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Subcutaneous trastuzumab noninferior to standard IV delivery
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Subcutaneous trastuzumab was observed to have a safety profile and efficacy similar to standard IV administration, offering a viable treatment alternative, according to study results published online.
IV infusion with trastuzumab (Herceptin, Genentech) currently represents the standard of care for HER-2–positive breast cancer, administered every 3 weeks for 1 year in patients with early breast cancer, or until disease progression in patients with metastatic disease. Recently, a novel subcutaneous trastuzumab formulation, containing a fixed dose of 600 mg and administered every 3 weeks, has been developed as an alternative to the IV regimen. Among the potential benefits of subcutaneous administration would be improved patient convenience, superior compliance, reduced pharmacy preparation times and optimization of medical resources.
To determine the pharmacokinetics, efficacy and safety comparability of the 600-mg subcutaneous trastuzumab fixed dose vs. the registered IV formulation, the researchers enrolled 596 patients from Oct. 19, 2009, to Dec. 1, 2010, at 81 centers in Europe, Asia, South America, North America and Africa.
Patients with HER-2–positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to receive eight cycles of neoadjuvant chemotherapy administered in tandem with either IV (n=299) or subcutaneous trastuzumab (n=297).
Chemotherapy included four cycles of docetaxel (75 mg/m²) followed by four cycles of fluorouracil (500 mg/m²), epirubicin (75 mg/m²) and cyclophosphamide (500 mg/m²) in 3-week intervals. After surgery, patients continued trastuzumab to complete 1 year of treatment.
Coprimary endpoints of the study consisted of serum trough concentration at pre-dose cycle eight before surgery — the noninferiority margin for the ratio between groups of 0.80 — and pathological complete response (pCR).
According to study results, 107 (40.7%) of 263 patients in the IV group and 118 (45.4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4.7% (95% CI, –4.0 to 13.4). Based on this outcome, subcutaneous trastuzumab was observed to be noninferior to IV trastuzumab for both coprimary endpoints.
The geometric mean pre-surgery serum trough concentration was 51.8 mcg/mL (coefficient of variation 52.5%) in the IV group and 69 mcg/mL (55.8%) in the subcutaneous group. The geometric mean ratio of serum trough concentration subcutaneous to serum trough concentration IV was 1.33 (90% CI, 1.24-1.44).
“Subcutaneous trastuzumab at a fixed dose of 600 mg administered every 3 weeks in about 5 minutes could thus provide a valid alternative to the intravenous regimen given every 3 weeks for HER-2–positive breast cancer,” the researchers wrote. “The shortened duration of administration with subcutaneous trastuzumab compared with intravenous delivery suggests the potential for substantial time-saving for patients, physicians and nursing staff.”
The most commonly reported adverse events included febrile neutropenia (3.4% of patients in the IV group; 5.7% of patients in the subcutaneous group), neutropenia (33.2% IV group; 29% subcutaneous group) and leucopenia (5.7% vs. 4%). However, more patients experienced serious adverse events in the subcutaneous group (21%) than in the IV group (12%), which was attributed to infections and infestations (8.1% in the subcutaneous group vs. 4.4% in the IV group).
Four adverse events led to death (one in the IV group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase — of these, the two in the subcutaneous group were considered to be treatment-related.
According to the researchers, “Overall, the safety profiles of the intravenous and subcutaneous formulations were comparable, and they were consistent with the known safety profile of intravenous trastuzumab. The imbalance in reporting of serious adverse events might have been related to differences in investigator behavior and interpretation of the reported adverse events.”
Disclosure: The researchers report clinical trial funding, honoraria, clinical research sponsorships and employment relationships with F. Hoffmann-La Roche.
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