Belantamab for MM: Benefit Outweighs Ocular Risk, FDA Panel Says

Kerry Dooley Young

July 15, 2020

A new first-in-class drug for use in the treatment of relapsed or refractory multiple myeloma looks to be a step closer to the market after a US Food and Drug Administration (FDA) advisory panel gave it a thumbs-up at a meeting held on July 14.

The drug, belantamab mafodotin (GlaxoSmithKline), has a novel mechanism of action: it is a drug conjugate composed of a humanized monoclonal antibody against B-cell maturation antigen (BCMA) linked to the cytotoxic agent auristatin F.

The FDA sought expert feedback on the company's application for accelerated approval of belantamab, which is largely based on a phase 2 study involving two doses of this drug.

The FDA's Oncologic Drugs Advisory Committee voted 12-0 in belantamab's favor on a question of whether the drug's demonstrated benefit outweighs the risks for people whose disease returns or persists. The FDA asked the panel to vote only on that question in regard to the belantamab application.

Concerns were raised about ocular toxicity, and the company proposed a risk evaluation and mitigation strategy (REMS) to detect and manage this.

The meeting was held remotely and was marked by technical difficulties, which caused it to run beyond its scheduled time. Two advisers didn't vote, having left the meeting before the vote was taken.

The FDA considers the recommendations of its advisory panels in its decisions and often follows them, although it is not bound by them.

GlaxoSmithKline is seeking an approval of belantamab for use in adults with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

The application rests heavily on a phase 2 study, DREAMM-2. Six-month primary results from this study were published in The Lancet Oncology in December. The overall response rate was 31% in the cohort given a 2.5-mg/kg dose of the drug; 30 of 97 patients had outcomes that met the study's positive threshold.

Another 99 patients in DREAMM-2 received a dose of 3.4 mg/kg, which was judged to have a less favorable safety profile, although the incidence of ocular toxicities did not differ substantially between the two doses.

Concern Over Ocular Toxicity

At issue with belantamab mafodotin is what the FDA described as "ocular toxicity," particularly keratopathy, which was seen in the trial participants.

In the DREAMM-2 study, 44% of patients in the group that received 2.5 mg/kg experienced at least one episode of severe keratopathy, FDA staff said in a briefing document for the meeting.

In some patients, the ocular side effects caused severe vision loss that interfered with the patients' activities of daily living, such as driving and reading, FDA staff said.

GlaxoSmithKline proposed an REMS to allow detection and treatment of potential complications of belantamab. This includes recommendations for ophthalmic examinations, including assessment of best corrected visual acuity prior to each treatment cycle and promptly for patients with worsening symptoms.

The FDA staff also recommended education of physicians who would prescribe belantamab and patient counseling about these risks.

Agency staff emphasized the need for examinations to spot complications that patients might not detect. Patients may not notice alterations in vision in one eye if the other eye can still see. Also, because of a lack of pain receptors inside the eye, damage to its interior structures may not be felt, according to the FDA staff.

"Additionally, many clinically relevant ocular toxicities are not necessarily symptomatic, but may be considered serious because they will lead to irreversible sequelae, such as vision loss, if left untreated," the agency staff said in the briefing document.

In discussing their reasons for voting in favor of belantamab, the FDA panelists appeared confident that the potential eye risk could be managed.

Gita Thanarajasingam, MD, an assistant professor of medicine at the Mayo Clinic, in Rochester, Minnesota, said belantamab appeared to be well tolerated but for ocular toxicity. Physicians need to acknowledge how severe this risk may be for patients while keeping in mind that belantamab still may be more tolerable for some people than current treatments, she said.

"It's reasonable to leave open the option for decision making. Patients can express their values and preferences," Thanarajasingam said. "There's adequate, albeit not complete, information to guide this risk-benefit discussion in a REMS program."

Heidi D. Klepin, MD, a professor at Wake Forest University Health Sciences, Winston Salem, North Carolina, agreed that the informed consent process should allow patients "to choose whether the trade-off is worth it to them" with belantamab.

Klepin urged GlaxoSmithKline to put more effort into recruiting people aged 75 and older into its studies of the drug. Many people who have refractory and relapsed myeloma fall into this group.

"At present, we don't have evidence on the benefit-to-risk ratio in that patient population, so I'd just put that bug in their ear to really try to focus on that group in the ongoing and future studies," Klepin said.

A randomized phase 3 confirmatory study, DREAMM-3, is underway to compare belantamab to a pomalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma who have received two or more prior lines of treatment, the FDA staff said in the briefing document.

Patients Exhaust Available Options

Even with recent advances in the treatment of multiple myeloma, this remains a disease in which available treatment options will be exhausted over time for most patients. Currently, as the disease advances, patients and their physicians reuse the same drug classes that were used in previous lines of therapy, and "with each subsequent relapse the progression-free survival is reduced," the FDA staff noted in the briefing document.

To date, 12 drugs have been approved for the treatment of multiple myeloma in the United States. Of these, five have been approved for people with relapsed and refractory disease who have received at least three prior therapies.

There are also more than 50 clinical trials of the use of chimeric antigen receptor (CAR) T-cell therapy for people who already have undergone repeated multiple myeloma treatments, according to a review published in the journal Leukemia. CAR T-cell therapy involves reengineering a patient's own cells, which are then reinjected in the body to fight cancer. The two products already on the market are for leukemia and lymphoma, both of which target CD19. Some of the CAR T cells in development for use in myeloma target BCMA, which is also the target for belantamab.

GlaxoSmithKline says belantamab is "a highly specific targeting mechanism for myeloma cells by binding to BCMA," according to the briefing document. GlaxoSmithKline says the drug kills "myeloma cells via a multi-modal mechanism of action that induces long-term responses."

However, FDA staff disagreed with GlaxoSmithKline's conclusion about the duration of response and also challenged the claim of specificity.

Belantamab "will target any hematopoietic cell that expresses BCMA, including myeloma cells," FDA staff said. It kills myeloma cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

Given the short duration of follow-up, the question of whether belantamab "induces long-term responses is still under review," the FDA said.

The novel approach used in belantamab piqued the interest of John DeFlice, MD, of Albuquerque, New Mexico, who served as the patient representative on the panel,

"It's a new class of drug for refractory and relapsed multiple myeloma with a positive benefit-risk profile and a drug that can be taken off the shelf," as opposed to requiring a special process, as CAR T-cell therapy does, DeFlice said. "So I wholeheartedly voted yes."

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