Antibody-drug conjugates continue their victory march

Benlatamab mafodotin, a BCMA-targeting antibody drug conjugate, significantly delays the progression of pre-treated or relapsed multiple myeloma – two major studies found. In one of them, the investigated ADC outperformed the standard therapy by nearly two years, increasing patients’ survival from 73% to 84% at 18 months.
Unfortunately the high efficacy of this ADC was offset by severe eye-related adverse reactions, which occur in almost all treated patients.
Benlatamab was previously approved as a fifth-line therapy but later withdrawn due to lack of efficacy in monotherapy. Having demonstrated benefits in second-line treatment, the manufacturer now hopes to regain approval.

It took nearly one hundred years for Paul Ehrlich’s vision of “magic bullets” to become true. The famous Nobel laureate conceived the idea of targeted treatment – a drug that eliminates tumor cells, while ignoring the healthy ones. This concept became a reality in the 1980s, with the introduction of highly specific monoclonal antibodies, followed in 2001 by the approval of first antibody-drug conjugate (ADC). As of 2024, there are now 14 US-approved ADCs and this number grows rapidly each year. New studies showing their vast benefits in the treatment of various cancers are published almost every month.

The victory march of ADCs continues unabated. The New England Journal of Medicine has recently published positive results from two Phase III studies of yet another ADC – belantamab mafodotin developed by GlaxoSmithKline. Both studies enrolled patients with multiple myeloma, who had relapsed or not responded to the first-line therapy. Early-stage trials had already pointed to significant activity in this cancer and now the larger studies have confirmed their findings with more robust endpoints. In the first study, abbreviated as DREAMM-7, belantamab delayed disease progression by nearly two years compared to standard therapy (36.6 versus 13.4 months) and improved patients’ survival (84% vs 73% patients alive at 18 months). The results of the second study, DREAMM-8, were similarly impressive with the time to disease progression or death almost doubled on ADC (10.3 vs 5.5 months). Overall survival rate followed the same trend as in the first trial (83% vs 76% at 12 months).

In both reported studies, patients in the control group received the standard treatment regimen, which itself is highly effective against multiple myeloma. It included bortezomib, a proteasome inhibitor, which in combination with two other drugs induced a complete response in 16% of DREAMM-8 trial participants. In the active arm, bortezomib was replaced with benlatamab mafodotin, boosting the response rate to 40%.

However, high efficacy of benlatamab comes at great cost. The drug impairs vision in nearly all treated patients (79% in DREAMM-7 and 89% in DREAMM-8). Visual acuity is compromised, image becomes blurry and painful corneal ulcers may form. The good news is that these events respond to dose modifications and mostly resolve after the drug discontinuation. Apart from vision deterioration, benlatamab was found to increase the risk of neutropenia and infections. Nevertheless, the substantial benefits in terms of delayed disease progression and improved survival seem to outweigh these severe but mainly transient side effects. Still, serious eye-related toxicities have raised concerns among oncologists, potentially limiting its broader application.

Benlatamab mafodotin consists of a humanized monoclonal antibody targeting the B-cell maturation antigen (BCMA) conjugated to a cytotoxic drug mcMMAF (maleimidocaproyl monomethyl auristatin F). Release of this chemical in the vicinity of tumor cells causes cell cycle arrest and the binding between mAb and BCMA induces antibody-dependent cellular cytotoxicity.

The regulatory history of benlatamab mafodotin has been quite complicated. Its approval as a fifth-line therapy for multiple myeloma, granted in 2020, was revoked in 2023 after failure in a confirmatory study that evaluated the drug as a standalone treatment. However, following the release of DREAMM-7 and -8 trial results, GSK hopes to reclaim approval, this time as a second-line combination therapy. The return of benlatamab to the EU- and US- markets and upgrade from fifth- to second-line treatment could turn upside down the current financial projections, which estimate only $56 mln sales by 2029

Prepared by:

Adam Tuszyner

Sources and further reading

Hungria, Vania, et al. “Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.” New England Journal of Medicine (2024).
Dimopoulos, Meletios Athanasios, et al. “Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma.” New England Journal of Medicine (2024).
Clinical Trials Arena “New hope for GSK’s once potential ADC blockbuster Blenrep.” (February 8, 2024). Link: https://www.clinicaltrialsarena.com/analyst-comment/new-hope-for-gsk-once-potential-adc-blockbuster-blenrep/.
Liu, Kaifeng, et al. “A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers.” Molecular Cancer 23.1 (2024): 62.