Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors

Robert S. Benjamin, Patrick Schöffski, Jörg Thomas Hartmann, Allan Van Oosterom, Binh Nguyen Bui, Justus Duyster, Scott Schuetze, Jean Yves Blay, Peter Reichardt, Lee S. Rosen, Keith Skubitz, Sheryl McCoy, Yu Nien Sun, Daniel E. Stepan, Laurence Baker

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Purpose: This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST). Methods: Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by 18FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety. Results: In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per 18FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15-24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing. Conclusions: In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.

Original languageEnglish (US)
Pages (from-to)69-77
Number of pages9
JournalCancer chemotherapy and pharmacology
Volume68
Issue number1
DOIs
StatePublished - Jul 2011

Bibliographical note

Funding Information:
Acknowledgments This study was funded by Amgen Inc. The authors would like to acknowledge the contributions of Isabelle Ray-Coquard, MD, and would like to thank Beate D Quednau, PhD (Amgen Inc.) for providing an initial draft of the manuscript and for general assistance in writing and editing of the manuscript.

Keywords

  • Angiogenesis
  • GIST
  • Imatinib
  • Kit receptor
  • Motesanib
  • VEGF receptor

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