5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial

Summary

Background

In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety.

Methods

In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) 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 every 3 weeks, increasing to 100 mg/m² from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m², epirubicin 90 mg/m², and cyclophosphamide 600 mg/m²) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov, number NCT00545688.

Findings

Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71–87) for group A, 86% (77–91) for group B, 73% (64–81) for group C, and 73% (63–81) for group D (hazard ratios 0·69 [95% CI 0·34–1·40] group B vs group A, 1·25 [0·68–2·30] group C vs group A, and 2·05 [1·07–3·93] group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72–88) for group A, 84% (72–91) for group B, 80% (70–86) for group C, and 75% (64–83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% [76–91] in patients who achieved total pathological response vs 76% [71–81] in patients who did not achieve total pathological response; hazard ratio 0·54 [95% CI 0·29–1·00]). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 [66%] of 107 patients; group B: 59 [55%] of 107; group C: 40 [37%] of 108; group D: 60 [64%] of 94), febrile neutropenia (group A: 10 [9%]; group B: 12 [11%]; group C: 5 [5%]; group D: 15 [16%]), and leucopenia (group A: 13 [12%]; group B: 6 [6%]; group C: 4 [4%]; group D: 8 [9%]). The number of patients with one or more serious adverse event was similar across groups (19–22 serious adverse events per group in 18–22% of patients).

Interpretation

Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer.

Funding

F Hoffmann-La Roche.

Introduction

The clinical benefit of combining the HER2-directed monoclonal antibodies pertuzumab and trastuzumab was first shown in patients with HER2-positive metastatic breast cancer whose disease had progressed during previous trastuzumab therapy.¹ On the basis of those results, pertuzumab, trastuzumab, and chemotherapy were tested in the HER2-positive neoadjuvant setting in the phase 2 NeoSphere² and TRYPHAENA studies,³ and in the phase 3 CLEOPATRA trial in metastatic breast cancer.4, 5 In TRYPHAENA,³ a high proportion of patients achieved a pathological complete response (57·3–66·2%) with pertuzumab and trastuzumab in combination with standard anthracycline-based and non-anthracycline-based neoadjuvant regimens. In CLEOPATRA,4, 5 first-line treatment with pertuzumab and trastuzumab plus docetaxel significantly improved progression-free survival and overall survival in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel.

The primary analysis of NeoSphere² showed that patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer, who received four cycles of neoadjuvant pertuzumab and trastuzumab plus docetaxel, had a significant improvement (16·8%) in pathological complete response in the breast (defined as absence of invasive cancer in the breast, regardless of ductal carcinoma in situ; 49 [46%] of 107 patients, 95% CI 36·1–55·7), compared with patients who received trastuzumab plus docetaxel (31 [29%] of 107 patients, 20·6–38·5; p=0·0141).² Similarly, there was a 17·8% increase in total pathological complete response (defined as absence of invasive cancer in the breast and axillary nodes, regardless of ductal carcinoma in situ) in patients who received pertuzumab and trastuzumab plus docetaxel (42 [39%] of 107 patients, 95% CI 30·0–49·2) compared with patients who received trastuzumab and docetaxel (23 [22%] of 107 patients, 14·1–30·5).² NeoSphere also assessed neoadjuvant pertuzumab and trastuzumab without chemotherapy, and pertuzumab plus docetaxel. Both combinations were active but were less so than trastuzumab plus docetaxel or than both antibodies plus docetaxel.²

After surgery, patients in NeoSphere received additional chemotherapy and adjuvant trastuzumab to provide all patients with optimal therapy for operable HER2-positive breast cancer.

In this second Article, we report prespecified secondary endpoints of progression-free survival, disease-free survival, and safety in NeoSphere, 5 years after randomisation of the last patient. We also examined the association between total pathological complete response and progression-free survival. Previous studies indicated that pathological complete response is likely to predict clinical benefit in patients with early-stage HER2-positive breast cancer.6, 7, 8, 9, 10, 11, 12 We used total pathological complete response rather than pathological complete response in the breast to align with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidance.13, 14