C inhibits receptor tyrosine kinases including MET, VEGF receptors, AXL, and RET. C has been approved in the US for the treatment of progressive, metastatic MTC and in the EU for progressive, unresectable locally advanced or metastatic MTC. In the phase 3 registrational study EXAM, pts were randomized 2:1 to receive 140 mg C or placebo (P) once daily (qd). The primary analysis for EXAM demonstrated a statistically significant improvement in progression-free survival (PFS) with a median PFS of 11.2 mo for C vs 4.0 mo for P (hazard ratio [HR] 0.28, 95% CI, 0.19–0.40; p < 0.001) (Elisei, JCO 2013). Dose reductions occurred commonly in the C arm with 82% of pts experiencing at least one dose reduction. While overall survival (OS) was not significantly improved in the overall population (median OS of 26.6 mo for C vs 21.1 mo for P; HR 0.85, 95% CI 0.64–1.12; p = 0.24), median OS was 44.3 mo for C vs 18.9 mo for P (HR 0.60, 95% CI 0.38–0.94) in the RET M918T-positive subgroup (Schlumberger, Ann Oncol 2017).
EXAMINER (NCT01896479) is a global, randomized, double-blind study comparing the safety and efficacy of C at 60 vs 140 mg qd in pts with progressive, metastatic MTC using a noninferiority study design. Approximately 188 pts will be randomized 1:1 to receive C at 140 mg qd as capsules or 60 mg qd as tablets in Europe, Asia, Canada, and other regions. Eligible pts must have measurable disease and documented progressive disease within 14 mo prior to enrollment. A recent tumor tissue sample to test for RET and RAS mutations or documentation of a RET or RAS mutation is required. Pts will be stratified based on RET M918T status. After randomization, pts will be treated until disease progression per RECIST 1.1 or intolerable toxicity. Tumor assessments will be performed every 12 weeks. PFS and objective response rate evaluated by independent review are the primary and secondary efficacy endpoints, respectively; safety and correlation of tumor mutation status with clinical response are additional endpoints. The EXAMINER study continues to enroll pts.
Clinical trial identification
Legal entity responsible for the study
The study was supported by Exelixis, Inc.
J. Krajewska: Honoraria and subinvestigator in clinical trials: Eisai, Exelixis, Sanofi-Genzyme, Bayer Health Care; Travel, accommodations, expenses: Sanofi-Genzyme, Ipsen, Novartis. B.G. Robinson: Stock or other ownership: Cochlear Ltd.; Honoraria, consulting or advisory role, speakers' bureau: Eisai; Travel, accommodations, expenses: Loxo. H. Gan: Consulting or advisory role: MSD, AbbVie; Speakers' bureau, travel, accommodations, expenses: Ignyta; Research funding: BMS, Ignyta. R. Elisei: Consulting or advisory role: Sanofi-Genzyme, Eisai, Loxo, Exelixis; Speakers' bureau: Sanofi-Genzyme, Eisai; Travel, accommodations, expenses: Sanofi-Genzyme. J. Partyka: Employment, research funding, travel, accommodations and expenses, stock or other ownership: Exelixis. A.E. Borgman: Employee, stock or other ownership: Exelixis. M. Schlumberger: Honoraria, research funding: Bayer, Eisai, Exelixis-Ipsen, Sanofi-Genzyme; Consulting or advisory role: Bayer, Eisai, Exelixis-Ipsen, Sanofi-Genzyme; Travel, accommodations, expenses: Bayer, Eisai, Sanofi-Genzyme. All other authors have declared no conflicts of interest.