Elsevier

The Lancet Oncology

Volume 14, Issue 10, September 2013, Pages 962-970
The Lancet Oncology

Articles
Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study

https://doi.org/10.1016/S1470-2045(13)70383-8Get rights and content

Summary

Background

Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab in the international, randomised PrefHer study.

Methods

Eligible patients were women aged 18 years or older with HER2-positive, histologically confirmed primary invasive breast adenocarcinoma, no evidence of residual, locally recurrent, or metastatic disease after completion of surgery and chemotherapy (neoadjuvant or adjuvant), an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left-ventricular ejection fraction of 55% or more before the first dose of trastuzumab. Radiotherapy or hormone therapy was allowed. Patients were randomised (randomly permuted blocks of four) to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a single-use injection device or hand-held syringe followed by four cycles of standard intravenous trastuzumab, or the reverse sequence. Randomisation was stratified by de-novo versus non-de-novo use of intravenous trastuzumab. The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous trastuzumab, assessed by patient interview in the evaluable intention-to-treat (ITT) population (patients who completed both interviews and had at least one administration of both subcutaneous and intravenous trastuzumab). Data collection for PrefHer is ongoing. This study is registered with ClinicalTrials.gov, number NCT01401166.

Findings

124 patients were randomly allocated to receive subcutaneous followed by intravenous trastuzumab, and 124 to receive the reverse sequence. 117 patients in the subcutaneous first group and 119 in the intravenous first group were included in the evaluable ITT population. Subcutaneous trastuzumab via the single-use injection device was preferred by 216 patients (91·5%, 95% CI 87·2–94·7; p<0·0001). Only 16 patients preferred intravenous trastuzumab (6·8%, 3·9–10·8), and four had no preference (1·7%, 0·5–4·3). Clinician-reported adverse events occurred in 141 of 242 (58%) patients during the pooled subcutaneous periods and 105 of 241 (44%) patients during the pooled intravenous periods; seven (3%) and five (2%) were grade 3, no patients had a grade 4 or 5 event. The most common grade 3 adverse event was influenza (two [0·8%] patients).

Interpretation

Patient preference and safety results from PrefHer, combined with the known non-inferior efficacy and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab administered subcutaneously every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients.

Funding

F Hoffmann-La Roche.

Introduction

Treatment regimens containing trastuzumab administered intravenously are the standard of care for patients with HER2-positive breast cancer. Trastuzumab provides a significant survival benefit in early-stage disease when given as adjuvant therapy for 12 months,1, 2, 3, 4, 5, 6, 7, 8 and in first-line treatment of metastatic disease.9, 10

Intravenous trastuzumab is administered according to bodyweight over 30–90 min in once-weekly or 3-weekly cycles. A subcutaneous formulation, containing a fixed dose of 600 mg trastuzumab and 10 000 U recombinant human hyaluronidase (rHuPH20, Halozyme Therapeutics, San Diego, CA, USA) as an excipient, has been developed for 3-weekly use as an alternative to the intravenous formulation. A single-use injection device provides an alternative to subcutaneous injection via hand-held syringe, and can enable self-administration.11 Pharmacokinetic bioequivalence between the two methods of subcutaneous administration was shown in the CP3 study (NCT01344863).11 Subcutaneous trastuzumab was well tolerated using both methods, with no grade 4 or 5, cardiac, or serious adverse events reported.11

The phase 3 HannaH study12 met its coprimary endpoints of non-inferior serum trough concentration and pathological complete response with neoadjuvant or adjuvant subcutaneous trastuzumab via hand-held syringe versus intravenous trastuzumab in 596 patients. The overall safety profile of subcutaneous trastuzumab was consistent with the known safety profile of intravenous treatment in early breast cancer.12 However, patient preference for route of administration has not been assessed to date.

The Preference for Herceptin SC or IV Administration (PrefHer) study was designed to assess patient preference for trastuzumab administered either subcutaneously or intravenously in the adjuvant breast cancer setting.

Section snippets

Study design and patients

PrefHer was an international, multicentre, open-label, randomised, two-cohort, two-arm, crossover study which used comprehensive telephone interviews to determine patient preference for route of administration of trastuzumab. The study design is shown in figure 1. Eligible patients were women aged 18 years or older with HER2-positive (immunohistochemistry 3+ or positive by in-situ hybridisation), histologically confirmed primary invasive breast adenocarcinoma, no evidence of residual, locally

Results

From Oct 27, 2011, to March 29, 2012, 265 patients completed the first interview, and 248 patients were randomised (figure 2) at 56 centres in Europe and Canada. Four randomised patients did not receive study treatment, so the safety population consisted of 244 patients: 122 per study group. Ten patients who were treated did not complete all eight cycles of trastuzumab, owing to disease recurrence (four), adverse events (three), withdrawal of consent (one), loss to follow-up (one), and refusal

Discussion

PrefHer showed that patients preferred fixed-dose subcutaneous delivery of trastuzumab via a single-use injection device over standard intravenous administration for the treatment of HER2-positive early breast cancer (panel).

Confirmed advantages of subcutaneous trastuzumab administration include improved patient convenience (injection time less than 5 min vs 30–90 min for intravenous administration,13 which is important in long-term or single-agent trastuzumab therapy) and reduced use of

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