Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC)

Abstract

CRA8003 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. Addition of vandetanib to docetaxel (doc) prolonged progression-free survival (PFS) in a randomized phase II study in patients (pts) with previously treated NSCLC (Heymach et al, JCO, 2007). Methods: The primary objective was to determine whether vandetanib 100 mg/day + doc 75 mg/m 2 every 21 days (max 6 cycles) prolonged PFS vs placebo + doc. Secondary endpoints included overall survival, objective response rate (ORR), time to deterioration of symptoms (TDS) and safety. Efficacy and safety in females were assessed as a co-primary analysis population. Eligibility criteria included stage IIIB/IV NSCLC, PS 0–1, and previous first-line chemotherapy. Results: Between May 2006 and April 2008, 1,391 pts (mean age, 58 years; 30% female; 25% squamous; 10% brain mets) were randomized to vandetanib + doc (n=694) or placebo + doc (n=697). Baseline characteristics were similar in both arms. Median duration of follow-up was 12.8 months, with 87% patients progressed and 59% dead. Addition of vandetanib to doc showed a statistically significant improvement in PFS vs doc (hazard ratio [HR] 0.79, 97.58% CI 0.70–0.90; P<0.001), and a similar advantage in females (HR 0.79; P=0.024). Significant advantages for vandetanib + doc were also seen for ORR (17% vs 10%, P<0.001) and TDS (HR 0.78, P=0.002; FACT-L Lung Cancer Subscale). Overall survival showed a positive trend for vandetanib + doc that was not statistically significant (HR 0.91, 97.52% CI 0.78–1.07; P=0.196). The adverse event (AE) profile was consistent with that previously observed for vandetanib in NSCLC. Common AEs occurring more frequently in the vandetanib arm included diarrhea (42% vs 33%), rash (42% vs 24%) and neutropenia (32% vs 27%). Nausea (23% vs 32%), vomiting (16% vs 21%) and anemia (10% vs 15%) were less frequent in the vandetanib arm. The incidence of protocol-defined QTc prolongation was <2% in pts receiving vandetanib. Conclusions: The study met its primary objective of PFS prolongation with vandetanib + doc vs doc. Vandetanib is the first oral targeted therapy in phase III trials to show significant evidence of clinical benefit when added to standard chemotherapy in NSCLC. [Table: see text]