Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): A randomized, double-blind phase III trial (ZEPHYR).

Abstract

7525 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This study assessed whether vandetanib conferred an overall survival (OS) benefit vs placebo in patients (pts) with locally advanced or metastatic NSCLC after failure of prior therapy with an EGFR TKI. Methods: Eligible pts (stage IIIB/IV NSCLC; WHO PS 0–2; all histologies permitted; 1–2 prior chemotherapies; prior EGFR TKI) were randomized 2:1 to receive vandetanib 300 mg/day or placebo until progression/toxicity. The primary objective was to show superiority in OS (> 90% power to detect ≥ 25% reduction in death rate; hazard ratio [HR] ≤ 0.75). Secondary efficacy endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) at 8 weeks. Results: Between Nov 2006–Nov 2008, 924 pts (mean age 60 yrs; 53% female; 56% East Asian; 53% non-smoker; 79% adenocarcinoma; 58% 2 previous chemotherapy regimens) received vandetanib (n = 617) or placebo (n = 307). Baseline characteristics were similar in both arms. At data cut-off (Oct 09), median follow-up was 15.4 months with 90% pts progressed and 76% pts dead. There was no difference in OS for pts receiving vandetanib vs placebo (HR 0.95, 95.2% CI 0.81–1.11; p = 0.527); median OS was 8.5 months (vandetanib) and 7.8 months (placebo). Significant advantages favoring vandetanib were seen for the secondary endpoints of PFS (HR 0.63, 95.2% CI 0.54–0.74; p < 0.0001), ORR (2.6% vs 0.7%: p = 0.028) and DCR at 8 weeks (30% vs 16%; p < 0.0001). Post-progression therapy was balanced across the arms in both number and type. Adverse events (AEs) observed for vandetanib were generally consistent with previous NSCLC studies of vandetanib 300 mg. Common AEs (any grade) occurring with a greater frequency in the vandetanib arm included diarrhea (46% vs 11%), rash (42% vs 11%) and hypertension (26% vs 3%). Conclusions: The study did not meet its primary objective of demonstrating an OS benefit with vandetanib vs placebo in pts with advanced NSCLC who had previously failed chemotherapy and received treatment with an EGFR TKI, although PFS was better with vandetanib vs placebo. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Boehringer Ingelheim, Lilly, Merck Serono, Novartis, Roche AstraZeneca, Boehringer Ingelheim, Lilly, Merck Serono, Novartis, Roche AstraZeneca