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

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.
AuthorsMassimo 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
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 137 Issue 2 Pg. 471-82 (Jan 2013) ISSN: 1573-7217 [Electronic] Netherlands
PMID23239151 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Indazoles
  • Pyrimidines
  • Quinazolines
  • Sulfonamides
  • Lapatinib
  • pazopanib
  • ERBB2 protein, human
  • Receptor, ErbB-2
Topics
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Diarrhea (chemically induced)
  • Disease-Free Survival
  • Female
  • Humans
  • Indazoles
  • Inflammatory Breast Neoplasms (drug therapy, metabolism, mortality)
  • Lapatinib
  • Middle Aged
  • Pyrimidines (administration & dosage, adverse effects, therapeutic use)
  • Quinazolines (administration & dosage, adverse effects, therapeutic use)
  • Receptor, ErbB-2 (metabolism)
  • Sulfonamides (administration & dosage, adverse effects, therapeutic use)
  • Treatment Outcome

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