Elsevier

The Lancet Oncology

Volume 13, Issue 9, September 2012, Pages 869-878
The Lancet Oncology

Articles
Subcutaneous 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

https://doi.org/10.1016/S1470-2045(12)70329-7Get rights and content

Summary

Background

A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer.

Methods

The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of 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), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (Ctrough) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of −12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300.

Findings

299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery Ctrough was 51·8 μg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 μg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of Ctrough subcutaneous to Ctrough intravenous was 1·33 (90% CI 1·24–1·44). 107 (40·7%) of 263 patients in the intravenous 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). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3–5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two—both in the subcutaneous group—were deemed to be treatment related.

Interpretation

Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.

Funding

F Hoffmann-La Roche.

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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