Results of the phase II DREAMM-2 trial recently published in The Lancet Oncology showed that the investigational agent belantamab mafodotin induced response rates above 30% and had a manageable safety profile in patients with heavily pretreated multiple myeloma.
Sagar Lonial, MD
Results of the phase II DREAMM-2 trial recently published inThe Lancet Oncologyshowed that the investigational agent belantamab mafodotin (GSK2857916) induced response rates above 30% and had a manageable safety profile in patients with heavily pretreated multiple myeloma.1
Belantamab mafodotin is an immunoconjugate targeting B-cell maturation antigen (BCMA) that has shown activity as a single agent in relapsed or refractory multiple myeloma in a phase I trial (NCT02064387).
“The data published today from DREAMM-2 not only reinforce the significance of BCMA as a potentially viable target, but also underscore the potential of belantamab mafodotin, if approved, as a practical treatment option in this patient population,” Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute at Emory University and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia, said in a press release.
DREAMM-2 is an open-label, 2-arm trial that recruited patients with relapsed or refractory disease with progression after 3 or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant, or both, to an anti-CD38 monoclonal antibody. Patients were randomized to receive 2 separate doses of the agent, either 2.5 mg/kg or 3.4 mg/kg, via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity.2
All patients had an ECOG performance status ≤2 and were stratified by previous lines of therapy and cytogenetics. Patients received a median of 7 prior lines of therapy in the 2.5-mg/kg arm and 6 prior lines in the 3.4-mg/kg group. Patients with high-risk cytogenetic features represented 42% and 47% of patients, respectively. High-risk features included the t(4;14) and t(14;16) translocations.
The overall response rate in each group exceeded 30%, with 31% of patients receiving 2.5 mg/kg (n = 97) and 34% of patients receiving 3.4 mg/kg (n = 99) achieving a response. Corresponding rates of very good partial response or better were 19% and 20%.
At the median duration of follow-up in each group, which was 6.3 months in the 2.5-mg/kg group and 6.9 months in the 3.4-mg/kg group, the median duration of response had not yet been reached. The probability of have a response lasting 4 months or longer was estimated to be 78% and 87%, respectively. Median progression-free survival was 2.9 months (95% CI, 2.1-3.7) in patients receiving 2.5 mg/kg and 4.9 months (95% CI, 2.3-6.2) in the group getting 3.4 mg/kg.
As of the data cutoff of June 21, 2019, 47 patients, 22 in the 2.5-mg/kg group (23%) and 25 in the 3.4-mg/kg group (25%), were still receiving study treatment. Patients in both groups received a median of 3 treatment cycles.
At least 1 adverse events (AEs) of any grade was observed in all patients, excluding 2 who were in the 2.5-mg/kg arm. AEs leading to dose delay were reported in 54% of patients in this group versus 62% of patients receiving 3.4 mg/kg, with dose reductions occurring in 29% and 41%, respectively. Corresponding rates of permanent treatment discontinuation due to AEs were 8% and 10%.
There were 2 deaths that the study investigators concluded could have been a result of study treatment. One was a case of sepsis in the 2.5-mg/kg group and the other was a case of hemophagocytic lymphohistiocytosis.
Infusion-related reactions were mostly limited to grade 1/2 events and occurred with the first infusion, with 18% of patients receiving 2.5 mg/kg and 15% of those receiving 3.4 kg/mg falling into this category. One patient in the 2.5-mg/kg arm had a grade 3 infusion-related reaction that led to discontinued treatment.
Keratopathy, or corneal epithelium changes observed by ophthalmic examination, was the most commonly observed AE was keratopathy, as well as the most prevalent cause of permanent treatment discontinuation. Grade 3/4 keratopathy was observed in 27% and 21% of patients in the 2.5-mg-kg and 3.4-mg/kg groups, respectively. Grade 3/4 thrombocytopenia (20% and 33%) and anemia (20% and 25%) were also common. Serious adverse events occurred at rates of 40% and 47%, respectively. The frequency of grade ≥3 pneumonia and upper respiratory tract infections was low.
An ocular substudy was performed in 30 patients to evaluate the efficacy of corticosteroid eye drops on keratopathy and patient-reported corneal-related symptoms in 1eye, with postbaseline data available in 29. In patients treated with 2.5 mg/kg, the rate of grade 3 events was 29% in the treated eye versus 18% in the untreated eye. In patients receiving 3.4 mg/kg, the rates of grade 3 events were 42% and 50%, respectively. The study investigators subsequently concluded that these suggest that corticosteroid eye drops are an ineffective prophylaxis for the development of change to the corneal epithelium.
Based on these data, GlaxoSmithKline, the company responsible for the agent’s development, will be moving forward with a submission to the FDA seeking approval of the 2.5 mg/kg dose. If it is approved, belantamab mafodotin will become the first BCMA targeting agent available to treating physicians in the United States.
In November 2017,GSK2857916 was granted breakthrough therapy designation by the FDA and a PRIME designation by the European Medicines Agencyfor the treatment of patients with relapsed/refractory multiple myeloma. Both designations are granted to expedite the development and review of agents in the United States and the European Union, respectively.
The open-label, randomized phase III DREAMM-3 trial evaluating the efficacy and safety of belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma has an estimated study start date of December 17, 2019 and will enroll approximately 380 participants (NCT04162210).