麻豆传媒

WASHINGTON -- An FDA advisory committee voted unanimously to recommend approval of the antibody-drug conjugate (ADC) belantamab mafodotin for last-line treatment of relapsed/refractory multiple myeloma (RRMM).

In voting 12-0 in favor of approval, the Oncologic Drugs Advisory Committee (ODAC) found that belantamab mafodotin's efficacy clearly outweighed the risk of a novel ocular toxicity not seen with other types of myeloma drugs. In a pivotal phase II clinical trial, almost a third of patients responded to the ADC, despite having received multiple prior therapies. All of the patients had disease that had proven refractory to protease inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies.

More than 70% of patients developed ocular toxicity in the form of keratopathy and corneal changes, but the adverse effect resolved in the vast majority of cases.

"I think it seems clear that this is an active agent. The toxicity is certainly not life threatening," said ODAC chair Philip Hoffman, MD, of the University of Chicago. "In many instances, [the toxicity] didn't even appear threatening, though evident on examinations. I do think patients are probably willing to take this risk."

Oncologists are quick learners when it comes to novel toxicities, and in collaboration with ophthalmologists, the ocular toxicity associated with belantamab mafodotin will be addressed adequately, said Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minnesota.

"We've clearly seen evidence in terms of overall response rate and also duration of response, which is meaningful in this group of patients with relapsed/refractory disease," he said. "I think the [risk mitigation] program that was put in place is very reassuring, and that the safety of this drug will be adequate when it is available to the community."

Echoing comments of other committee members, Heidi Klepin, MD, of Wake Forest University Health Sciences in Winston-Salem, North Carolina, noted that the overall efficacy-toxicity ratio remained favorable even in a heavily pretreated population. She encouraged sponsor GlaxoSmithKline (GSK) to evaluate the drug in patients 75 or older, who were poorly represented in the trial. "We don't have enough evidence on the benefit-to-risk ratio in that population."

Weighing the Evidence

Most of the evidence reviewed during the ODAC meeting, held virtually because of the COVID-19 pandemic, came from the pivotal DREAMM-2 trial. The 6-month results showed objective responses in 31% of patients treated with the recommended 2.5 mg/kg dose and 34% in patients who received 3.4 mg/kg. The 9-month update of the trial results showed a median duration of response (DoR) of at least 9 months and median overall survival of 11.9 months.

The ADC achieved a higher response rate, longer DoR, and better OS as compared with the recently approved combination of selinexor (Xpovio) and dexamethasone, said Sagar Lonial, MD, of Emory University and Winship Cancer Institute in Atlanta and global principal investigator for the DREAMM-2 trial. Additionally, belantamab mafodotin had a more favorable safety profile, as 8% of patients on the 2.5-mg/kg dose discontinued treatment because of adverse events, versus 27% in the pivotal trial of selinexor and dexamethasone.

The efficacy shown in DREAMM-2 clearly outweighed the risk of ocular toxicity, said Lonial, who spoke at the request of GSK. Patients enrolled in the trial had received an average of seven prior regimens, essentially exhausting all treatment options. Targeting B-cell maturation antigen (BCMA), belantamab mafodotin represents a completely new class of therapy not previously available to patients with myeloma, he said.

"From my view, BCMA presents an important treatment target, and it doesn't make sense to wait an additional 2 to 3 years to have an off-the-shelf therapy for patients with triple-class refractory myeloma," said Lonial. "The benefit far exceeds the potential risks of use. Our patients should be afforded this treatment option to determine, in informed decision making with their oncologist, if it is right for them."

Although 72% of patients treated with the recommended dose developed keratopathy, half of the patients developed symptoms of the condition, and 17% had changes in visual acuity during treatment with belantamab mafodotin, said ophthalmologist Kathryn Colby, MD, PhD, of the University of Chicago. Only one of 17 patients who developed clinically meaningful vision loss did not have resolution of the problem at the 9-month follow-up visit.

The functional impact of the vision disturbance varied from patient to patient, and quality-of-life data showed no significant deterioration at any time during the study.

"As an ophthalmologist, I am comfortable with these events. It is the myeloma that worries me," said Colby, who also spoke during the sponsor's presentation. "I can assure you when keratopathy occurs, it will be identified and effectively managed with dose modifications. Keratopathy exam findings improve with time."

Lonial and Colby emphasized that use of the drug requires close cooperation between oncologists and ophthalmologists.

Caveats

FDA scientist Andrea Baines, MD, PhD, acknowledged the efficacy of belantamab mafodotin in heavily treated patients who have run out of treatment options. However, she highlighted issues related to the safety and efficacy of the drug.

Although the ocular toxicity resolved in most cases, the keratopathy and corneal ulceration did have adverse functional effects for some patients. The mechanisms of ocular toxicity remain poorly understood, and the high proportion of patients with asymptomatic keratopathy (49%) has no obvious explanation. Long-term implications of asymptomatic keratopathy are unknown.

Additionally, the 2.5 mg/kg group in the DREAMM-2 trial had a median age of 65, versus a median age of 69 for the general population of patients with multiple myeloma, Baines continued. Only one patient 75 or older responded to treatment with the ADC.

GSK has proposed a black box warning about the risk of ocular toxicity, as well as a risk mitigation strategy.

"Ocular toxicity associated with belantamab mafodotin remains a major safety concern," said Baines. "The incidence and severity of keratopathy was high, in association with a decrease in visual acuity, including severe visual loss in some and significant impact on daily activities."

Considering the rates and severity of ocular toxicity, the FDA remains unconvinced that a black-box warning and the proposed mitigation strategy would actually reduce the risk, said Baines, adding that "it's not clear if the benefit outweighs the risk of ocular toxicity."

The FDA is not required to follow advisory committee recommendations, but it usually does.

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