Phase 2 Trial to Evaluate the Efficacy and Safety of Dovitinib in Patients (Pts) with Gastrointestinal Stromal Tumor (Gist) Refractory and/or Intolerant to Imatinib (Im)

Abstract

ABSTRACT Aim: Sunitinib is approved for advanced GIST resistant/refractory to IM; however, disease control rate (DCR) at 12 wk was only ≈ 40%. Thus, novel therapeutic second-line strategies are needed to improve outcomes. Dovitinib inhibits several tyrosine kinases (eg, FGFR, VEGFR, PDGFRb, KIT). DOVIGIST (NCT01478373) is a multicenter, single-arm study to evaluate the efficacy and safety of second-line dovitinib in GIST. Methods: Eligible pts (≥ 18 y) had histologically confirmed GIST; pts had advanced/metastatic GIST refractory/intolerant to IM ≥ 400 mg/day or recurrent GIST after adjuvant IM. All pts had ≥ 1 measurable lesion at baseline. Prior tyrosine kinase inhibitors other than IM were not allowed. Pts received dovitinib 500 mg/day (5 days on/2 days off) until progressive disease (PD), unacceptable toxicity, death, or discontinuation. The primary endpoint was DCR (per RECIST 1.1) at 12 wk. Based on prior trials, DCR ≥45% was deemed clinically meaningful. Key secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and safety. Results: Of 39 pts who received ≥1 dose of dovitinib, 1 had unconfirmed GIST histology; thus, the efficacy analysis included 38 pts (median age, 60 y). The median time from diagnosis to first dose of dovitinib was 46.3 mo; 81.6% had PD on IM, 13.2% discontinued IM due to intolerance, and 5.2% had intolerance and PD. The most common grade 3/4 dovitinib-related adverse events (AEs) were fatigue (12.8%), diarrhea, vomiting, and hypertriglyceridemia (7.7% each); 21.1% discontinued due to AEs. One pt died of a heart attack (suspected drug related). The median PFS was 20.1 wk (90% CI, 12.3-32.1). DCR at 12 wk was 52.6% (Table). Conclusions: DOVIGIST met its primary endpoint. The DCR of 52.6% compares favorably with that of other second-line treatments. Dovitinib had promising efficacy and a manageable safety profile, warranting further studies in GIST. Best Response at 12 Wk, n = 38 n % 90% CI Partial response (PR) 1 2.6 Stable disease (SD) 19 50.0 PD 5 13.2 Unknowna 13 34.2 ORR (≥ PR) 1 2.6 0.1-11.9 DCR (≥ SD) 20 52.6 38.2-66.7 a Not all baseline lesions evaluated during follow-up; no PD detected ≤12 wk on dovitinib. Disclosure: H. Joensuu: The Clinical Research Institute of Helsinki University Hospital has received financial support from Novartis and Bayer AG because HJ participated in advisory group meetings or speaking events; J-Y. Blay: Received research support and honoraria from Novartis, GSK, Roche, Pharmamar, Bayer, MSD, JNJ; E. Fumagalli: Founds for studies and research activities: Amgen Dompe, Bayer, Glaxo SK, Merck SD, Novartis, Pfizer, PharmaMar, Sanofi-Aventis, ImClone, Infinity, Janssen Cilag, Lilly, Molmed, Merck SD, Schering Plough Travel for medical meetings: Novartis; G.E. Grignani: Received travel reimbursement from PharmaMar. Expert opinion for Bayer and Glaxo-Welcome; O. Bouche: Received research support and honoraria from Novartis; S. Bauer: received honoraria by Novartis, Pfizer, Bayer and have received a research grant by Novartis (for a clinical trial). Advisory board for Pfizer; C. Barone: Received honoraria as a speaker and chairman; C. Weiss, S. Crippa, M. Camozzi and R. Castellana: Novartis employee; A. Le Cesne: Received honoraria from GSK, Novartis, Pharmamar and Pfizer for advisory board. All other authors have declared no conflicts of interest.