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/m2 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]

Vascular normalization: a real benefit?

“…7 The inhibitors of VEGF in the therapy of central nervous system malignancy normalizes tumor vasculature and decrease tumor interstitial pressure, leading to an improved access of cytoreductive drugs and radiotherapy efficacy, due to an increased oxygen delivery [39]. However, these agents may also restore the low permability characteristics of normal brain microvasculature, counteracting beneficial effects.…”

“…It appears that bevacizumab can be a component of an effective combination therapy approach to colorectal cancer, non-small-cell-lung cancer (NSCLC), and breast cancer [3][4][5]. Encouraging results have also been obtained when chemotherapy has been used in combination with an anti-VEGF receptor-2 (VEGFR-2) monoclonal antibody (cediranib) [6] and an oral tyrosine kinase inhibitor of VEGFRs and epidermal growth factor receptor (EGFR) (vandetanib) [7,8]. The observation that combining chemotherapy with angiogenesis inhibitors causes increased apoptosis in tumors in vivo [9,10] suggest that angiogenesis inhibitors may have an additive effect when administered in combination with chemotherapy.…”

Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

“…[7] Data have recently been reported from three double-blind, randomized, phase III studies of vandetanib in patients with advanced, previously-treated non-small cell lung cancer (NSCLC). [8][9][10] In the ZODIAC (ZactimaÔ in cOmbination with Docetaxel In non-small cell lung Cancer) study, vandetanib in combination with docetaxel produced a significant improvement in progression-free survival compared with docetaxel alone (p < 0.001). [9] Results from the ZEAL (ZactimaÔ Efficacy with Alimta Ò in Lung cancer) [8] and ZEST (ZactimaÔ Efficacy when Studied versus Tarceva Ò ) [10] studies demonstrated activity in NSCLC for the combination of vandetanib with pemetrexed, [8] and for monotherapy with vandetanib.…”

Standing the test of time in Europe? Gefitinib in the treatment of non-small-cell lung cancer

“…[45][46][47][48][49] Zodiac compared docetaxel with or without the addition of vandetanib at 100 mg daily or 300 mg daily in 1391 patients. A statistically significant increase in PFS was seen with vandetanib at either dose, compared to docetaxel alone (12 weeks versus 18.7 weeks and 17 weeks respectively).…”