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Breast Cancer Research and Treatment

, Volume 137, Issue 3, pp 755–766 | Cite as

A randomized and open-label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer

  • Stephen R. D. Johnston
  • Henry Gómez
  • Salomon M. Stemmer
  • Maria Richie
  • Michael Durante
  • Lini Pandite
  • Vicki Goodman
  • Dennis Slamon
Clinical Trial

Abstract

This phase II study (VEG20007; NCT00347919) with randomized and open-label components evaluated first-line lapatinib plus pazopanib therapy and/or lapatinib monotherapy in patients with human epidermal growth factor receptor type 2 (HER2)-positive advanced/metastatic breast cancer. Patients were enrolled sequentially into two cohorts: Cohort 1, patients were randomly assigned to lapatinib 1,000 mg plus pazopanib 400 mg or lapatinib 1,500 mg monotherapy; Cohort 2, patients received lapatinib 1,500 mg plus pazopanib 800 mg. The primary endpoint was week-12 progressive disease rate (PDR) for Cohort 1. The principal secondary endpoint was week-12 response rate (RR) for Cohort 2. Efficacy was assessed in patients with centrally confirmed HER2 positivity (modified intent-to-treat population [MITT]). The study enrolled 190 patients (Cohort 1, combination n = 77, lapatinib n = 73; Cohort 2, n = 40). The MITT population comprised n = 141 (Cohort 1) and n = 36 (Cohort 2). In Cohort 1, week-12 PDRs were 36.2 % (combination) versus 38.9 % (lapatinib; P = 0.37 for the difference). Week-12 RRs were 36.2 % (combination) versus 22.2 % (lapatinib). In Cohort 2, week-12 RR was 33.3 %. In Cohort 1, grade 3/4 adverse events (AEs) included diarrhea (combination, 9 %; lapatinib, 5 %) and hypertension (combination, 5 %; lapatinib, 0 %). Grades 3/4 AEs in Cohort 2 included diarrhea (40 %), hypertension (5 %), and fatigue (5 %). Alanine aminotransferase elevations >5 times the upper limit of normal occurred in Cohort 1 (combination, 18 %; lapatinib, 5 %) and Cohort 2 (20 %). Upon conclusion, the combination of lapatinib plus pazopanib did not improve PDR compared with lapatinib monotherapy, although RR was increased. Toxicity was higher with the combination, including increased diarrhea and liver enzyme elevations.

Keywords:

