Subcutaneous Daratumumab Safe, Effective in Myeloma

Saad Z. Usmani, MD

Saad Z. Usmani, MD

Subcutaneous delivery of daratumumab (Darzalex) was well tolerated with comparable efficacy to the FDA-approved intravenous (IV) dose in patients with relapsed/refractory multiple myeloma, according to results from the phase Ib PAVO trial.

“The tolerability, safety, and pharmacokinetic data support continued development of subcutaneous daratumumab in different settings,” lead author Saad Z. Usmani, MD, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, said when presenting the results at the 2016 ASH Annual Meeting.

The open-label, multicenter, dose-escalation phase Ib PAVO study sought to examine whether a subcutaneous daratumumab dosing platform that takes only minutes to administer could be as safe and effective as the current intravenous dosing regimen that lasts several hours per dose. To enable subcutaneous delivery, recombinant human hyaluronidase (rHuPH20) was administered along with daratumumab.

Enrolled patients had relapsed/refractory multiple myeloma and had received ≥2 prior lines of therapy, but had not been treated with anti-CD38 agents. Patients were examined in 2 groups. The first group of 8 patients received a 1200-mg fixed subcutaneous (SC) dose of daratumumab combined with rHuPH20 at 30,000 U. The second group of 45 patients received SC daratumumab at 1800 mg and rHuPH20 at 45,000 U. The infusion times for the 2 doses were 20 and 30 minutes, respectively. Each treatment cycle was 28 days.

The primary endpoints of the study were pharmacokinetics and safety. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, duration of response, and time to response.

Baseline patient demographics were well balanced between the treatment groups. In the 1200-mg group, the median age was 66 years (range, 49-78), the median weight was 75 kg (range, 53-82.5), and 63% of patients had prior autologous stem cell transplant (ASCT).

The median number of prior therapy lines was 5 (range, 2-10). All patients had previously received an immune-modulating drug (IMiD) and a proteasome inhibitor (PI). Sixty-three percent of patients were refractory to both a PI and an IMiD, and 88% were refractory to their last line of therapy.

In the 1800-mg group, the median age was 63 years, the median weight was 74.8 kg (range, 48-133), and 82% of patients had prior ASCT. The median number of prior therapy lines was 4 (range, 2-11). All patients had previously received an IMiD and a PI. Fifty-eight percent of patients were refractory to both a PI and an IMiD and 71% were refractory to their last line of therapy.

“This patient population was fairly comparable with the daratumumab monotherapy studies that have been reported and published in the past,” said Usmani.

As of the November 15, 2016, data cutoff date, the median follow-up was 6.4 months (range, 1.6-12) in the 1200-mg arm and 4.3 months (range, 0.8-8.6) in the 1800-mg arm. The median duration of treatment was 2.6 months (range, 0.7-12) and 3.4 months (range, 0.7-8.6), respectively.

Deeper responses were observed in the 1800-mg group versus the 1200-mg arm. In the 1800-mg group, the ORR was 38% (n = 17), which included a stringent complete response rate of 2%, a very good partial response rate of 7%, and a partial response (PR) rate of 29%. The minimal response (MR), stable disease (SD), and progressive disease (PD) rates were 11%, 38%, and 13%, respectively.

Among patients receiving the 1200-mg dose the ORR was 25% (n = 2), comprised of all PRs. The MR, SD, and PD rates were 13%, 50%, and 13%, respectively. The responses in both groups were consistent to what has been observed with the IV formulation.

Eighty-eight percent (n = 7) of the 1200-mg arm discontinued treatment due to progressive disease (n = 5), patient withdrawal (n = 1), or death (n = 1). Thirty-three percent (n = 15) of the 1800-mg arm discontinued treatment due to progressive disease (n = 12), physician decision (n = 2), or death (n = 1).

The most common all-grade hematologic treatment-emergent adverse events (TEAEs) were anemia and thrombocytopenia, which occurred in 25% versus 31% and 38% versus 18% of the 1200-mg and 1800-mg arms, respectively.

The most common all-grade nonhematologic TEAEs were upper respiratory infection, insomnia, and decreased appetite, which occurred in 38% versus 9%, 38% versus 9% and 38% versus 7% of the the 1200-mg and 1800-mg arms, respectively.

Grade 3/4 TEAEs in the 1200 mg-arm included hypertension (n = 2), fatigue (n = 2), anemia (n = 1), thrombocytopenia (n = 1), neutropenia (n = 1). In the 1800-mg arm, grade 3/4 TEAEs included anemia (n = 6), thrombocytopenia (n = 3), neutropenia (n = 3), lymphopenia (n = 3), hypertension (n = 2), device-related infection (n = 2), hyponatremia (n = 2), and fatigue (n =1).

“The AE profile appeared to be consistent with what we have observed with the IV daratumumab formulation,” said Usmani.

Infusion-related reactions (IRRs) in the 1800-mg group were mostly grade 1 or 2, and they occurred in about 24% of the patients. “The IRRs consisted of what we have already observed with the IV daratumumab formulation,” Usmani noted.

There was only 1 grade 3 IRR observed and it occurred in a patient in the 1200-mg group. The overall incidence of IRRs in this arm was 13%. No grade 4 IRRs were reported. All IRRs occurred during or within 4 hours of the first infusion. Abdominal wall subcutaneous injections were well tolerated.

With regard to pharmacokinetics, Usmani said, “The 1800-mg dose appears to be replicating what we have observed with the 16-mg/kg IV dose in previous studies.” However, a simulation of the mean concentration of subcutaneous and IV dosing showed lower levels with the 1200-mg subcutaneous dose than with what has been observed with the IV dose.

In November 2015, the FDA approved the CD38-targeted monoclonal antibody daratumumab as a monotherapy for patients with multiple myeloma following at least 3 prior therapies. In November 2016, the FDA approved daratumumab in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy.

__________________________________________________________________________

Usmani SZ, Nahi H,Mateos M-V, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1149.