FDA Schedules ODAC Meeting on Belantamab Mafodotin in Relapsed/Refractory Myeloma

The FDA has scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for July 14, 2020, to discuss data supporting a biologics license application (BLA) for belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma who have previously received at least 4 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor, and a CD38-directed antibody.¹

In November 2017, the novel antibody-drug conjugate (ADC) received a breakthrough therapy designation; 3 years later, in January 2020, the BLA for belantamab mafodotin was granted priority review status from the FDA for use in this setting, based on findings from the pivotal phase 2 DREAMM-2 trial.

Results from the trial demonstrated that the agent induced an overall response rate (ORR) of 31% (97.5% CI, 20.8%-42.6%) in patients with relapsed/refractory disease who received the recommended 2.5 mg/kg dose.² In patients who received the ADC at a dose of 3.4 mg/kg, the ORR was even higher, at 34% (97.5% CI, 23.9%-46.0%). Both ORRs were evaluated by an independent review committee.

“We believe belantamab mafodotin and the results from the DREAMM clinical trial programme have significant potential for patients with relapsed/refractory multiple myeloma who have limited treatment options,” Axel Hoos, MD, PhD, stated in a press release. “We look forward to participating in the upcoming advisory committee meeting and working with the FDA to complete its review of the BLA.”

In the open-label, 2-arm trial, a total of 196 patients with relapsed/refractory myeloma were accrued to the intent-to-treat population from June 18, 2018 through January 2, 2019. Patients were randomized 1:1 to receive intravenous belantamab mafodotin at either 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) every 3 weeks until progressive disease or unacceptable toxicity.

Patients had to have an ECOG performance status ranging from 0 to 2, have experienced disease progression on 3 or more lines of therapy, been refractory to a proteasome inhibitor and an IMiD, and have been refractory and/or intolerant to a CD38-directed monoclonal antibody to be eligible for enrollment on the trial.

Patient characteristics were found to be well balanced between the arms. In the cohort that received the ADC at 2.5 mg/kg, the median age was 65 years; 53% of participants were male and 42% had high-risk cytogenetics. Participants had received a median of 7 prior lines of treatment (range, 3-21).

Notably, the majority of patients, or 84%, had received more than 4 prior lines of therapy. Prior treatment included bortezomib (Velcade; 98%), carfilzomib (Kyprolis; 76%), and isatuzimab-irfc (Sarclisa; 3%). All patients had received lenalidomide (Revlimid).

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

In the cohort that received the ADC at a dose of 3.4 mg/kg, the median age was 67; 57% were male and 47% had high-risk cytogenetics. These patients had received a median of 6 previous lines of treatment with 83% having received >4 lines. Prior therapies in this arm were bortezomib (98%), carfilzomib (65%), lenalidomide (100%), pomalidomide (85%), daratumumab (97%), and isatuximab (2%). Seventy-five percent of patients were refractory to bortezomib, 58% to carfilzomib, 89% to lenalidomide, 78% to pomalidomide, 92% to daratumumab, and 1% to isatuximab.

Additional data from the trial demonstrated a 31% ORR in those who received the 2.5-mg/kg cohort; this included a very good partial response (VGPR) or better in 18 (19%) patients. The ORR was 34% in the 3.4-mg/kg arm, with a VGPR or better achieved in 20 (20%) patients. Three stringent complete responses (sCRs) or complete responses (CRs) were observed in each cohort.

The median follow-up for the 2.5-mg/kg cohort was 6.3 months versus 6.9 months in the 3.4-mg/kg cohort. Overall, the median duration of response (DOR) had not yet been reached. At the data cutoff date, 18 patients who received the ADC at 2.5 mg/kg, and 25 patients who had received it at 3.4 mg/kg, experienced a DOR of ≥4 months.

The median progression-free survival at that time was 2.9 months in the 2.5-mg/kg cohort versus 4.9 months in the 3.4-mg/kg cohort.

