WASHINGTON — The regulatory fate of a new multiple myeloma drug could hinge on a novel ocular toxicity uncommon among other therapies for the disease.
During a virtual meeting on Tuesday, an FDA advisory committee will consider the antibody-drug conjugate (ADC) belantamab mafodotin, which showed activity in triple-refractory disease, including patients who did not benefit from treatment with an anti-CD38 antibody. However, more than 70% of patients treated with either of two doses of the drug developed keratopathy or changes to the corneal epithelium. About 20% of patients had grade 3/4 ocular adverse events (grade 3 in all but one).
After 9 months of follow-up, more than half of patients with keratopathy still had the condition, according to FDA staff comments in a briefing document prepared for the Oncologic Drugs Advisory Committee (ODAC). Additionally, 21% of patients stopped driving because of vision problems, and 20% either had extreme difficulty reading or gave it up altogether.
Neither the mechanism nor the extent of reversibility of the ocular toxicity is completely understood.
“Given the incomplete data regarding the reversibility of ocular toxicity, there is uncertainty at this time whether the dose modification strategy proposed by the applicant is sufficient to mitigate the risk of ocular toxicity with belantamab mafodotin,” FDA staff authors wrote.
Belantamab mafodotin consists of a humanized monoclonal antibody against B-cell maturation antigen conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF). Internalization of MMAF into myeloma cells leads to cell cycle arrest, apoptosis, and release of immunogenic cell death markers that can stimulate immune cells, as described by drugmaker GlaxoSmithKline (GSK). Observed toxicities secondary to inflammatory responses in animals and humans are consistent with ADCs containing MMAF.
GSK seeks accelerated approval of the ADC to fill the niche of last-line therapy in relapsed/refractory multiple myeloma (RRMM), specifically disease that has proven refractory to protease inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. Currently, the only approved regimen for that niche is selinexor (Xpovio) plus dexamethasone, which produced an objective response rate of 26% and median duration of response of 4.4 months. The application seeks approval for use in patients who have received at least four prior lines of therapy.
Principal support for the approval application came from the pivotal uncontrolled DREAMM-2 trial that evaluated two different doses of the ADC in patients who had triple-refractory RRMM. An intention-to-treat analysis involving 198 patients showed response rates of 31% and 34% among patients who received 2.5 mg/kg or 3.4 mg/kg, respectively. At the 6-month cutoff, data remained immature to calculate duration of response (DoR).
Efficacy data focused primarily on the 2.5 mg/kg dose, which the sponsor has proposed as the approved dosage. The 9-month update suggested a DoR of “at least 9 months” in the 2.5 mg/kg cohort, more than twice that achieved with selinexor-dexamethasone. The estimated median overall survival was 11.9 months, approximately 3 months longer than compared with historical benchmarks, according to the briefing document.
When ODAC convenes Tuesday morning, the panel will address two issues: whether the DREAMM-2 trial adequately characterized the risk of ocular toxicity associated with belantamab mafodotin and the impact of ocular toxicity on the drugs benefit-risk profile. Following the discussion, the panel will be asked to vote on a single question: Does the demonstrated benefit of belantamab mafodotin outweigh the risks in the proposed patient population with multiple myeloma.
The meeting begins at 9 a.m. EDT and will be webcast publicly here.
Last Updated July 13, 2020
Source: MedicalNewsToday.com
