Elsevier

The Lancet Oncology

Volume 16, Issue 15, November 2015, Pages 1556-1568
The Lancet Oncology

Articles
Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00332-0Get rights and content

Summary

Background

New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.

Methods

In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m2 as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0–1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101.

Findings

Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0–13·6] for the etirinotecan pegol group vs 10·3 months [9·0–11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75–1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock).

Interpretation

This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients.

Funding

Nektar Therapeutics.

Introduction

Chemotherapy is a mainstay of treatment for metastatic breast cancer. It prolongs survival and can improve quality of life, but the use of sequential single-agent regimens requires careful balancing of safety and effectiveness.1, 2 The development of cumulative toxic effects, such as neuropathy and cardiotoxicity, and the emergence of resistant or refractory disease, ultimately restricts the use of the drugs used in the metastatic setting, including anthracyclines, taxanes, and capecitabine. New treatments with novel mechanisms of action and non-overlapping toxicity profiles are urgently needed, particularly for patients with heavily pretreated, resistant, or refractory disease.

Research in context

Evidence before this study

At the time that this study design was finalised in 2010, we searched PubMed, with the search terms “advanced breast cancer”, “phase 3 clinical trial”, “taxane”, “anthracycline”,“capecitabine”, and major oncology society meeting websites, which showed no standard of care or universal chemotherapeutic approach for treatment of patients with advanced breast cancer who progress after an anthracycline, taxane, and capecitabine. Choice of chemotherapeutic drug was driven by the nature and timing of previous therapy, extent of disease burden, cancer-related symptoms, patient and clinician preference, and availability of specific drugs in a given country or region. Available drugs produced suboptimum outcomes and an expected survival of less than 1 year. An urgent need existed for new chemotherapeutic drugs, especially those with a non-overlapping mechanism of action to ensure no cross-resistance and reduce overlapping toxicities.

Added value of this study

It had been postulated that a drug with a different mechanism of action and non-overlapping toxicities might improve survival in patients with heavily advanced disease, especially when most of the commonly used drugs are microtubule-targeting agents. Although we did not demonstrate a significant difference between groups in overall survival, the overlapping adverse event profile and improved global quality of life are encouraging.

Implications of all the available evidence

Although there was no difference in overall survival between groups in the overall population, the suggestion of benefit with etirinotecan pegol in the predefined subgroups of patients with advanced breast cancer and a history of brain metastases and liver metastases deserves further investigation in clinical trials, as does the investigation of predictive biomarkers such as circulating tumour cells that have the potential to identify appropriate patients for treatment with this novel drug.

Etirinotecan pegol is a unique, long-acting topoisomerase-I inhibitor designed to improve the pharmacokinetics and distribution of the prodrug irinotecan. Etirinotecan pegol contains a large-chain polyethylene glycol (PEG) core to which four molecules of irinotecan are attached via a cleavable ester-based linker.3 The linker slowly hydrolyses in vivo to release irinotecan, which is subsequently converted to SN38, the active metabolite of irinotecan. The high molecular weight of etirinotecan pegol (nominal molecular weight 22 kDa) limits its ability to freely cross intact vasculature into healthy tissues but promotes extravasation through the leaky tumour microvasculature, consistent with the enhanced permeation and retention effect shown for macromolecules.4 In non-clinical models, tumour localisation of etirinotecan pegol via enhanced permeation and retention was pronounced and resulted in high and sustained tumour exposure to SN38.3 Sustained exposure to this S-phase specific drug could enhance antitumour activity, while avoiding the high plasma levels of irinotecan and SN38 that are associated with toxicity in current clinical practice.5, 6

In the initial phase 1 study, the mean half-life of SN38 was extended from 2 days with conventional irinotecan to 50 days with etirinotecan pegol, and fewer cases of early-onset cholinergic diarrhoea and neutropenia were noted relative to irinotecan-treated historical controls.6, 7 A randomised phase 2 study assessing two schedules of etirinotecan pegol (145 mg/m2 every 14 or 21 days) reported that the drug produced substantial antitumour activity in patients who had received a median of two previous regimens for metastatic breast cancer.8 Objective responses were noted in 29% of patients, including two complete responses with each schedule. Activity was seen in subsets of patients with particularly poor prognoses, including those with triple-negative breast cancer (objective response in 39%) and visceral disease (objective response in 30%). Although the trial was not designed to formally compare the two treatment schedules, patients randomly assigned to the every 3-week regimen had less toxicity and slightly extended median progression-free survival and overall survival than the 2-week schedule, which led to the selection of the every 3-week dosing regimen for further clinical development.

We aimed to assess whether etirinotecan pegol given every 3 weeks is superior to single-drug treatment of physician's choice with respect to overall survival in patients with heavily pretreated, locally recurrent, or metastatic breast cancer.

Section snippets

Study design and participants

This open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102) was conducted at 135 sites in 11 countries (the UK, the USA, Canada, France, Spain, Belgium, the Netherlands, Italy, Germany, Russia, and South Korea; appendix). Medical centres included a mix of community and academic centres (about half of each).

Eligible patients were 18 years and older with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 who had histologically

Results

Between Dec 19, 2011, and Aug 20, 2013, 852 patients (comprising the intention-to-treat population) were enrolled at 135 centres in North America, Europe, and Asia. Of these, 429 patients were randomly assigned to etirinotecan pegol and 423 to treatment of physician's choice (figure 1). Four patients in the etirinotecan pegol group and 17 in the treatment of physician's choice group did not receive the allocated intervention because the patient's condition deteriorated between randomisation and

Discussion

The BEACON study assessed whether etirinotecan pegol, a novel long-acting topoisomerase I inhibitor, is superior to currently available cytotoxic drugs used for the treatment of patients with advanced breast cancer who have already received an anthracycline, a taxane, and capecitabine. The study was designed to detect an HR of 0·77 for overall survival relative to the control group, a composite of seven different single drugs commonly used in this clinical setting. Although the difference

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