FDA Approval Sought for Belantamab Mafodotin in Relapsed/Refractory Myeloma

Sagar Lonial, MD, FACP

A biologics license application (BLA) has been filed with the FDA for belantamab mafodotin (GSK2857916) for the treatment of patients with relapsed or refractory multiple myeloma whose prior therapy included an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody, according to GlaxoSmithKline (GSK), the manufacturer of the BCMA-targeting antibody-drug conjugate (ADC).¹

The BLA is based on results from the phase II DREAMM-2 trial, the results of which were recently published in the Lancet Oncology.² The study met its primary endpoint, demonstrating a clinically meaningful overall response rate (ORR) of 31% (n = 30; 97.5% CI, 20.8-42.6) in a cohort of 97 patients with relapsed/refractory multiple myeloma treated with the ADC at the recommended dose of 2.5 mg/kg. The ORR included 18 (19%) patients with a very good partial response (VGPR) or better, 3 of whom had a complete response (CR) or stringent CR (sCR).

“Each day in my practice, I see patients who would benefit from additional therapeutic options because their disease has advanced and is no longer responding to available treatments. In recent years, BCMA has become one of the most promising targets in multiple myeloma research,” principal investigator Sagar Lonial, MD, chief medical officer, Winship Cancer Institute of Emory University, chair of Emory Department of Hematology and Medical Oncology, said in in the press release.

“The data published today from DREAMM-2 not only reinforce the significance of BCMA as a potentially viable target, but also underscore the potential of belantamab mafodotin, if approved, as a practical treatment option in this patient population,” added Lonial.

The open-label, 2-arm phase II DREAMM-2 study accrued 196 patients with relapsed/refractory myeloma for the intent-to-treat population between June 18, 2018, and January 2, 2019. Patients had an ECOG performance status of 0 to 2, disease progression on ≥3 lines of therapy, were PI- and IMiD-refractory, and were refractory and/or intolerant to an anti-CD38 monoclonal antibody. Patients were randomly assigned in a 1:1 ratio to belantamab mafodotin at 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) intravenously every 3 weeks until disease progression or unacceptable toxicity.

Patient characteristics were well balanced between the 2 treatment arms. The median age in the 2.5-mg/kg arm 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 therapy, with 84% having received >4 lines. Prior therapies received included bortezomib (Velcade; 98%), carfilzomib (Kyprolis; 76%), lenalidomide (Revlimid; 100%), pomalidomide (Pomalyst; 92%), daratumumab (Darzalex; 100%), and isatuximab (3%). The rate of the overall cohort refractory to each of these therapies was bortezomib, 76%; carfilzomib, 65%; lenalidomide, 90%; pomalidomide, 87%; daratumumab, 100%; and isatuximab, 3%.

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) 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%.

At the June 21, 2019, cutoff date for the primary analysis, the ORR in the 3.4 mg/kg arm was 34% (n = 34; 97.5% CI; 23.9-46). Twenty (20%) patients in this cohort reached a VGPR or better, included an sCR or CR in 3 patients.

The safety analysis included 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 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 smaller- versus larger-dose cohorts, respectively. Investigators reported 2 patient deaths that were potentially related to treatment: a case of sepsis in the 2.5-mg/kg arm and a case of hemophagocytic lymphohistiocytosis in the 3.4 mg/kg cohort.

AE-related dose delays occurred in 54% of 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 discontinuation of treatment due to AEs occurred in 8% of the 2.5-mg/kg arm and 10% of the 3.4-mg/kg arm.

Given the similar efficacy and better safety profile in the lower-dose arm, 2.5 mg/kg was selected as the recommended dose for future research.

The authors noted in their discussion remarks that a posthoc analysis in DREAMM-2 showed that the median overall survival among patients achieving an overall response or a minimal response had not yet been reached. “These results suggest that clinical responses obtained with belantamab mafodotin treatment persist beyond the 6-month follow-up period for this primary analysis,” Lonial et al wrote.

The DREAMM-2 results were consistent with previously reported results for a similar subset of patients from the DREAMM-1 study.

The FDA granted belantamab mafodotin a breakthrough therapy designation in November 2017 for the treatment of patients with relapsed/refractory multiple myeloma who have failed ≥3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a PI and an IMiD.

References

1. Pivotal DREAMM-2 study demonstrated a clinically meaningful overall response rate with belantamab mafodotin (GSK2857916) for patients with relapsed/refractory multiple myeloma. GSK. Published December 16, 2019. https://bit.ly/38SugFV. Accessed December 16, 2019.
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.