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.
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/m(2) 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.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
Nektar Therapeutics.
Mayo Clinic, Jacksonville, FL, USA. Electronic address: perez.edith@mayo.edu.
Edith A
EA
Perez
Medical Oncology Clinic, Jules Bordet Institute, Brussels, Belgium.
Ahmad
A
Awada
Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA.
Joyce
J
O'Shaughnessy
University of California, San Francisco, CA, USA.
Hope S
HS
Rugo
University of Leeds and St James's University Hospital, Leeds, UK.
Chris
C
Twelves
Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Seock-Ah
SA
Im
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Patricia
P
Gómez-Pardo
The West Clinic, Memphis, TN, USA.
Lee S
LS
Schwartzberg
Institut Curie, Paris, France.
Veronique
V
Diéras
Sarah Cannon Research Institute, Nashville, TN, USA.
Denise A
DA
Yardley
University of Minnesota Department of Medicine and Masonic Cancer Center, Minneapolis, MN, USA.
David A
DA
Potter
Centre Oscar Lambret, Lille, France.
Audrey
A
Mailliez
Mayo Clinic, Jacksonville, FL, USA.
Alvaro
A
Moreno-Aspitia
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Jin-Seok
JS
Ahn
Nektar Therapeutics, San Francisco, CA, USA.
Carol
C
Zhao
Nektar Therapeutics, San Francisco, CA, USA.
Ute
U
Hoch
Nektar Therapeutics, San Francisco, CA, USA.
Mary
M
Tagliaferri
Sebastopol, CA, USA.
Alison L
AL
Hannah
Vall d'Hebron Institute of Oncology, Barcelona, Spain; Ramon y Cajal University Hospital, Madrid, Spain.
Javier
J
Cortes
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D000069287:Capecitabine / Q000627:therapeutic use; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010820:Physicians; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; D043823:Taxoids; C080625:taxane; D011092:Polyethylene Glycols; D000069287:Capecitabine; C581703:etirinotecan pegol