A Look Back at FDA News from January 2020
February 08, 2020 07:00pm
By Danielle Ternyila
The FDA has approved the use of daratumumab in combination with hyaluronidase-fihj (Darzalex Faspro) for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma. The newly approved product allowed for subcutaneous dosing of daratumumab.
The FDA has approved the use of daratumumab in combination with hyaluronidase-fihj (Darzalex Faspro) for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma. The newly approved product allowed for subcutaneous dosing of daratumumab.1
The regimen is approved for use: 1) in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) in newly diagnosed patients who are ineligible for autologous stem cell transplant (ASCT); 2) in combination with lenalidomide (Revlimid) and dexamethasone (Rd) in newly diagnosed patients who are ineligible for ASCT and in patients with relapsed or refractory multiple myeloma who have received ≥1 prior therapy; 3) in combination with bortezomib and dexamethasone (Vd) in patients who have received ≥1 prior therapy; and 4) as a monotherapy in patients who have received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double-refractory to a PI and an IMiD. None of these indications were previously unavailable with the intravenous formulation of daratumumab.
“The approval of the subcutaneous formulation of daratumumab, Darzalex Faspro, is a landmark event in the development of daratumumab. Not only is it now the first and only subcutaneous CD38 antibody approved for the treatment of multiple myeloma, the subcutaneous administration of Darzalex Faspro considerably reduces treatment burden, as the fixed-dose injection is administered in approximately three to five minutes, offering patients a more convenient treatment experience. As seen in the pivotal study supporting the approval, this reduction in infusion time from hours to minutes led to higher satisfaction levels for patients and in addition, infusion-related reactions were both mild and significantly reduced with this formulation of daratumumab,” said Jan van de Winkel, PhD, CEO of Genmab, in a statement.2 “We are very much looking forward to the launch of Darzalex Faspro in the US and the potential for positive impact it will have on the lives of the patients receiving the drug.”
Data from both the COLUMBA and PLEIADES trials supported the approval for Darzalex Faspro in these indications.
Findings from the phase III COLUMBA trial (NT03277105) supported the approval for the fourth indication showing an objective response rate of 41.1% with the use of daratumumab and hyaluronidase-fihj compared with 37.1% for intravenous daratumumab (risk ratio, 1.11; 95% CI, 0.89-1.37). An improved safety profile was also found with the subcutaneous dosing of daratumumab.
The multicenter, open-label, non-inferiority, randomized trial explored the potential of subcutaneous daratumumab as a more convenient formulation for administering daratumumab in comparison with the intravenous formulation. Patients with relapsed or refractory multiple myeloma who had received ≥3 prior lines of therapy or were double refractory to both a PI and IMiD were included in the study.
A total of 522 patients were randomized to the subcutaneous group (n = 263) or the intravenous group (n = 259). In the subcutaneous arm, patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20. In the intravenous arm, patients received 16 mg/kg of intravenous daratumumab once weekly for the first two 28-day cycles, then every 2 weeks for the next 4 cycles, and every 4 weeks thereafter until progressive disease or unacceptable toxicity.3
The co-primary end points were overall response rate and maximum trough concentration (Ctrough) on cycle 3, day 1. The non-inferiority margin for overall response was define with a 60% retention of the lower bound (20.8%) of the 95% confidence interval.
Patients were followed for a median of 7.5 months (range, 6.5-9.3) before the end points met the predefined criteria for non-inferiority. As of this point, 296 patients had discontinued treatment, 43% in the subcutaneous arm due to progressive disease and 44% in the intravenous group due to progressive disease. Patients received a median of 6 cycles in each arm.
The maximum Ctrough was 593 µg/mL (standard derivation [SD], 306) in the subcutaneous arm versus 522 µg/mL (SD, 226) in the intravenous arm. The geometric means ratio of maximum Ctrough was 107.93% in the subcutaneous group, with the lower limit of the 90% confidence interval surpassing 80%, which met the non-inferiority criterion.
The median progression-free survival was 5.6 months with the subcutaneous formulation versus 6.1 months with the intravenous formulation (HR, 0.99; 95% CI, 0.78-1.26; P = .93). Overall survival data were not mature at cutoff but favored subcutaneous daratumumab (HR, 0.90; 95% CI, 0.59-1.35; P = .60).
The rate of infusion-related reactions was lower in the subcutaneous daratumumab group as compared with the intravenous group (13% vs 34%; odds ratio, 0.28; 95% CI, 0.18-0.44; P <.0001), with the most common events being chills (5% vs 12%, respectively), pyrexia (5% vs 3%), and dyspnea (1% vs 7%). Grade 3 infusion-related reactions were observed in 2% and 5% of patients in the subcutaneous and intravenous arms, respectively.
Another study, PLEIADES (NCT03412565), evaluated the efficacy of daratumumab and hyaluronidase-fihj in 3 combinations: with VMP, RD, or bortezomib, lenalidomide, and dexamethasone (VRd). Patients with newly diagnosed multiple myeloma who were ineligible for transplant received D-VMP, whereas patients who had received ≥1 prior therapy received D-Rd. The ORR observed in the D-VMP cohort was 88.1% (90% CI, 77.8%-94.7%). In the D-Rd cohort, the ORR was 90.8% (90% CI, 82.6%-95.9%). In both cohorts, the complete response (CR) rate, duration of response (DOR), and MRD-negativity rate had not yet been reached at the time the data were presented at the 2019 International Myeloma Workshop.4
A notable safety signal seen with both combination regimens was all-grade injection-site reactions, which occurred in 7.5% of patients across all cohorts of the study. In terms of treatment-emergent adverse events (TEAEs), 68.7% of patients in the D-VMP cohort experienced a grade 3 or 4 event, as did 78.5% of the D-Rd cohort. In all cohort, 5% of patients discontinued treatment due to a TEAE. Overall, the study investigators determined that the safety profile of all combination in the study were consistent with known safety of daratumumab and the backbone standard-of care regimens.
PLEIADES is an ongoing multi-cohort, open‑label, phase II trial which is primarily assessing ORR and very good partial response with D-VMP, D-Rd, and D-Kd in patients with multiple myeloma. The key secondary end points of the study include CR rate, DOR, and MRD. The study has accrued the target 265 patients to continue its investigation.
The most common adverse events (≥20%) reported with Darzalex Faspro monotherapy is upper respiratory tract infection. The most common events (≥20%) with D-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. The most common events (≥20%) with D-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia and dyspnea.1
The most common hematologic laboratory abnormalities observed with Darzalex Faspro include decreased leukocytes, lymphocytes, neutrophils, platelets, and hemoglobin.
The FDA recommended a dose of 1800 mg of daratumumab and 30,000 units of administered subcutaneously into the abdomen over approximately 3 to 5 minutes. This is substantially less time than the intravenous formulation for daratumumab.