Belantamab Mafodotin/Pd Triplet Demonstrates Manageable Safety Profile in Relapsed/Refractory Myeloma

Pipeline Report | <b>Pipeline Report: December 2021</b>

The triplet regimen of belantamab mafodotin plus pomalidomide and dexamethasone was revealed to have a manageable safety profile, which is consistent with the known individual safety profiles of belantamab mafodotin or pomalidomide and dexamethasone, in patients with relapsed/refractory multiple myeloma.

The triplet regimen of belantamab mafodotin-blmf (Blenrep) plus pomalidomide (Pomalyst) and dexamethasone (Pd) was revealed to have a manageable safety profile, which is consistent with the known individual safety profiles of belantamab mafodotin or Pd, in patients with relapsed/refractory multiple myeloma, according to updated findings from the ongoing, phase 1/2 Algonquin study (NCT03715478) that were presented during the 2021 ASH Annual Meeting.

The regimen was explored across 6 cohorts at different dosing schedules of belantamab mafodotin. Following a correlation with lower rates of blurred vision, neutropenia, and a superior progression-free survival (PFS), 2.5 mg/kw every 8 weeks was selected as the recommended phase 2 dose (RP2D) for this agent.

“Belantamab mafodotin in combination with pomalidomide and dexamethasone demonstrates a manageable safety profile that is consistent with the known safety profiles of belantamab mafodotin and pomalidomide, individually,” Suzanna Trudel, MD, of the Princess Margaret Cancer Centre, in a presentation of the findings. “Both those cohorts, [at a dose of] 1.92 mg/kg and 2.5 mg/kg every 4 weeks, demonstrated deep and durable responses, however, the 2.5-mg/kg dose cohort appears to have better efficacy with a [median] PFS of 25.3 months versus 16.2 months.

Belantamab mafodotin is a BCMA-targeting antibody-drug conjugate (ADC) that is currently approved for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

As part of the ongoing phase 1/2 Algonquin study, 56 patients were enrolled in October 2021 to receive either 1.92 mg/kg or 2.5 mg/kg of belantamab mafodotin plus Pd. There were 6 cohorts in total: belantamab mafodotin at 1.92 mg/kg as a single dose every 4 weeks (cohort 1; n = 12), at 2.5as a single dose and a 2.5-mg/kg loading dose followed by 1.92 mg/kg every 4 weeks (cohort 1a; n = 12), at a split dose of 2.5 mg/kg (n = 8), at a split dose at 3.4 mg/kg every 4 weeks (cohort 2; n = 12), at a bi-monthly dose of 2.5 mg/kg every 8 weeks (cohort 3a; n = 12), and at a tri-monthly dose of 2.5 mg/kg (cohort 3b; n = 8).

Patients in all cohorts also received pomalidomide at 4 mg on days 1 to 21 and dexamethasone at 40mg weekly. Treatment continued until either disease progression or unacceptable toxicity.

In part 1 of the trial, the primary end points were maximum-tolerated dose (MTD) and/or highest dose with acceptable toxicity (RP2D), and objective response rate (ORR) was the primary end point in the part 2 portion. Secondary endpoints were defined as efficacy—progression-free survival (PFS), overall survival (OS), duration of response (DOR)—and safety, including ocular toxicities.

Among all participants, the median age was 64 years (range, 36-81) and the median prior lines of treatment was 2.5 (range, 1-5). All enrolled patents were exposed to a PI and lenalidomide, while 75.4% were PI/lenalidomide refractory and 48.2% were daratumumab/lenalidomide/PI refractory.

The 4 cohorts presented at the 2021 ASH Annual Meeting included 1.92 mg/kg every 4 weeks, 2.5 mg/kg every 4 weeks, 2.5 mg/kg every 8 weeks, and 2.5 mg/kg every 12 weeks.

Among the 54 patients who were eligible for assessment at a median follow-up of 11.0 months, the ORR (>partial response [PR])/very good partial response [VGPR] rates) were 88.9%/72.2%. In a lenalidomide-/proteasome inhibitor (PI)–refractory group, the rates were 86.7%/86.7%; in a lenalidomide/PI/daratumumab (Darzalex)–refractory group, the rates were 92.3%/69.2%. The median progression-free survival (PFS) was 17 months (95% CI, 14.5–not reached [NR]), 25.3 months (24.9-NR), and 16.2 (8.7-NR), across the same groups, respectively.

Across the 4 study dose cohorts, the ORRs were as follows: 81.8%, 95.0%, 83.3% and 90.9%, in the 1.92-mg/kg every-4-weeks, 2.5-mg/kg every-4-weeks, 2.5-mg/kg every 8-weeks, and 2.5-mg/kg every-12-weeks cohorts, respectively. PR rates were 18.2%, 10.0%, 8.3%, and 36.4%, respectively; VGPR rates were 36.4%, 45.0%, 58.3%, and 45.5%, respectively.

The median PFS by different study dose cohorts were as follows: 16.2 months (95% CI, 8.7-NR) in the 1.92-mg/kg every-4-weeks cohort, 25.3 months in the 2.5-mg/kgevery-4-weeks cohort, and not reached in the 2.5-mg/kg every 8- and 12- weeks cohorts.

In total, 96.4% of patients experienced treatment-emergent AEs. Frequently occurring TEAS included keratopathy and blurred vision, which were reported by 100% of patients in the 1.92-mg/kg every-4-weeks cohort, 2.5-mg/kg every-4-weeks cohort, and 2.5-mg/kg every-8-weeks cohorts (N = 44) and 83.3% of patients in the 2.5-mg/kg every-12-weeks cohort (n = 10). Additional commonly occurring TEAEs included fatigue, thrombocytopenia, neutropenia, constipation, fever, diarrhea, and nausea.

Grade 3 or higher TEAEs included keratopathy, blurred vision, neutropenia, and thrombocytopenia. The authors noted that neutropenia and thrombocytopenia were represented high grade non-ocular TEAEs to emerge in the study.

Severe adverse events (SAEs) presented in 50% of patients and 1 patient died due to acute respiratory syndrome. Two patients discontinued treatment because of an AE; 1 patient in the 2.5-mg/every-4-weeks cohort had leukoencephalopathy, which was not related to treatment, and 1 patient in the 2.5-mg/every-12-weeks cohort had elevated alanine aminotransferase, which was considered to be possibly related to treatment.

“[The median] PFS of 16.2 months for triple-refractory patients is favorable when compared with historical data from the management study, where an overall survival of 9.2 months is reported,” concluded Trudel. “2.5 mg/kg every 8 weeks was selected as the recommended phase 2 dose, based on the following a lower rate of grade 3 or higher blurred vision and neutropenia and a superior PFS.”

Reference

Trudel S, McCurdy A, Sutherland H, et al. Part 1 results of a dose-finding study of belantamab mafodotin in combination with pomalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (RRMM). Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 1653.