ZETA

Background

Phase III double-blind RCT (ZETA). N=331 patients with symptomatic or radiographically progressive hereditary or sporadic MTC, ECOG PS 0–2. Enrolled 2006–2007 at 137 global sites. Randomized 2:1 (vandetanib:placebo). Vandetanib is an oral multikinase inhibitor targeting RET, VEGFR1–3, and EGFR. Designed before emergence of selective RET inhibitors. First phase III trial to demonstrate efficacy of a targeted agent in MTC; FDA approved based on this trial.

Interventions and follow up

Arm A: Vandetanib 300 mg oral daily until PD or unacceptable toxicity
Arm B: Placebo (crossover at PD permitted)
Primary endpoint: PFS
mFollow up: 24 month

Results

mPFS (vandetanib): Not reached vs 19.3 months (placebo), HR 0.46 (95% CI 0.31–0.69), P<.001
ORR: 45% vs 13%
DCR: 87% vs 71%
Calcitonin response rate: 69% vs 3%
OS: Not significantly different (crossover confounded)

Adverse events

Main adverse events: Grade ≥3 AEs: 55% (vandetanib) vs 36% (placebo). QTc prolongation grade ≥3: 8% — BLACK BOX WARNING; TdP reported. Diarrhea grade ≥3: 11%. Rash 5%. Hypertension 9%. Bradycardia. Requires REMS program (US) with ECG monitoring at baseline and during treatment.

Conclusions

Vandetanib significantly improved PFS (HR 0.46) and ORR (45% vs 13%) with calcitonin tumor marker reduction in 69% of patients. The PFS median was not reached in the vandetanib arm, demonstrating durable disease control in progressive MTC. ZETA led to FDA approval of vandetanib for unresectable, locally advanced or metastatic MTC in 2011.

Key Limitations

Key Limitations: No OS benefit demonstrated; trial duration/crossover confounded this analysis. QT prolongation is a clinically significant toxicity requiring black box warning and REMS; drug interactions and careful monitoring required. The 300 mg dose is associated with substantial toxicity. ORR of 45% appears impressive but includes many short-lived partial responses. RET-selective inhibitors (selpercatinib, pralsetinib) now demonstrate ORR >60–70% with better selectivity and tolerability in RET-mutant MTC, superseding vandetanib as preferred.

Clinical Context

FDA approved vandetanib 300 mg for progressive MTC in April 2011 based on ZETA — the first targeted therapy approval in MTC. Together with cabozantinib (EXAM), vandetanib defined a new treatment era. However, the emergence of highly selective RET inhibitors (selpercatinib/LIBRETTO-001, pralsetinib/ARROW) has shifted practice. NCCN now lists selpercatinib or pralsetinib as preferred for RET-mutant MTC; vandetanib and cabozantinib are category 2A alternatives or first-line for RET-wild-type/unknown MTC.

References

References: Wells SA et al, JCO 2012 (primary)