Saad Z. Usmani, MD
The CD38 monoclonal antibody daratumumab (Darzalex) demonstrated a 31% overall response rate (ORR) as monotherapy for patients with heavily pretreated multiple myeloma, according to a combined analysis of two pivotal studies presented at the 2015 ASH Annual Meeting.
In combined data from the GEN501 and SIRIUS studies, the rate of complete response plus very good partial response was 13% for patients treated with daratumumab at 16 mg/kg. The 12-month progression-free survival (PFS) rate was 50% (95% CI, 33.6-63.9) and median overall survival (OS) was 19.9 months (95% CI, 15.1-not evaluable).
“As a single agent, daratumumab induced rapid, deep, and durable responses in a heavily pretreated/highly refractory population,” said lead investigator Saad Z. Usmani, MD, Levine Cancer Institute/Carolinas Healthcare System. “Remarkable depth of response was observed in patients refractory to newer agents, including pomalidomide and carfilzomib.”
On November 16, 2015, the FDA granted an accelerated approval to daratumumab as a monotherapy for patients with multiple myeloma following at least 3 prior therapies, based on findings from the GEN501 and SIRIUS trials. The combined analysis of these studies represents an update to previously published data.
In the SIRIUS study, the first 34 patients enrolled received daratumumab at 16 mg/kg (n = 16) or 8 mg/kg (n = 18). After a response evaluation, the 16 mg/kg dose was selected for future study, with an additional 90 patients enrolled at this dose (N = 106). In the GEN501 study, 32 patients were treated with daratumumab at various doses, in order to find a recommended dose and schedule. In the second phase of the trial, 72 patients received daratumumab at either 8 mg/kg (n = 30) or 16 mg/kg (n = 42).
Data from patients treated with the 16 mg/kg dose from across the two trials were examined for the ASH analysis (N = 148). The median age of patients across the combined analysis was 64 years, with 46% over the age of 65. The median number of prior therapies was 5.1 (range, 0.8-23.8).
Prior to entering the study, patients had received bortezomib (99%), carfilzomib (41%), lenalidomide (99%), pomalidomide (55%), and thalidomide (45%). A majority of patients (91%) were refractory to their last line of therapy, including carfilzomib (39%) and pomalidomide (55%).
In the combined analysis, the median duration of treatment was 3.4 months (range, 0-20). The median number of infusions of daratumumab was 12 (range, 1-33). At the time of the analysis, 86% of patients had discontinued treatment, primarily due to progressive disease (77%).
Of the 46 patients who responded, 40 were still alive at a median follow-up of 14.8 months (87%). The median duration of response was 7.6 months. In addition to responses, 6% of patients experienced a minimal response (MR) and 46% had stable disease (SD).
In responders, the median PFS was not evaluable. For those with MR/SD, the median PFS was 3.2 months. For those with progressive disease, PFS was 0.9 months.
The 1-year OS rate was 69% (95% CI, 60.4-75.6). The median OS could not be estimated in patients who responded to daratumumab. In the MR/SD arm, the median OS was 17.5 months, which is double what has traditionally been seen for patients with relapsed/refractory multiple myeloma, according to Usmani.
"Daratumumab conferred an OS benefit, even in patients who achieved stable disease or minimal response," said Usmani. "Daratumumab has immune-mediated and immunomodulatory mechanisms that may be contributing to a survival benefit."
Independently, in the phase II SIRIUS study, daratumumab demonstrated a 65% one-year OS rate and a 29.2% ORR. In the phase I/II GEN501 study, the ORR was 36%, median PFS was 5.6 months (95% CI, 4.2-8.1), and the one-year OS rate was 77% (95% CI, 58-88).
"Updated analysis of the combined dataset of GEN501 and SIRIUS did not identify any new safety signals," according to Usmani.
Adverse events (AEs) in the combined analysis were similar to what had been seen in the two individual studies. The most frequent all-grade AEs were fatigue (41%), nausea (28%), anemia (28%), back pain (24%), cough (22%), neutropenia (20%), thrombocytopenia (20%), and upper respiratory tract infection (20%).
The most common treatment-related grade ≥3 AEs were anemia (18%), thrombocytopenia (14%), neutropenia (10%), fatigue (2%), back pain (2%), and upper respiratory tract infection (<1%). Overall, 48% of patients experienced infusion-related reactions, which primary occurred with the first infusion.
In addition to single-agent activity, daratumumab is also being explored in a number of combination studies. At this time, several phase III clinical trials are looking at the antibody in various treatment settings.