Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA†

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Abstract

In a retrospective analysis of the EMILIA study, the rate of central nervous system (CNS) progression in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer was similar for trastuzumab emtansine (T-DM1) and for capecitabine–lapatinib. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved overall survival versus capecitabine–lapatinib.

Abstract

Background

We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine–lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.

Patients and methods

In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out.

Results

Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed.

Conclusion

In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.

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Most cited references 26

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Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.

Jill Barnholtz-Sloan, Andrew Sloan, Faith G. Davis … (2004)

Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer. Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs. Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites. Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.

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Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer.

E C Dijkers, T H Oude Munnink, J G Kosterink … (2010)

We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium-89 ((89)Zr)-trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)-positive lesions. Fourteen patients with HER2-positive metastatic breast cancer received 37 MBq of (89)Zr-trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab-naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of (89)Zr-trastuzumab uptake by tumors was 4-5 days after the injection. For optimal PET-scan results, trastuzumab-naive patients required a 50 mg dose of (89)Zr-trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of (89)Zr-trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean +/- SEM) were 12.8 +/- 5.8, 4.1 +/- 1.6, and 3.5 +/- 4.2 in liver, bone, and brain lesions, respectively, and 5.9 +/- 2.4, 2.8 +/- 0.7, 4.0 +/- 0.7, and 0.20 +/- 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of (89)Zr-trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2-positive lesions in patients with metastatic breast cancer.

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Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.

Thomas Bachelot, Gilles Romieu, Mario Campone … (2013)

Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m(2), orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031. Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2-27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1-79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. GlaxoSmithKline-France and UNICANCER. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Oncol

Journal ID (iso-abbrev): Ann. Oncol

Journal ID (publisher-id): annonc

Journal ID (hwp): annonc

Title: Annals of Oncology

Publisher: Oxford University Press

ISSN (Print): 0923-7534

ISSN (Electronic): 1569-8041

Publication date (Print): January 2015

Publication date (Electronic): 29 October 2014

Publication date PMC-release: 29 October 2014

Volume: 26

Issue: 1

Pages: 113-119

Affiliations

[1 ]Department of Medical Oncology, Dana-Farber Cancer Institute , Boston

[2 ]Department of Medicine, Duke University Medical Center , Durham

[3 ]Product Development, Oncology, Genentech, Inc. , South San Francisco, USA

[4 ]Department of Medical Oncology and Breast Centre, Cantonal Hospital , St Gallen, Switzerland

[5 ]Department of Medical Oncology, Mount Vernon Cancer Centre , Northwood, UK

[6 ]Biostatistics, Genentech, Inc. , South San Francisco, USA

[7 ]Hematology, Medical Office , Aschaffenburg, Germany

[8 ]Department of Medical Oncology, Institut Curie , Paris, France

Author notes

[* ] Correspondence to: Dr Ian E. Krop, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard University School of Medicine, Breast Oncology Center, 450 Brookline Avenue, Boston, MA 02215, USA. Tel: +1-617-632-6973; Fax: +1-617-632-1930; E-mail: ikrop@ 123456partners.org

[†]

These data were presented in part at: The 36th Annual San Antonio Breast Cancer Symposium; San Antonio, TX, USA; 10–14 December 2013. I. Krop, N. Lin, K. Blackwell et al. Efficacy and safety of trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer and central nervous system metastases: results from a retrospective exploratory analysis of EMILIA.

[‡]

Present Address: Department of Gynecology, University of Ulm, Ulm, Germany.

Article

Publisher ID: mdu486

DOI: 10.1093/annonc/mdu486

PMC ID: 4679405

PubMed ID: 25355722

SO-VID: ae36896d-0247-47f0-b0cd-85f2a5b72d7b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

History

Date received : 15 August 2014

Date revision received : 24 September 2014

Date accepted : 30 September 2014

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