Pazopanib Lapatinib HER2-positive Advanced breast cancer First-line therapy 

Abbreviations

AE

Adverse event

CI

Confidence interval

ECOG

Eastern Cooperative Oncology Group

FISH

Fluorescence in situ hybridization

HER2

Human epidermal growth factor receptor type 2

HR

Hazard ratio

LVEF

Left ventricular ejection fraction

MITT

Modified intent-to-treat

PDGFR

Platelet-derived growth factor receptor

PDR

Progressive disease rate

PFS

Progression-free survival

RECIST

Response Evaluation Criteria in Solid Tumors

RR

Response rate

SAE

Serious adverse event

VEGFR

Vascular endothelial growth factor receptor

Notes

Acknowledgments

The authors wish to acknowledge the following investigators who enrolled patients in this study: David Fenton, Cross Cancer Institute, Edmonton, Canada; Tallal Younis, Queen Elizabeth II Health Sciences Centre, Halifax, Canada; Jacques Bonneterre, Centre Oscar Lambret, Lille, France; Véronique Diéras, Institut Curie, Paris, France; Louis-Marie Dourthe, Centre de Radiothérapie, Clinique Sainte Anne, Strasbourg, France; Magdolna Dank, Semmelweis Egyetem, Budapest, Hungary; István Láng, Országos Onkológiai Intézet, Budapest, Hungary; Tamás Pintér, Petz Aladár Megyei Kórház, Győr, Hungary; Lokanatha Dasappa, Kidwai Memorial Institute of Oncology, Bangalore, India; Dinesh Doval, Rajiv Gandhi Cancer Institute, Delhi, India; Sudeep Gupta, Tata Memorial Hospital, Parel, Mumbai, India; Hemant Malhotra, SMS Medical College, Jaipur, India; Anantbhushan Ranade, Dinanath Mangeshkar Hospital, Pune, India; Santosh Thyagu, Regional Cancer Centre, Trivandrum, India; Noa Efrat, Kaplan MC, Rehovot, Israel; Ron Epelbaum, Rambam MC, Haifa, Israel; Alberto Gabizon Barchilon, Shaare-Zedek Medical Centre, Jerusalem, Israel; Bella Kaufman, Sheba MC, Ramat Gan, Israel; Salomon M. Stemmer, Rabin MC, Campus Beilinson, Petach Tikva, Israel; Sung-Bae Kim, Asan Medical Center, Seoul, Korea; Christina Ng, University Malaya Medical Centre, Kuala Lumpur, Malaysia; Tirzo Súarez-Sahui, Hospital Regional ISSSTE “Mérida”, Merida, Mexico; Zeba Aziz, Hameed Latif Hospital, Lahore, Pakistan; Abrar Javed, Nishtar Medical College and Hospital, Multan, Pakistan; Humera Mahmood, NORI, Islamabad, Pakistan; Neelam Siddiqui, Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan; Naila Zahid, Liaquat National Hospital, Karachi, Pakistan; Henry Gomez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Fernando Hurtado de Mendoza, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; Manuel Philco, Hospital Nacional Alberto Sabogal Sologuren, Callao, Peru; Agnieszka Jagiello-Gruszfeld, Samodzielny Publiczny Zespol Pulmonologii i Onk., Olsztyn, Poland; Jolanta Smok-Kalwat, Swietokrzyskie Centrum Onkologii, Kielce, Poland; Natalya Dobrovolskaya, Russian Scientific Center of Roentgeno-Radiology, Moscow, Russian Federation; Alexey Manikhas, St Petersburg City Oncology Dispensary, St. Petersburg, Russian Federation; Vladimir Semiglazov, Petrov Research Institute of Oncology, St. Petersburg, Russian Federation; Sergei Tjulandin, Cancer Research Center, Moscow, Russian Federation; Nan-Soon Wong, National Cancer Centre, Singapore, Singapore; Virote Sriuranpong, Chulalongkorn Hospital, Bangkok, Thailand; Peter Canney, The Beatson West of Scotland Cancer Centre, Glasgow, UK; Stephen Chan, Nottingham City Hospital NHS Trust, Nottingham, UK; Neville Davidson, Broomfield Hospital, Chelmsford, UK; Mark Harries, Guy’s Hospital, London, UK; Stephen Johnston, The Royal Marsden NHS Foundation Trust, London, UK; Andrew Wardley, Christie Hospital, Withington, Manchester, UK; Mary Ann Allison, Comprehensive Cancer Centers of Nevada, Las Vegas, USA; David Chan, Cancer Care Associates Medical Group, Inc., Redondo Beach, USA; Fairooz Kabbinavar, UCLA, Los Angeles, USA; Frederic Kass, Santa Barbara Hematology Oncology Medical, Santa Barbara, USA; Andre Liem, Pacific Shores Medical Group, Long Beach, USA; Giribala Patel, California Medical Research Group, Inc., Fullerton, USA; Ravi Patel, Comprehensive Blood and Cancer Center, Bakersfield, USA; Gladys Rodriguez, South Texas Oncology and Hematology, San Antonio, USA; Carroll Scroggin, Jr., NEA Clinic, Jonesboro, USA; Joseph Sparano, Montefiore Medical, Bronx, USA. Laura Evans, Phillips Gilmore Oncology Communications, and William Sinkins, PhD, ProEd Communications, Inc., provided medical editorial assistance with this manuscript. This study (VEG20007; NCT00347919) was sponsored by GlaxoSmithKline, Philadelphia, PA, and financial support for medical editorial assistance was provided by GlaxoSmithKline.

Conflict of interest

Drs. Richie, Durante, Pandite, and Goodman are GlaxoSmithKline employees and stock holders. Drs. Johnston and Slamon have received speakers bureau honoraria from GlaxoSmithKline and Dr. Johnston’s institution has received research funding from GlaxoSmithKline. Drs. Gómez and Stemmer report no competing financial interests.

Ethical standards

The institutional review board for each participating institution approved the study protocol and the study complied with each country’s laws.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Stephen R. D. Johnston
    • 1
  • Henry Gómez
    • 2
  • Salomon M. Stemmer
    • 3
  • Maria Richie
    • 4
  • Michael Durante
    • 4
  • Lini Pandite
    • 5
  • Vicki Goodman
    • 4
  • Dennis Slamon
    • 6
  1. 1.Royal Marsden NHS Foundation Trust and Institute of Cancer ResearchLondonUK
  2. 2.National Institute of Neoplastic DiseasesLimaPeru
  3. 3.Institute of Oncology, Davidoff Center, Rabin Medical CenterPetach TikvaIsrael
  4. 4.GlaxoSmithKlineCollegevilleUSA
  5. 5.GlaxoSmithKlineResearch Triangle ParkUSA
  6. 6.University of CaliforniaLos AngelesUSA

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