New, updated, data on belantamab mafodotin, also known as GSK2857916, an investigational anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC), were presented at the 24th Congress of the European Hematology Association (EHA) held in Amsterdam, The Netherlands, June 13 – 16, 2019.

Belantamab mafodotin (GSK2857916) is a humanized monoclonal anti-BCMA antibody (Belantamab or GSK2857914), which is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF). The payload of the ADC, MMAF, is a member of the dolastatin family of microtubule inhibitors, potent anti-tumor agents that can lead to immunogenic cell death (ICD), a type of cell death that stimulates host immune responses.[*]

Upon binding to B-cell maturation antigen (BCMA), a tumor necrosis factor receptor (TNFR) family member, selectively expressed on terminally differentiated B-lymphocytes including multiple myeloma (MM) tumor cells, the investigational drug is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released. In turn, this leads to direct cell death.

Prelinical results
In preclinical studies, belantamab mafodotin potently delayed tumor growth and promoted a durable complete regressions in vivo. The anti-tumor activity of the agent is associated with increased tumor T lymphocyte and DC infiltration and activation, and is abrogated upon depletion of CD8+ T cells.

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In an immune-competent setting imunogenic cell death (ICD) and engagement of the host immune system potentiate the anti-tumor activity of belantamab mafodotin, which constitutes a key mechanisms of activity. Based on the engagement of the host immune system, combinations with immuno-modulatory agonists such as anti-OX40 are expected to create a synergistic effect. As a result, scientists are planning to evaluate belantamab mafodotin in combination with an anti-OX40 agonist in the upcoming DREAMM-5 clinical trial.

First in human trial
The first-in-human study with belantamab mafodotin (DREAMM-1; BMA117159; NCT02064387) in patients with relapsed/refractory multiple myeloma was an open-label, 2-part Phase I study conducted in 9 centers across the United States, Canada and United Kingdom in adults with multiple myeloma and progressive disease after stem cell transplantation (or considered transplant ineligible), alkylators, proteasome inhibitors and immunomodulators.

In Part 1 of the trial patients were treated with the recommended dose of 3.4 mg/kg.  This part of the trial enrolled 38 patients with a mean (range) age of 59 (39–79) years. In Part 2 of the trial patients received belantamab mafodotin 3.4 mg/kg once every 3 weeks for up to 16 cycles (~1 year).

Overall, the scientists observed that belantamab mafodotin was well tolerated and demonstrated rapid deep and durable responses in heavily pre-treated patients with patients with relapsed/refractory multiple myeloma. The additional follow-up confirmed complete responses and considerably longer Progression Free Survival in the final analysis compared with interim analysis.

The study showed encouraging clinical responses, with an overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1–76.1), and progression-free survival of 12.0 months (95% confidence interval [CI] 3.1 to not estimable), a median duration of response of was 14.3 months (95% CI: 10.6–not estimable) and median time to first response of 1.2 months (95% CI: 0.7–1.4).

A confirmed overall response was observed in 18/32 (56.3%; 95% CI: 37.7–73.6) patients refractory to both immunomodulators (IMiD) and PI, 15/21 (71.4%; 95% CI: 47.8–88.7) patients without prior daratumumab treatment and 5/13 (38.5%; 95% CI: 13.9–68.4) patients refractory to both IMiD and PI with prior daratumumab treatment.

Adverse events
Corneal and thrombocytopenia are known toxicities of other MMAF-linked antibody-drug conjugates and in studies with belantamab mafodotin the observed adverse events were consistent with earlier findings with MMAF. The most frequently reported included corneal events (24/35; 69%), most commonly blurred vision (18/35; 51%), dry eye (13/35; 37%) and photophobia (10/35; 29%); the median duration (for patients with a resolution date [n=16]) was 35 days. The second-most frequent Adverse Event was thrombocytopenia (22/35; 63%). Treatment-related serious events were experienced by 7/35 (20%) patients, most commonly infusion-related reactions (2/35; 6.0%).

Qualitative research
Based the encouraging clinical responses observed, the scientists added a qualitative research component part to evaluate how patients experienced the treatment with the investigational agent and to help them develop strategies for future trials and increase the efficiency of the methodology, of these trials. [2]

The qualitative research component was added to part 2 of the trial. Patients were asked to complete bone pain and fatigue patient-reported outcomes diaries and an optional End of Treatment (EOT) interview. However, because the qualitative research was implemented via a protocol amendment, a majority of patients were already off-study and unavailable for participation.[2]

Reported qualitative results
The results demonstrated that patients treated with belantamab mafodotin 3.4 mg/kg once every 3 weeks as part of the DREAMM-1 study reported improvements in fatigue and bone pain based on patient diaries and EOT interviews. And while most patients experienced visual symptoms, they were generally manageable and ongoing improvements were commonly reported after stopping the treatment.

The reported outcomes from the interim analysis of the EOT interview demonstrated high levels of treatment satisfaction. Patients also reported that treatment was generally described as manageable and having less impact on daily life compared with previous treatments.

While the study was limited as a result of the small sample sizes, the combination of qualitative and quantitative data provides valuable preliminary insight into the patient experience of belantamab mafodotin. This will scientists in the developments of future studies with is investigational agent and help them understand the impact of treatment belantamab mafodotin on patient’s symptoms, functioning and the tolerability of the drug.

[*] Drug linker technology used in the novel trial agent is licensed from Seattle Genetics, while the antibody was produced using POTELLIGENT® Technology licensed from BioWa.

[1] Montes De Oca R, Bhattacharya S, Vitali N, et. al. The Anti-BCMA Antibody-Drug Conjugate GSK2857916 Drives Immunogenic Cell Death and Immune-Mediated Anti-Tumor Responses, and in Combination with an OX40 Agonist Potentiates in Vivo Activity. Abstract #PF558. presented during the 24th Congress of the European Hematology Association (EHA) held in Amsterdam, The Netherlands, June 13 – 16, 2019. [Poster]
[2] Popat R, Opalinska L, Eliason J, et. al. Patient Reported Experience from Part 2 of the First Time in Human Study of the BCMA Antibody-Drug Conjugate GSK2857916 for Advanced Relapsed Refractory Multiple Myeloma (DREAMM-1) Abstract #PS1401, presented during the 24th Congress of the European Hematology Association (EHA) held in Amsterdam, The Netherlands, June 13 – 16, 2019. [Poster]
[3] Popat R, Lendvai S, Trudel PM, et. al B-cell Maturation Antigen Antibody-Drug Conjugate (ADC), GSK2857916, in Relapsed/Refractory Multiple Myeloma (RRMM): Final Safety, Efficacy and Pharmacokinetic (PK) Analyses From a Pivotal Phase I Study. Abstract #PS1372 presented during the 24th Congress of the European Hematology Association (EHA) held in Amsterdam, The Netherlands, June 13 – 16, 2019.[Poster]]

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