Featured Image: Doctor explaining clinical trial to patient. Courtesy: © 2019. Fotolia Used with permission.

Earlier today positive headline results from the pivotal DREAMM-2 open-label, randomized study of two doses of belantamab mafodotin (GSK2857916), an anti-BCMA antibody-drug conjugate or ADC, being developed by GlaxoSmithKline for the treatment of patients with multiple myeloma, were released.

The study results show that in the DREAMM-2 trial of the investigational drug met it’s primary endpoint, demonstrating a clinically meaningful overall response rate (ORR) in patients with relapsed/refractory multiple myeloma.

Based on these results, belantamab mafodotin is on track for regulatory submission by the end of 2019.

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Belantamab mafodotin is being investigated in the DREAMM clinical trial program. The novel agent includes a humanized anti-B cell maturation antigen (BCMA) monoclonal antibody (mAb) conjugated to the cytotoxic agent auristatin F via non-cleavable linker. The drug linker technology used in this agent is licensed from Seattle Genetics while the monoclonal antibody is produced using technology licensed from BioWa.[1]

In 2017, belantamab mafodotin was awarded Breakthrough Therapy designation from the U.S. Food and Drug Administration and PRIME designation from the European Medicines Agency. These designations are intended to facilitate development of investigational medicines that have shown clinical promise for conditions where there is significant unmet need.

In June, during a presentation at the annual meeting of the American Society of Clinical Oncology, Sagar Lonial, MD, FACP, Chief Medical Officer at the Winship Cancer Institute at Emory University in Atlanta, noted: “In earlier trials, both phase I and phase II, belantamab mafodotin demonstrated a 60% overall response rate (ORR), and some of those responses are quite durable, with a recent update demonstrating about a 12-month progression-free survival.”

Side effects
The most common adverse events see in clinical trials belantamab mafodotin included limited suppression of the blood counts as well as corneal or eye toxicities. According to Lonial, “while these side effects are definitely a nuisance, they appear to be reversible.”

DREAMM-2 Trial
The 196 patients in the trial had relapsed multiple myeloma, were refractory to an immunomodulatory drug, a proteasome inhibitor, and to treatment with an anti-CD38 antibody. The two-arm study met its primary objective and demonstrated a clinically meaningful overall response rate with belantamab mafodotin in the participating patient population. The safety and tolerability profile was consistent with that observed in DREAMM-1, the first time in human study of belantamab mafodotin.

Hal V. Barron. MD, joined GSK as Chief Scientific Officer and President, R&D on 1 January 2018. He is a member of the Board and the Corporate Executive Team.

“I am pleased with the results of the DREAMM-2 study and excited about what these data could mean for patients with multiple myeloma who have exhausted other lines of treatment. We are on track to file belantamab mafodotin later this year and continue to investigate how it could help even more patients with this disease,” noted Hal V. Barron, Chief Scientific Officer and President R&D, GSK.

Data from the DREAMM-2 study will be the basis for regulatory filings starting later this year.

Common blood cancer
Multiple myeloma, a plasma cell malignancy characterized by clonal proliferation of plasma cells within the bone marrow, is the second most common blood cancer and is generally considered treatable, but not curable. The disease accounts for approximately 1% of all cancers and for 10% of all hematologic malignancies. This presents a major medical need and research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments. [1]

The latest safety and efficacy results from the DREAMM-2 study will be submitted for presentation at an upcoming scientific meeting. Additional ongoing studies are testing the effect of belantamab mafodotin as third-line monotherapy in relapsed/refractory multiple myeloma and as a combination treatment in the first and second line setting as part of the broader DREAMM clinical development program.

B-cell maturation antigen
The restricted expression pattern of BCMA also known as TNFRSF17 or CD269, makes it an ideal tumor associated antigen or TAA for the treatment of myeloma. [2]

The normal function of BCMA, a cell surface protein expressed on a subset of B cells and mature plasma cells, 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.[3]

Clinical trials
DREAM-1 (NCT02064387) – Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of GSK2857916
DREAM-2 (NCT03525678) – A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Subjects With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody

References
[1] Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, Richardson PG, Hoos A, 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 J. 2019 Mar 20;9(4):37. doi: 10.1038/s41408-019-0196-6. [PubMed][Article]
[2] Panowski SH, Kuo TC, Zhang Y, Chen A, Geng T, Aschenbrenner L, Kamperschroer C, Pascua E, et al. Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma. Mol Cancer Ther. 2019 Aug 21. pii: molcanther.0007.2019. doi: 10.1158/1535-7163.MCT-19-0007.[Pubmed][Article]
[3] Sanchez E, Smith EJ, Yashar MA, Patil S, Li M, Porter AL, Tanenbaum EJ, Schlossberg RE, et al. The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma. Target Oncol. 2018 Feb;13(1):39-47. doi: 10.1007/s11523-017-0538-x