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Prolonged Survival in Patients with Breast Cancer and a History of Brain

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Prolonged Survival in Patients with Breast Cancer and a History of Brain Breast Cancer Res Treat (2017) 165:329–341 DOI 10.1007/s10549-017-4304-7 CLINICAL TRIAL Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial 1 2 3 4 Javier Corte´s • Hope S. Rugo • Ahmad Awada • Chris Twelves • 5 6 7 8 Edith A. Perez • Seock–Ah Im • Patricia Go´mez-Pardo • Lee S. Schwartzberg • 9 10 11 12 Veronique Die´ras • Denise A. Yardley • David A. Potter • Audrey Mailliez • 1 13 14 14 Alvaro Moreno-Aspitia • Jin-Seok Ahn • Carol Zhao • Ute Hoch • 14 15 16 Mary Tagliaferri • Alison L. Hannah • Joyce O’Shaughnessy Received: 12 May 2017 / Accepted: 16 May 2017 / Published online: 13 June 2017 Ó The Author(s) 2017. This article is an open access publication Abstract those with treated, stable brain metastases. The primary Purpose Conventional chemotherapy has limited activity endpoint, overall survival (OS), was assessed in a pre-de- in patients with breast cancer and brain metastases fined subgroup of BCBM patients; an exploratory post hoc (BCBM). Etirinotecan pegol (EP), a novel long-acting analysis adjusting for the diagnosis-specific graded prog- topoisomerase-1 inhibitor, was designed using advanced nostic assessment (GPA) index was also conducted. polymer technology to preferentially accumulate in tumor Results In the trial, 67 BCBM patients were randomized tissue including brain metastases, providing sustained (EP, n = 36; TPC, n = 31). Treatment subgroups were cytotoxic SN38 levels. balanced for baseline characteristics and GPA indices. EP Methods The phase 3 BEACON trial enrolled 852 women was associated with a significant reduction in the risk of with heavily pretreated locally recurrent or metastatic death (HR 0.51; P \ 0.01) versus TPC; median OS was breast cancer between 2011 and 2013. BEACON compared 10.0 and 4.8 months, respectively. Improvement in OS was EP with treatment of physician’s choice (TPC; eribulin, observed in both poorer and better GPA prognostic groups. vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, Survival rates at 12 months were 44.4% for EP versus ixabepilone, or docetaxel) in patients previously treated 19.4% for TPC. Consistent with the overall BEACON with anthracycline, taxane, and capecitabine, including population, fewer patients on EP experienced grade C3 toxicity (50 vs. 70%). Conclusions The significant improvement in survival in Electronic supplementary material The online version of this BCBM patients provides encouraging data for EP in this article (doi:10.1007/s10549-017-4304-7) contains supplementary material, which is available to authorized users. & Joyce O’Shaughnessy 8 The West Clinic, Memphis, TN, USA [email protected] 9 Institut Curie, Paris, France 1 Ramon y Cajal University Hospital, Madrid, Spain, and Vall 10 Sarah Cannon Research Institute, Nashville, TN, USA d’Hebron Institute of Oncology (VHIO), Barcelona, Spain 11 Department of Medicine, Masonic Cancer Center, University 2 University of California, San Francisco, CA, USA of Minnesota, Minneapolis, MN, USA 3 Medical Oncology Clinic, Jules Bordet Institute, Brussels, 12 Centre Oscar Lambret, Lille, France Belgium 13 Department of Medicine, Samsung Medical Center, 4 Leeds Institute of Cancer and Pathology and St James’s Sungkyunkwan University School of Medicine, Seoul, Korea University Hospital, Leeds, UK 14 Nektar Therapeutics, San Francisco, CA, USA 5 Mayo Clinic, Jacksonville, FL, USA 15 Consultant, Sebastopol, CA, USA 6 Seoul National University Hospital, Cancer Research 16 Texas Oncology-Baylor Charles A. Sammons Cancer Center/ Institute, Seoul National University College of Medicine, U.S. Oncology, 3410 Worth Street, Suite 400, Dallas, Seoul, Korea TX 75246, USA 7 Vall d’Hebron Institute of Oncology, Barcelona, Spain 123 330 Breast Cancer Res Treat (2017) 165:329–341 difficult-to-treat subgroup of patients. A phase three trial of therapeutic strategies must control intra-cranial and extra- EP in BCBM patients is underway (ClinicalTrials.gov cranial disease while maintaining or improving patients’ NCT02915744). quality of life (QoL) [7, 8]. Indeed, in patients with breast cancer and BM (BCBM), control of systemic Keywords Brain metastases Á Etirinotecan pegol Á NKTR- disease is strongly associated with improved outcomes 102 Á Chemotherapy Á Metastatic breast cancer [9–11]. Treatment options for patients with BCBM, whether de novo, recurrent following prior local surgery Abbreviations and/or radiotherapy, or progressive disease on radiother- AE Adverse events apy are dismal, with small prospective trials showing BC Breast cancer modest response rates and short palliative benefit BCBM Breast cancer and brain metastases [5, 