statement.

“GSK plans to rapidly advance clinical trials with this promising therapy, alone and in combination with other therapies, to further investigate how GSK2857916 could benefit patients with multiple myeloma. The monotherapy data that we have seen for GSK2857916 support its transformational potential and we look forward to working with regulators as we progress the development program,” added Hoos.

GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. GSK2857916 exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation of the FC domain which increases affinity to FCγRIIIa expressed on immune effector cells.

The breakthrough designation is based on results from a phase I open-label, dose escalation and expansion study in patients with relapsed/refractory multiple myeloma, irrespective of BCMA expression. Data from this ongoing trial are scheduled to be presented in December at the 2017 ASH Annual Meeting

In phase I data presented at last year’s ASH Annual Meeting, 24 patients enrolled at 8 dose levels. GSK2857916 is administered every 3 weeks with no mandatory prophylaxis for infusion related reactions (IRRs).

There was 1 minimal response (MR) at the 0.24 mg/kg dose, and 1 very good partial response, 3 partial responses, and 1 MR at doses ≥0.96 mg/kg. Including unconfirmed responses, the clinical benefit rate was 25%.

The median age was 60 years (range, 39-71) and 50% of the cohort was male. Eighty-three percent received ≥4 prior lines of therapy. Sixty-three percent had IgG and 29% had IgA types.

Seven patients (29%) had adverse cytogenetics, defined as del17p13 or t(4;14). Twenty-three patients (96%) experienced adverse events (AEs). The most frequently reported AE, regardless of cause, was nausea (42%), followed by fatigue (38%), anemia (29%), chills (29%), pyrexia (29%), thrombocytopenia (29%), dry eye (21%), and hypercalcemia (21%).

Grade 3/4 AEs reported in ≥10% of patients included thrombocytopenia, anemia, and neutropenia. There were 8 serious AEs reported among 6 patients, with 1 incidence of unresolved limbal stem cell dysfunction that was considered drug related.

There were no AEs leading to treatment discontinuation. Four patients required dose reduction due to AEs, 1 each of ocular toxicity, corneal disorder/ocular toxicity, dry eyes, and keratitis. Across all dose levels, 7 patients (29%) experienced IRRs, all of which were grade 1 or 2 and occurred during the first dose administration. The most frequent symptoms were chills.

Investigators did not observe any dose-limiting toxicities. One patient completed 16 cycles of scheduled treatment and 8 patients were ongoing at the time of the analysis. Fourteen patients discontinued treatment due to disease progression.

The EMA and FDA have both designated GSK2857916 as an orphan drug for multiple myeloma.

Cohen AD, Popat R, Trudel S, et al. First in human study with GSK2857916, an antibody drug conjugated to microtubule-disrupting agent directed against b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma (MM): Results from study BMA117159 part 1 dose escalation. Blood, 128(22).