ArticlesSubcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial
Introduction
Treatment with trastuzumab represents the standard of care for HER2-positive breast cancer.1, 2, 3, 4 This drug is administered every 3 weeks for 1 year in patients with early breast cancer, or until disease progression in patients with metastatic disease.5 A 90 min intravenous infusion is administered for the first dose and if well tolerated, delivered as a 30 min infusion for subsequent doses, with dosage adjusted according to bodyweight.5
A new subcutaneous trastuzumab formulation, containing a fixed dose of 600 mg and recombinant human hyaluronidase PH-20 (rHuPH-20) as an excipient, administered every 3 weeks, has been developed as an alternative to the intravenous regimen. rHuPH-20 is an enzyme that temporarily degrades interstitial hyaluronan in the subcutaneous space, thereby increasing the volume that can be administered subcutaneously and aiding delivery of trastuzumab to the circulation.6, 7 Subcutaneous trastuzumab injection typically takes less than 5 min. Potential benefits of such administration include improved patient convenience, better compliance, reduced pharmacy preparation times, and optimisation of medical resources.8
The fixed dose of 600 mg subcutaneous trastuzumab given every 3 weeks was determined by pharmacokinetic modelling of data from a phase 1 study that investigated different weight-based doses.9 Dose selection was made on the basis of several factors. First, trastuzumab is an antibody with a mechanism of action that is mediated through binding to the target receptor HER2. Full receptor saturation is expected to drive efficacy; therefore, the subcutaneous fixed dose should provide serum trough concentrations (Ctrough; the lowest serum concentration following a dose) at least as high as those obtained with the intravenous formulation given every 3 weeks to ensure similar efficacy. Second, to omit a loading dose, Ctrough after the cycle-1 dose should exceed the trastuzumab therapeutic target threshold concentration of 20 μg/mL10 and be similar to the Ctrough achieved with the intravenous loading dose. Third, serum trastuzumab exposure, as measured by the area under the concentration–time curve (AUC), should be similar to the intravenous regimen given every 3 weeks.
We investigated the comparability of the 600 mg subcutaneous trastuzumab fixed dose and the registered intravenous formulation with respect to pharmacokinetics, efficacy, and safety.
Section snippets
Study design and patients
The HannaH study (enHANced treatment with NeoAdjuvant Herceptin) was a phase 3, randomised, international, open-label, study in the (neo)adjuvant setting.
Eligible patients were aged 18 years or older, had HER2-positive (defined as immunohistochemistry 3+ or in-situ hybridisation positive), newly diagnosed, non-metastatic, primary, invasive adenocarcinoma of the breast (clinical stage I to IIIC) with primary tumours 1 cm or larger by ultrasound or 2 cm or larger by palpation, a baseline Eastern
Results
596 patients were enrolled into the study from Oct 19, 2009, to Dec 1, 2010 (figure 2) at 81 centres (Europe, 47 centres; Asia, 12; South America and Central America, 17; North America, one; and Africa, four). At the time of the primary analysis, 116 patients in each group had completed full treatment, and no patient had completed the follow-up phase. The median duration of follow-up was 12·2 (range 1·0–20·8) months in the intravenous group and 12·4 (0·3–20·4) months in the subcutaneous group.
Discussion
Our study shows that, in terms of pharmacokinetics and pCR, subcutaneous trastuzumab given at a fixed dose of 600 mg every 3 weeks is non-inferior to the licensed bodyweight-based intravenous trastuzumab regimen given every 3 weeks (panel).
The trastuzumab Ctrough concentration before surgery was about 30% higher in the subcutaneous groups. Most patients in the subcutaneous group showed Ctrough concentrations above the therapeutic target threshold of 20 μg/mL, suggesting that the fixed dose was
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