Not only a time-saving approach: Is it the time of subcutaneous formulation for daratumumab administration?

Abstract

Available data from studies of monoclonal antibodies administered by subcutaneous injection (e.g. subcutaneous trastuzumab and rituximab/hyaluronidase human) have shown that a change in the route from intravenous infusion results in a non-inferior serum trough concentration, consistent antitumor activity, and comparable safety. For example, intravenous pertuzumab with subcutaneous trastuzumab injection offers a more convenient option (2–5 min administration time), while maintaining similar efficacy and safety to intravenous pertuzumab plus trastuzumab. Subcutaneous injection reduces the administration burden and the time patients spend in infusion chairs, has the potential to optimize medical resource use, is preferred by patients, and is more satisfactory for health-care professionals. Subcutaneous injection might also potentially allow home administration, promoting a transition from inpatient to outpatient setting: several studies have shown cost, resource, and quality-of-life benefits. This way, efforts are underway to assess the feasibility of administering monoclonal antibodies at home. Daratumumab (dara) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Intravenous dara 16 mg/kg has been approved as a monotherapy and in combination with bortezomib/dexamethasone, lenalidomide/dexamethasone, bortezomib/melphalan/ prednisone, bortezomib/thalidomide/dexamethasone (Italy) in different settings for patients suffering from multiple myeloma. In clinical studies of dara, the median durations of the first, second, and subsequent dara infusions were 7.0, 4.3, and 3.4 h, respectively. For the convenience of patients and healthcare providers, the first dose of dara 16 mg/kg may be split over 2 days (8 mg/kg administered on days 1 and 2 of cycle 1), which is associated with a shorter median infusion duration. Furthermore, a shorter, 90 min infusion for subsequent (cycle 1 day 15 and beyond) 16 mg/kg administrations of dara was shown to be well tolerated: infusion-related reactions (IRRs) occur in ∼50% of patients treated with dara; all these reactions are manageable and occur primarily during the first infusion. As reported by Lombardi and colleagues, the use of 90 min protocol retains a good tolerability and safety profile in relapse/refractory (R/R) multiple myeloma patients receiving their third infusion (or later). Good safety profile can be explained by the fact that premedication was administered in compliance with the recommendations in overall patients. Of particular interest, 40% of the infusions were administered in patients with comorbidities without inducing IRRs. Subcutaneous formulation of dara is commercially available as 1800 mg fixed-dose co-formulated with 2000 U/mL recombinant human hyaluronidase PH20. Safety and tolerability profiles have been assessed in PAVO study: the adverse events profile of subcutaneous dara was consistent with intravenous route, with no new safety concerns and a lower IRR rate. Consequently, COLUMBA study investigated whether the efficacy and pharmacokinetics of subcutaneous dara are non-inferior to intravenous one: it was found that subcutaneous dara was non-inferior to intravenous one in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with R/R multiple myeloma.