Elsevier

The Lancet Oncology

Volume 13, Issue 1, January 2012, Pages 25-32
The Lancet Oncology

Articles
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(11)70336-9Get rights and content

Summary

Background

Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.

Methods

In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2, escalating, if tolerated, to 100 mg/m2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688.

Findings

Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1–55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6–38·5]; p=0·0141). 23 of 96 (24·0% [15·8–33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3–25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients).

Interpretation

Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.

Funding

F Hoffmann-La Roche.

Introduction

20–25% of breast cancers overexpress HER2 and are associated with poor prognosis if untreated.1 Trastuzumab, a HER2-directed humanised monoclonal antibody, combined with chemotherapy, significantly improves response rates, time to progression, and overall survival in women with HER2-positive metastatic breast cancer compared with chemotherapy alone.2 Furthermore, in women with operable disease, trastuzumab improves disease-free survival and overall survival when given for 1 year in combination with or sequentially after chemotherapy, as recommended for adjuvant therapy with trastuzumab.3, 4 Positive efficacy outcomes with trastuzumab prompted the search to identify other HER2-targeted drugs capable of improving the therapeutic effects of trastuzumab in combination or in sequential administration.5

Pertuzumab is an investigational humanised monoclonal antibody directed at the dimerisation domain of HER2.6 Because of their different bindings sites, trastuzumab and pertuzumab have complementary mechanisms of action. Whereas trastuzumab blocks HER2 cleavage and inhibits ligand-independent signalling,7 pertuzumab exerts its effects by inhibiting ligand-dependent signalling, particularly between HER2 and HER3, which is known to activate a potent cell survival and proliferation signal.8, 9 Both antibodies induce antibody-dependent cell-mediated cytotoxic effects.10 In a phase 2 trial11 in patients with HER2-positive metastatic breast cancer, almost a quarter of patients treated with pertuzumab and trastuzumab after tumour progression during previous trastuzumab-based therapy achieved an objective response.

Administration of drug therapy to women with operable or locally advanced breast cancer before surgery (neoadjuvant therapy) has emerged as a successful approach to allow for surgery in cases that are inoperable at diagnosis, or to allow use of breast-sparing approaches rather than mastectomy.12, 13 A corollary aspect of neoadjuvant treatment is the ability to assess antitumour activity of new treatment regimens in terms of pathological findings instead of imaging results or late-emerging evidence such as survival. Based on comparative rates of pathological complete response, neoadjuvant trials are ideally suited to accelerate the assessment of new drugs. Pathological complete response consists of pathological evidence of eradication of invasive cancer after pre-surgery drug administration and serves as a surrogate for long-term efficacy,12, 14, 15 providing a robust rationale to design adjuvant trials. Combination of neoadjuvant chemotherapy with trastuzumab has substantially improved rates of pathological complete response.14, 16

Here, we present the results of the NeoSphere study in which the activity of pertuzumab was assessed by comparing the therapeutic effects of the conventional combination of trastuzumab plus docetaxel with the combination of pertuzumab with either docetaxel or trastuzumab, or both, in a neoadjuvant setting.

Section snippets

Study design and patients

NeoSphere is a randomised, multicentre, international, open-label phase 2 study in women with locally advanced, inflammatory, or early HER2-positive breast cancer.

All eligible patients had centrally confirmed HER2-positive, operable (T2–3, N0–1, M0), locally advanced (T2–3, N2–3, M0 or T4a–c, any N, M0), or inflammatory (T4d, any N, M0) breast cancer with primary tumours larger than 2 cm in diameter, were aged 18 years or older, and had not received any previous cancer therapy. Tumours had to

Results

Patients were enrolled across 59 centres in 16 countries from Dec 17, 2007, to Dec 22, 2009. Figure 1 shows patient disposition. Of 417 eligible patients, 392 underwent surgery as planned, and all those who did so had a valid assessment of pathological response. Baseline characteristics were balanced across treatment groups (table 1). The baseline median tumour size at clinical breast examination was at least 50 mm across all groups of the study (table 1). The median docetaxel dose intensity

Discussion

In this study, a significantly higher proportion of women given neoadjuvant pertuzumab and trastuzumab plus docetaxel achieved a pathological complete response in the breast than did those given trastuzumab and docetaxel alone, as measured after only 12 weeks of neoadjuvant treatment in a population in which a third of patients were affected by locally advanced disease.

Although pertuzumab plus docetaxel was efficacious, the combination of chemotherapy with both antibodies was more active than

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