Vandetanib for thyroid cancer

Abstract

Vandetanib is an oral multi-receptor tyrosine kinase inhibitor, which inhibits VEGFR- 2, VEGFR-3, RET, and EGFR. It was approved as the first targeted drug for medullary thyroid cancer (MTC) in US (2011), EU (2012), then Japan (2015). Phase II study for 30 patients (pts) with advanced hereditary MTC showed 20% response rate and 73% control rate. Multi-institutional randomized, placebo-controlled phase III study in 331 pts with advanced MTC (ZETA) showed significant improvement in PFS (HR 0.46, not reached versus 19.3 months). Response rate was 45%, and was higher in pts with RET M918T mutation. Adverse events of grade 3 or more were diarrhea (11%), hypertension (9%), QTc elongation (85), fatigue (6%), and eruption (4%). In Japanese multicenter open-label phase I study, 14 pts (7 male, 7 female) with hereditary or sporadic, locally advanced or metastatic MTC received vandetanib 300 mg qd (median exposure period: 56 weeks). Diarrhea (79%), hypertension (64%), and Rash (43%) were commonly detected. 3 pts (21%) had QTc-related AEs. One serious AE (interstitial lung disease) led to discontinuation. Of 13 pts analyzed for efficacy, 5 (39%) had partial response and 8 (62%) had stable disease (>=12 weeks). PFS at 6 and 12 months was 100% and 85%, respectively. This study demonstrated that vandetanib monotherapy would be beneficial for Japanese MTC pts. Vandetanib phase III study for pts with differentiated thyroid cancer is also ongoing.