In briefing documents released Friday ahead of an FDA advisory panel meeting set for July 14, agency staff highlighted ocular toxicity issues associated with GlaxoSmithKline's BCMA-directed antibody-drug conjugate (ADC) belantamab mafodotin as "a major safety concern." FDA reviewers said that while results from the pivotal DREAMM-2 trial suggest a benefit with belantamab mafodotin in patients with relapsed or refractory multiple myeloma, the incidence and severity of keratopathy in the study was "high," so it is "not clear whether the benefit outweighs the risks."
The FDA is evaluating GlaxoSmithKline's filing for belantamab mafodotin under a priority review that was granted in January. The drugmaker is seeking to have the 2.5 mg/kg dose of the treatment, also known as GSK2857916, approved for adults with relapsed or refractory multiple myeloma who received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulatory agent. If approved, GlaxoSmithKline has said belantamab mafodotin would be the first anti-BCMA agent available in the US.
Detailed findings from the 196-patient DREAMM-2 trial demonstrated that belantamab mafodotin achieved the primary endpoint of clinically meaningful overall response rate (ORR), with an ORR of 31% for patients in the 2.5 mg/kg dose cohort, and 34% for those who received the higher 3.4 mg/kg dose.
Aside from conventional side effects for anti-myeloma agents, such as thrombocytopenia and anaemia, FDA reviewers said ocular toxicity as reported in the DREAMM-2 study was "unique" among such treatments. They noted that keratopathy was the most common adverse event reported in the trial, with an overall incidence of 71%, while 44% of patients experienced at least one episode of severe keratopathy at the 2.5 mg/kg dose. "The absence of other ocular symptoms in more than half of patients raises concern that in the absence of close monitoring with frequent ophthalmic exams, keratopathy could go undetected," agency staffers warned, adding that treatment with belantamab mafodotin was also associated with a clinically significant decline in visual acuity, including severe vision loss.
Moreover, agency reviewers noted that despite implementing dose modifications, ocular toxicities were "recurrent and persistent," with a high proportion of patients still having the condition unresolved as of the last follow-up. GlaxoSmithKline suggested that corneal changes are a known class-effect of BCMA-directed ADCs and can be managed in part with dose modifications, adding they "do not appear to result in permanent sequalae," although the FDA said this may depend on events being identified early. "Given the incomplete characterisation of reversibility, there is uncertainty whether the dose modification strategy…is sufficient to mitigate the risk of ocular toxicity," FDA staff concluded.
Commenting on the staff report, Jefferies analysts indicated that "our confidence is dented by the FDA's remarks." For related analysis, see Spotlight On: Six new drug approvals to watch in H2 2020.
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