Belantamab Mafodotin Myeloma Application Fast-Tracked in EU

The European Medicines Agency (EMA) has validated a Marketing Authorization Application (MAA) for belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma whose prior therapy included an immunomodulatory (IMiD) agent, a proteasome inhibitor, and a CD38-directed monoclonal antibody.¹

The antibody-drug conjugate was accepted for accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use, GlaxoSmithKline, the developer of belantamab mafodotin, stated in a press release.

The MAA is based on findings from the pivotal DREAMM-2 study, in which belantamab mafodotin demonstrated an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6) with the 2.5-mg/kg dose of belantamab mafodotin in this patient population.² In patients who received belantamab mafodotin at 3.4 mg/kg, the ORR was 34% (97.5% CI; 23.9-46.0); both ORRs were assessed by an independent review committee (IRC).

The safety data were consistent with previously reported data on belantamab mafodotin.

In the open-label, 2-arm, phase II DREAMM-2 trial, investigators accrued 196 patients with relapsed/refractory myeloma for the intent-to-treat population between June 18, 2018, and January 2, 2019. Patients were randomized 1:1 to receive belantamab mafodotin at either 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) intravenously every 3 weeks until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients had an ECOG performance status of 0 to 2, experienced disease progression on ≥3 lines of therapy, were refractory to a proteasome inhibitor and an IMiD, and were refractory and/or intolerant to a CD38-directed monoclonal antibody.

Patient characteristics were well balanced between the 2 treatment arms. In the 2.5-mg/kg arm, the median age was 65 years (range, 60-70), 53% were male, and 42% had high-risk cytogenetics. Patients had received a median of 7 (range, 3-21) lines of prior treatment, with 84% of patients having received >4 lines of therapy. Prior therapies included bortezomib (Velcade; 98%), carfilzomib (Kyprolis; 76%), lenalidomide (Revlimid; 100%), pomalidomide (Pomalyst; 92%), daratumumab (Darzalex; 100%), and isatuximab (3%).

Additionally, 76% of patients were refractory to bortezomib, 65% were refractory to carfilzomib, 90% were refractory to lenalidomide, 87% were refractory to pomalidomide, 100% were refractory to daratumumab, and 3% of patients were refractory to isatuximab.

The median age in the 3.4-mg/kg arm was 67 years (range, 61-72), 57% were male, and 47% had high-risk cytogenetics. Patients had received a median of 6 (range, 3-21) prior lines of therapy, with 83% having received >4 lines. Prior therapies received included bortezomib (98%), carfilzomib (65%), lenalidomide (100%), pomalidomide (85%), daratumumab (97%), and isatuximab (2%). The rate of the overall cohort refractory to each of these therapies was bortezomib, 75%; carfilzomib, 58%; lenalidomide, 89%; pomalidomide, 78%; daratumumab, 92%; and isatuximab, 1%.

The 31% ORR in the 2.5-mg/kg cohort included a very good partial response (VGPR) or better in 18 (19%) patients. Of the 34% ORR in the 3.4-mg/kg arm, a ≥VGPR was achieved in 20 (20%) of patients. There were 3 stringent complete responses or complete responses in each cohort.

The median follow-up was 6.3 months and 6.9 months in the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Overall, the median duration of response (DOR) was not reached. At the data cutoff date, 18 patients receiving belantamab mafodotin at 2.5 mg/kg and 25 at the 3.4-mg/kg dose had a DOR of ≥4 months; the authors noted that progression-free survival (PFS) follow-up was ongoing and patients were continuing on treatment.

The median PFS was 2.9 months (95% CI, 2.1-3.7) and 4.9 months (95% CI, 2.3-6.2) in the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Overall survival data were immature at the time of the analysis.

Regarding the safety analysis, there were 95 patients in the 2.5-mg/kg arm and all 99 patients in the 3.4-mg/kg arm. The most frequently reported grade 3/4 adverse events (AEs) included keratopathy (27% in the 2.5-mg/kg cohort vs 21% in the 3.4-mg/kg cohort), thrombocytopenia (20% vs 33%, respectively) and anemia (20% vs 25%, respectively). Serious AEs occurred in 40% versus 47% of the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Investigators reported 2 deaths that were potentially related to treatment: 1 case of sepsis in the 2.5-mg/kg cohort and 1 case of hemophagocytic lymphohistiocytosis in the 3.4-mg/kg group.

Moreover, dose delays that were related to AEs occurred in 54% of patients on the 2.5-mg/kg cohort compared with 62% of the 3.4-mg/kg cohort. AE-related dose reductions occurred in 29% versus 41% of the 2 cohorts, respectively. Permanent treatment discontinuation due to AEs occurred in 8% and 10% of patients on the 2.5-mg/kg and 3.4-mg/kg arms, respectively.

The authors noted that 2.5 mg/kg was selected as the recommended dose for future studies with belantamab mafodotin, given the similar efficacy and a more favorable safety profile compared with the 3.4-mg/kg dose.

In January 2020, the FDA granted a priority review designation to a biologics license application for belantamab mafodotin as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug, a proteasome inhibitor, and a CD38-directed antibody. The decision was also based on the DREAMM-2 findings.

In 2017, the European Medicines Agency granted PRIME designation to belantamab mafodotin; PRIME is intended to expedite development of investigational agents that have demonstrated efficacy in patients with conditions that are a significant unmet need.

The DREAMM clinical trial program is evaluating belantamab mafodotin in various settings in multiple myeloma. The phase I/II DREAMM-4 trial (NCT03848845) is exploring the antibody-drug conjugate in combination with pembrolizumab (Keytruda) in patients with relapsed/refractory myeloma; the phase I/II DREAMM-5 study (NCT04126200) is combining belantamab mafodotin with various agents in patients with relapsed/refractory myeloma.

Additionally, the phase I/II DREAMM-6 trial (NCT03544281) is investigating belantamab mafodotin combined with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade)/dexamethasone in patients with relapsed/refractory myeloma. The DREAMM-9 trial (NCT04091126) is combining belantamab mafodotin with bortezomib plus lenalidomide/low-dose dexamethasone (VRd) vs VRd alone in patients with newly diagnosed multiple myeloma who are ineligible for transplant.

References

1. GSK announces European Medicines Agency (EMA) accepted marketing authorisation application for belantamab mafodotin for the treatment of relapsed or refractory multiple myeloma [news release]: London, UK. GlaxoSmithKline. Published February 3, 2020. https://bit.ly/37UZPh9. Accessed February 3, 2020.
2. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study [published online December 16, 2019]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30788-0.