A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

Massimo Cristofanilli*, Stephen R D Johnston, Alexey Manikhas, Henry L. Gomez, Oleg Gladkov, Zhimin Shao, Sufia Safina, Kimberly L. Blackwell, Ricardo H. Alvarez, Stephen D. Rubin, Sulabha Ranganathan, Suman Redhu, Maureen E. Trudeau

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.

Original languageEnglish (US)
Pages (from-to)471-482
Number of pages12
JournalBreast Cancer Research and Treatment
Volume137
Issue number2
DOIs
StatePublished - Jan 2013

Keywords

  • HER2-positive breast cancer
  • Inflammatory breast cancer
  • Lapatinib
  • Pazopanib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cristofanilli, M., Johnston, S. R. D., Manikhas, A., Gomez, H. L., Gladkov, O., Shao, Z., Safina, S., Blackwell, K. L., Alvarez, R. H., Rubin, S. D., Ranganathan, S., Redhu, S., & Trudeau, M. E. (2013). A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer. Breast Cancer Research and Treatment, 137(2), 471-482. https://doi.org/10.1007/s10549-012-2369-x