Suzanne Trudel, MD
The B-cell maturation antigen (BCMA) antibody-drug conjugate GSK2857916 induced an overall response rate (ORR) of 60% in heavily pretreated patients with multiple myeloma, according to findings from the phase I DREAMM-1 study presented at the 2017 ASH Annual Meeting.
The 60% (n = 21; 95% CI, 42.1-76.1) ORR included, 2 complete responses (CRs), 1 stringent CR, 15 very good partial responses, and 3 partial responses. The median progression-free survival was 7.9 months (95% CI, 3.1 to NE).
In November 2017, the FDA granted GSK2857916 a breakthrough therapy designation for the treatment of patients with relapsed/refractory multiple myeloma who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD).
“GSK2857916 induces high responses that are deep and durable…and also shows unprecedented progression-free survival compared to any approved drug in this heavily pretreated patient population,” lead author Suzanne Trudel, MD, University of Toronto, Princess Margaret Cancer Centre, said when presenting the data at ASH.
The 2 part DREAMM-1 (BMA117159) trial accrued patients with relapsed/refractory multiple myeloma who had undergone stem cell transplant (if eligible), and had prior treatment with ≥3 classes or alkylators, PIs, and IMiDs. Patients had to have progression on or within 60 days of completion of their last therapy and measurable disease.
BCMA expression was not required for eligibility, patients had an ECOG performance status of 0 or 1, and albuminuria ≤500 mg per 24 hours. Premedication for infusion reactions was not permitted with the first dose and was not mandated at subsequent doses.
Part 1 of the study was a dose-escalation phase, which enrolled 38 patients. Results from this phase were presented at the 2016 ASH Annual Meeting. There were no dose-limiting toxicities experienced and the dose chosen for phase II was 3.4 mg/kg administered as a 1-hr infusion once every 3 weeks for up to 16 cycles (1 year).
The part 2 ongoing expansion phase included 2 cohorts. Cohort 1 has completed enrollment with 35 patients with relapsed/refractory multiple myeloma. The second cohort is enrolling patients with BCMA-positive relapsed diffuse large B-cell lymphoma or follicular lymphoma, and has thus far enrolled 6 of its goal of 10 patients.
The data Trudel presented at ASH were for the 35 myeloma patients in cohort 1 of the part 2 expansion phase. The median patient age was 60 (range, 46-75) and 57% of patients had received ≥5 prior lines of therapy. Thirty percent of patients were considered high risk based on local lab cytogenetics.
All patients had received an IMiD and a PI, and 89% of patients were double refractory to both of these classes of treatments. Forty percent of patients had received daratumumab (Darzalex) and all but one were refractory to the monoclonal antibody. Thirty-four percent of patients were double-refractory to IMiD/PI and had received daratumumab.
At the June 26, 2017, data cutoff, 49% (n = 17) of patients were still receiving study treatment. Among the 18 patients who discontinued, the reasons included disease progression (n = 15), adverse event (AE; n = 2), and decision by subject or proxy (n = 1).
The median follow-up was 6.6 months (range, 1-10) and the median number of infusions administered was 5 (range, 1-13). The median duration of response for responding patients has not yet been reached (95% CI, 6.7 to NE).
The ORR was 43% (6/14) among patients with prior daratumumab, 58% (18/31) in patients double refractory to IMiD and PI, and 42% (5/12) in double-refractory IMiD/PI patients with daratumumab exposure.
“Responses occurred early—usually within 1 or 2 doses—and in most cases, were durable, and dose reductions did not lead to loss of response,” noted Trudel.
All patients experienced an AE, 80% had grade 3/4 AEs, and 14% had a serious AE related to study treatment. Infusion-related reactions occurred in 23% of patients. Dose-modification was required in approximately two-thirds of patients, the majority of which were related to corneal toxicity or thrombocytopenia.
The most frequent grade ≥3 AEs were thrombocytopenia (34%) and anemia (14%). There were no patient deaths.
Of note, one of the most common toxicities was corneal events, including grade 3 cases of dry eye (n = 1), keratitis (n = 2), and eye pain (n = 1). The median time to onset of corneal events was 23 days (2 doses). There were no grade 4 events and no patients discontinued treatment due to corneal toxicities. The median time to resolution of corneal events was 30 days.
GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. The treatment exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation of the FC domain which increases affinity to FCγRIIIa expressed on immune effector cells.
“The target and the therapeutic mechanisms of action [of GSK2857916] are unique compared to all approved drugs, and the mechanisms of action lends [the drug] to combination strategies, particularly with immuno-oncology drugs,” said Trudel.
Beyond the ongoing DREAMM-1 study, additional single-agent and combination trials are planned.
Trudel S, MD, Lendvai N, Popat R, et al. Deep and durable responses in patients (Pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 741.