11–15]. BEACON BrEAst cancer outcomes with NKTR-102 No cytotoxic or molecularly targeted agent is approved BM Brain metastases for the treatment or prevention of BCBM [11, 12]. BMH History of treated, stable breast cancer brain Molecular weight, lipophilicity, biodistribution, and drug metastases efflux pumps all contribute to poor penetration of drugs CI Confidence interval through the blood–brain barrier and into the brain [16], CNS Central nervous system although extent to which therapeutic resistance relates to CTCAE Common toxicity criteria for adverse events, inadequate drug penetration remains unclear, as does the version 4.0 degree to which the blood–tumor barrier is disrupted ECOG Eastern Cooperative Oncology Group [11, 12, 15]. Current therapies have limited activity in EP Etirinotecan pegol patients with BCBM, especially those recurring post-ra- ER Estrogen receptor diation therapy [5, 11–14, 17]. This is particularly GBM Glioblastoma multiforme important for patients with triple-negative breast cancer GPA Graded prognostic assessment (TNBC), who have a high incidence of BM and for whom HER2 Human epidermal growth factor receptor 2 there are currently no approved targeted therapies HR Hazard ratio [9, 18–20]. ITT Intention-to-treat Etirinotecan pegol (EP) is a novel long-acting topoi- KM Kaplan–Meier somerase-1 inhibitor designed to improve safety and KPS Karnofsky performance score efficacy of irinotecan by generating lower peak plasma LR Locally recurrent concentrations, significantly extending the effective half- MBC Metastatic breast cancer life of the SN38, the active moiety of irinotecan, from 2 MMRM Repeated measure linear mixed model to approximately 38 days [21], and concentrate deposition NCI National Cancer Institute of the parent drug within tumor tissue. Using an experi- ORR Objective response rate mental mouse model with established BM, a significant OS Overall survival reduction in both the number and size of established BM PD Progressive disease and a 50% survival rate were reported for mice treated PFS Progression-free survival with EP; surviving animals harbored only minimal PR Progesterone receptor residual disease [21–23]. These findings support the PS Performance status ability of EP to cross the blood–tumor barrier, leading to RECIST Response evaluation criteria in solid tumors preferential accumulation and retention in BM, followed RT Radiation therapy by sustained exposure to SN38 at concentrations leading TPC Treatment of physician’s choice to cytotoxicity. In the phase 3 BEACON (BrEAst Cancer Outcomes with NKTR-102) trial, patients with heavily pretreated Introduction MBC were randomized 1:1 to EP or single-agent treatment of physician’s choice (TPC) [24]. The trial allowed inclu- The rising incidence of brain metastases (BM) as a late sion of patients with a history of treated, stable BM. To manifestation of advanced malignancies is a major clin- assess the efficacy of EP in these patients, pre-specified ical problem [1–8], with a prevalence in unselected subgroup analyses of efficacy and safety were conducted patients with metastatic breast cancer (MBC) reaching as and are reported herein. In addition, we report a post hoc high as 30% [2]. Depending on the breast cancer sub- analysis of survival stratified retrospectively according to type, the vast majority of patients who develop BM have the validated breast cancer-specific Graded Prognostic synchronous extra-cranial disease; consequently, effective Assessment (GPA) index [25, 26]. 123 Breast Cancer Res Treat (2017) 165:329–341 331 Materials and methods according to local product labeling. Prior to randomization, the investigator selected and centrally registered the rele- Patients vant TPC agent. Patients eligible for the BEACON study were women Assessments (18 years or older) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; had Radiological examination was required B28 days prior to histologically or cytologically confirmed carcinoma of the randomization and every 8 weeks (±7 days) thereafter breast; measurable (by Response Evaluation Criteria in until progressive disease (PD) was noted. The same Solid Tumors [RECIST] version 1.1) [27] or non-measur- imaging modality was required for subsequent radiographic able disease; prior therapy (in neoadjuvant, adjuvant and/or assessment, whether there was measurable or non-mea- metastatic setting) with an anthracycline (unless not med- surable disease (RECIST v1.1). Adverse events (AEs) were ically appropriate or contraindicated), a taxane, and cape- assessed from the first dose of treatment until 30 days after citabine; and received between 2 and 5 prior cytotoxic the last dose and graded according to the National Cancer regimens for locally recurrent and/or MBC, with the last Institute (NCI) Common
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