Phase i trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

Guy Jerusalem, Angelica Fasolo, Veronique Dieras, Fatima Cardoso, Jonas Bergh, Luc Vittori, Yufen Zhang, Cristian Massacesi, Tarek Sahmoud, Luca Gianni

Research output: Contribution to journalArticlepeer-review

Abstract

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m 2 on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).

Original languageEnglish
Pages (from-to)447-455
Number of pages9
JournalBreast Cancer Research and Treatment
Volume125
Issue number2
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Everolimus
  • HER2-overexpressing metastatic breast cancer
  • mTOR
  • Phase I
  • Trastuzumab
  • Vinorelbine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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