Updated results from the trial were presented at the 2020 ASCO Virtual Scientific Program, and a 13-month follow-up analysis revealed an ORR of 32% (97.5% CI, 21.7%-43.6%) in those treated in the 2.5-mg/kg cohort and 35% (97.5% CI, 23.9%-46.0%) in the 3.4-mg/kg cohort.³

The DOR had not been reached in either cohort, but the median DOR estimate was 11.0 months (95% CI, 4.2–not reached [NR]) in the 2.5-kg/mg cohort versus 6.2 months (95% CI, 4.8–NR) in the 3.4-mg/kg cohort. Additionally, over half of patients who achieved a response in both cohorts had a VGPR or better (58% in the 2.5-mg/kg cohort versus 66% in the 3.4-mg/kg cohort). Of the 11 patients with a VGPR, 5 had a CR and 2 had a sCR in the 2.5-mg/kg cohort. Of the 18 patients in the 3.4-mg/kg cohort who had a VGPR, 3 achieved CR and 2 had sCR.

With regard to safety, all-grade adverse effects(AEs)were reported in 98% of patients in the lower-dose cohort and in 100% of those on the higher-dose cohort. Treatment-related AEs were reported in 88% versus 95% of patients, respectively. Grade 3 or higher AEs were experienced by 84% of patients in both cohorts, and included keratopathy (46% vs 42%, respectively), anemia (21% vs 27%), thrombocytopenia (22% vs 32%), decrease in lymphocyte count (13% vs 7%), and neutropenia (11% vs 7%).

During the 2020 ASCO Virtual Scientific Program, investigators also reported outcomes of patients with renal impairment who had received single-agent belantamab mafodotin at either dose as part of a post-hoc analysis of the trial.

Results showed that ORRs were comparable in patients with or without renal impairment. In those with normal renal function who received the 2.5-mg/kg dose and the 3.4-mg/kg dose, the ORR was 37% versus 35%, respectively.⁴ In those with mild renal impairment, the ORRs were 31% versus 40%, respectively, while in those with moderate renal impairment the rates were 33% and 27%, respectively.

The median DOR had not yet been reached in patients with mild or moderate impairment who were in the 2.5-mg/kg cohort. However, the DOR was 5.6 months in the 2.5-mg/kg cohort. For those with normal renal function, the median DOR was 4.2 months in the 2.5-mg/kg cohort versus 6.2 months in the 3.4-mg/kg cohort. The median PFS was found to be similar in those with and without impairment.

Results from another analysis of the DREAMM-2 study, pertaining to outcomes of patients with high-risk cytogenetics, were also presented during the ASCO meeting. The ORRs were found to be similar in both the high-risk and standard-risk patients. Although some numerical differences had been reported, they were not determined to have statistical significance.⁵

In the 2.5-mg/kg and 3.4-mg/kg cohorts, the ORR was 27% (97.5% CI, 14.2%-42.9%) versus 40% (97.5% CI, 24.1%-56.7%), respectively, in the high-risk patients, and 34% (97.5% CI, 20.4%-49.7%) versus 31% (97.5% CI, 17.7%-47.9%), respectively, in standard-risk patients.

References

1. GSK announces FDA Advisory Committee meeting to review belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma. News release. GlaxoSmithKline plc. June 19, 2020. Accessed June 19, 2020. bit.ly/3epTvS3.
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. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0
3. Lonial S, Lee C, Badros A, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mABs). J Clin Oncol. 2020;38(suppl 15):8536. doi:10.1200/JCO.2020.38.15_suppl.8536
4. Lee HC, Cohen AD, Chari A, et al. DREAMM-2: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment. J Clin Oncol. 2020;38(suppl 15):8519. doi:10.1200/JCO.20.38.15_suppl.8519
5. Cohen AD, Trudel S, Lonial S, et al. DREAMM-2: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics. J Clin Oncol. 2020;38(suppl 15):8541. doi:10.1200/JCO.2020.38.15_suppl.8541