The FDA’s Oncologic Drugs Advisory Committee voted 12 to 0 in favor of approving 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, a proteasome inhibitor, and a CD38-directed antibody.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to 0 in favor of approving 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, a proteasome inhibitor, and a CD38-directed antibody.
The FDA previously scheduled the hearing to discuss data supporting a biologics license application (BLA) for belantamab mafodotin for use in this setting. Specifically, the panel sought to determine whether the risk of ocular toxicity has been adequately characterized in the pivotal DREAMM-2 trial to allow for an assessment of the benefit-risk profile, and the impact of ocular toxicity on the benefit-risk profile for belantamab mafodotin.1
One of the associated, and arguably most notable, adverse effects of belantamab mafodotin is ocular toxicity, which includes keratopathy and changes in visual acuity assessed by ocular examinations, and symptoms of blurred vision and dry eyes, as noted in the FDA's briefing document ahead of ODAC hearing.
"It seems clear that this is an active agent," ODAC chairperson Philip C. Hoffman, MD, a professor of medicine at University of Chicago Medicine, stated during the hearing. "The toxicity is certainly not life threatening; in many instances, it isn't even comfort threatening, though evident on examinations. I do think patients are probably willing to take this risk, and the mitigation strategy that the company has outlined for thorough exams before each dosing, a grading system, and so on, addresses the concerns."
The hearing followed a January 2020 priority review designation granted to the BLA, and prior to that in November 2017, a breakthrough therapy designation.
The designations were based on findings from the pivotal phase 2 DREAMM-2 trial, which showed that the antibody-drug conjugate induced a 31% overall response rate (ORR; 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 agent at 3.4 mg/kg, the ORR was 34% (97.5% CI, 23.9%-46.0%). Both ORRs were evaluated by an independent review committee.
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%).
In the FDA's briefing document ahead of the ODAC hearing, it was noted that ocular toxicity of keratopathy was the most frequently reported toxicity with belantamab mafodotin. The agency also conducted their own analysis of ocular toxicities in the DREAMM-2 trial.
Their results showed that the overall incidence of keratopathy was 71%, and 44% of patients experienced at least 1 episode of severe keratopathy at the 2.5-mg/kg dose. Moreover, the FDA stated that the incidence of ocular toxicities did not differ substantially between the 2 doses in the DREAMM-2 trial, aiding to the discussion that the ocular toxicity with belantamab mafodotin has not been fully characterized.
Also in the FDA's analysis it was found that the incidence of patients requiring a dose delay due to blurred vision was 5% in the 2.5-mg/kg cohort and 9% in the 3.4-mg/kg cohort, which was found to be higher than what was submitted by GlaxoSmithKline, the developer of belantamab mafodotin.
The company announced that it had developed an Ocular Risk Evaluation and Mitigation Strategy (REMS) to provide education to all physicians prescribing belantamab mafodotin and their patients regarding the risk of corneal adverse reactions.
Heidi D. Klepin, MD, professor of hematology and oncology at Wake Forest School of Medicine, shared the reasoning for her vote.
"I think the efficacy and toxicity remains favorable in the highly pretreated patient population that was studied," Klepin said. "I think the informed consent process will allow patients to choose whether this tradeoff is worth it to them. I would encourage the sponsor to really put some additional effort into enrolling and reporting on a representative number of patients aged 75 or older, since that particular subgroup was poorly represented and is a large and growing group of patients who may have this choice. At present, we don't have enough evidence on the benefit to risk ratio in that patient population."
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.
Two panelists were absent from the voting process: Christian S. Hinrichs, MD, and Anthony D. Sung, MD.