“The tolerability, safety, and pharmacokinetic data support continued development of subcutaneous daratumumab in different settings,” lead author Saad Z. Usmani, MD, of the Levine Cancer Institute/Carolinas HealthCare System, said when presenting the results at the 2016 annual meeting of the American Society of Hematology held December 3-6 in San Diego.
The open-label, multicenter, dose-escalation phase Ib PAVO study examined whether subcutaneous (SC) daratumumab that takes only minutes to administer could be as safe and effective as the current IV dosing regimen that lasts several hours per dose.
To enable SC delivery, recombinant human hyaluronidase (rHuPH20) was administered along with daratumumab.
Enrolled patients had relapsed/refractory multiple myeloma and received at least 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 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, for each 28-day cycle.
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 and treatment history were well balanced between the 2 groups.
At data cutoff on November 15, 2016, 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 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). Infusion-related reactions (IRRs) in the 1800-mg group were mostly grade 1 or 2, and they occurred in about 24% of the patients. Usmani noted that both the AE and IRR profiles aligned with previous experience with the IV daratumumab formulation. Only 1 grade 3 IRR was 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 SC 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 SC 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 daratumumab as a monotherapy for patients with multiple myeloma following at least 3 prior therapies. In November 2016, the FDA approved it in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone for patients with relapsed, multiple myeloma following at least 1 prior therapy.
Daratumumab (DARA) is currently administered as an intravenous (IV) infusion. While IV DARA is well tolerated and highly efficacious, more than half of patients experience infusion-related reactions (IRR). The phase Ib PAVO study is the first to assess subcutaneous (SC) administration of DARA + PH20 in patients with relapsed or refractory multiple myeloma. Overall, data from this trial indicate:
In general, safety, efficacy, preference, and pharmacoeconomics govern the choice of administration route. When safety and efficacy of IV and SC formulations are equivalent, choosing the option that favors patient preference will increase treatment adherence and improve patient satisfaction, whereas attention to pharmacoeconomics can help address the issue of nursing staff shortages and may reduce healthcare costs.
The transition from IV to SC DARA has the potential to provide multiple benefits. With SC administration, chair time and pharmaceutical preparation time are reduced. SC administration constitutes an alternative for patients with poor venous access, limits infectious complications, may be performed in the ambulatory setting, and may allow self-administration in educated patients. One of the biggest advantages of SC over IV administration is patient convenience and the potential to improve compliance.
From a nursing perspective, it is important to consider patient characteristic– related factors (eg, body-mass index, age, comorbidities) with SC chemotherapeutics. Would IV DARA be better suited for overweight or underweight individuals? Would thrombocytopenia influence mode of administration to decrease bleeding risk? Inflammation or irritation at the injection site, leakage of drug, and allergic reactions also can be disadvantages associated with SC administration.
Sites of administration typically need to be rotated, and the injected volume is limited to approximately 2 mL to reduce pain. Separate injection sites per dose may be required, which can cause discomfort. In general, SC injections in the abdomen cause fewer injection site reactions compared to the thigh, likely the reason the PAVO trial tested SC DARA in the abdomen.
Adopting a nursing protocol for SC chemotherapeutic administration that aims to reduce the incidence and severity of injection site reactions—while ensuring drug delivery into the adipose tissue—will facilitate the benefits associated with the SC route. Injection site nursing protocols should include guidelines for site selection, needle size, volume of medication per site, patient education for post-injection care, and guidelines for documentation.