European Commission Grants Conditional Marketing Authorization to GSK for the Use of Belantamab Mafodotin in Patients with Multiple Myeloma

The European Commission has granted conditional marketing authorization* for the use of GlaxoSmithKline’s anti-B-cell maturation antigen (BCMA) therapy belantamab mafodotin (Blenrep®) as monotherapy for the treatment of adult patients with multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

The European approval follows the recent approval of belantamab mafodotin by the U.S. Food and Drug Administration (FDA).

Belantamab mafodotin is a first-in-class humanized anti-BCMA treatment for patients whose disease has progressed despite the current standard of care. The novel antibody-drug conjugate includes an afucosylated, humanized anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent maleimidocaproyl monomethyl auristatin F  (mcMMAF) via a non-cleavable linker, resulting in a multi-faceted mechanism of action. [1][2]

Multiple myeloma is the second most common blood cancer. Each year approximately 48,000 new cases of multiple myeloma diagnosed across Europe.[3] Hence, research into new treatments is needed as most patients will relapse or become refractory to available therapies.[4] Belantamab mafodotin is one potential treatment that may meet the unmet medical needs of these patients.

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The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival. BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.[5]

Belantamab mafodotin is directed towards BCMA, a cell-surface protein that plays an important role in the survival of plasma cells and is expressed on multiple myeloma cells. The antibody-drug conjugate binds to BCMA on myeloma cell surfaces causing cell cycle arrest and inducing antibody-dependent cellular cytotoxicity.

According to the summary of opinion issued the Committee for Medicinal Products for Human Use (CHMP) in July 2020, the benefit [of treating patients] with belantamab mafodotin is its ability to provide durable responses in patients with relapsed and refractory multiple myeloma.

An important step
“The approval of [belantamab mafodotin] marks an important step forward for patients in Europe where nearly 50,000 new cases of multiple myeloma are diagnosed each year,” said Hal Barron, M.D., Chief Scientific Officer, and President R&D, GSK.

“Unfortunately, most of these patients will relapse or stop responding to current therapies so I am pleased that today’s news will give patients with limited treatment options access to the first approved anti-BCMA therapy,” Hall added.

DREAMM-2 studies
The approval by the European Commission is based on data from the pivotal DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2-) study, including 13-month follow-up data. These data demonstrated that treatment with single-agent belantamab mafodotin, administered as a 2.5 mg/kg dose every three weeks (Q3W), resulted in an overall response rate of 32%. The median duration of response was 11 months and the median overall survival was 13.7 months.

Adverse events
The safety and tolerability profile was consistent with previously reported data on belantamab mafodotin.

The most commonly reported adverse events (in ≥30% of patients) in the 2.5 mg/kg arm (greater than or equal to 20%) were keratopathy/microcyst-like epithelial changes or MECs (71%), thrombocytopenia (38%), anaemia (27%), blurred vision events (25%), nausea (25%), pyrexia (23%), increased aspartate aminotransferase (AST) (21%), infusion-related reactions (21%), and lymphopenia (20%).

To limit the potential adverse events following treatment with belantamab mafodotin,  ophthalmic examinations, including assessment of visual acuity and slit-lamp examination, should be performed at baseline, before the subsequent 3 treatment cycles and during treatment as clinically indicated. Furthermore, patients experiencing corneal adverse reactions may require dose modifications or treatment discontinuation based on the severity of the findings.

In clinical trials, cases of corneal ulcers, including ulcerative and infective keratitis have been reported with the treatment with belantamab mafodotin. Physicians should manage these cases promptly by interrupting treatment with belantamab mafodotin until the corneal ulcer has healed.

Also, due to the risk of thrombocytopenic events, physicians should obtain a complete blood count at baseline and monitor patients during treatment. Patients on concomitant anticoagulant treatments may require more frequent monitoring and should be managed with a dose delay or reductions. If a moderate or severe infusion-related reaction occurs, interrupt the infusion and provide supportive treatment. Once symptoms resolve, physicians can resume treatment with belantamab mafodotin at a lower infusion rate. However, if anaphylactic or life-threatening infusion reactions occur, treatment with belantamab mafodotin should be permanently discontinued.

Advances
“Despite advances in treatment, multiple myeloma remains incurable and patients continue to cycle through therapies, with their prognosis worsening with each relapse,” noted Katja Christina Weisel, M.D., Deputy Director and Associate Professor of Haematology/Oncology in the Department of Oncology, Haematology and Bone Marrow Transplantation with Department of Pneumonology, University Medical Centre Hamburg-Eppendorf in Germany and an investigator for the DREAMM-2 trial.

A novel mechanism of action
“The approval of belantamab mafodotin, with its novel mechanism of action, represents a new class of treatment that patients can turn to when their cancer stops responding to another standard of care options,” Weisel explained

Brian G.M. Durie, Chairman of the Board of the International Myeloma Foundation, added: “The European Commission’s (EU) approval of belantamab mafodotin is good news for patients with refractory multiple myeloma whose cancer continues to progress and are in dire need of new treatment options. We appreciate GSK’s efforts to bring this new therapy to patients in the EU and for the commitment to addressing the needs of the multiple myeloma community.”

Previous regulatory decisions
Belantamab mafodotin was granted PRIME designation in 2017 and the Conditional Marketing Authorisation Application was reviewed under European Medicines Agency’s accelerated assessment procedure, which is given if the EMA’s Committee for Medicinal Products for Human Use determines the treatment is of major interest from a public health perspective and represents a therapeutic innovation.

Earlier this month, the US Food and Drug Administration approved belantamab mafodotin as a monotherapy treatment for adult patients 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, following a priority review for the company’s Biologics License Application (BLA)

Notes
* A conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required. GSK, as the marketing authorization holder for belantamab mafodotin, is likely to provide comprehensive clinical data at a later stage.

Highlights of prescribing information
Belantamab mafodotin (Blenrep®) – Highlights of Prescribing Information (USA)

Reference
[1] NCI Drug Dictionary – Anti-BCMA Antibody-Drug Conjugate GSK2857916. National Cancer Institute. Online. Last accessed on August 25, 2020.
[2] Trudel S, Lendvai N, Popat R, et al. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose-expansion phase I study. Blood Cancer Journal. 2019;9(4). DOI:10.1038/s41408-019-0196-6.
[3] Multiple Myeloma. World Health Organization International Agency for Research on Cancer. https://gco.iarc.fr/today/data/factsheets/cancers/35-Multiple-myeloma-fact-sheet.pdf. Accessed August 2020.
[4] Nooka A, Kastritis E, Dimopoulos M, Lonial S. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20):3085-3099. DOI:10.1182/blood-2014-11-568923.
[5] Lonial, S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomized, open-label, phase 2 study. Lancet Oncol. 2020; 21(2):207–21.

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