Anticancer therapeutics that specifically target the well-defined signaling pathways important for cancer cell proliferation, invasion and metastasis such as EGFR or VEGFR pathway have shown promising clinical benefit in the treatment of advanced NSCLC 
. Furthermore, EGFR is known to regulate the expression of VEGF, and the resistance to tyrosine kinase inhibitors (TKIs) targeting EGFR may be partly associated with a rise in both host and tumor-derived VEGF 
. These were the basis for vandetanib, a once-daily oral anticancer agent that targets VEGFR, EGFR and RET signaling, to be combined with chemotherapy for advanced NSCLC in the clinical trials.
Our meta-analysis showed that addition of vandetanib to chemotherapy increased ORR and PFS, but did not improve OS in patients with advanced NSCLC. The results were consistent with the recently published meta-analysis on this subject conducted by Xiao YY et al
. However, the clinical trials included in our analysis are more complete. Because the case volume in the Herbst et al
. trial was the largest (occupied approximately 61% among the five RCTs), it led to 68%, 61%, and 57% relative weight in the OS, PFS, and ORR analysis respectively. However, when we performed additional analysis with the subtraction of the Herbst et al
. trial data, the overall results remained similar [HR for OS was 0.99 [0.83–1.18], p
0%), HR for PFS was 0.80 [0.68–0.93], p
0%), the RR for ORR was 1.82 (1.34–2.48), p
0%)]. Therefore, the weight of the Herbst et al
. trial did not impact the overall results.
The most frequently reported adverse effect from vandetanib treatment was rash. Side effects caused by vandetanib, and particularly rash, appeared to be more frequent at higher doses. The meta-analysis conducted by Rosen et al
. showed that patients who received vandetanib 300 mg had a significantly increased risk of developing all-grade rash in comparison with controls, with a relative risk of 2.43 (95% CI, 1.37–4.29; p
. Our meta-analysis showed that 100mg vandetanib could also increase the risk of grade≥3 rash (RR 5.77 [3.32–10.04], p
<0.00001). The risk of grade≥3 diarrhea was also increased with the treatment of all dosage vandetanib. But the treatment of 100 mg vandetanib showed no statistically difference (RR 1.50 [0.99–2.26], p
0.05). The prolongation of QTc by vandetanib requires further post-marketing surveillance.
Interestingly, we found that anemia was mitigated in the combination arm. But definitive conclusions could not be drawn because only 2 trials included in this analysis reported the side effect of anemia 
. The explanation of the reducted incidence of anemia treated with vandetanib might be that inhibition of VEGF signaling enhanced erythropoiesis through hypoxia induced factor (HIFa), which had been confirmed in preclinical models 
. Awareness of these adverse events is critical for clinicians to ensure the best possible clinical benefit.
OS is the gold standard endpoint for clinical improvement in cancer patients. Our meta-analysis showed no improvement on OS, but significant on PFS. The rapid emergence of resistance to vandetanib may be responsible for this discrepancy between OS and PFS, and the ability to overcome drug resistance can obviously change patient outcome outcome and is an important future endeavor. The significant improvement on PFS suggests that vandetanib has activity in NSCLC, and there may be a subgroup of patients who could benefit from this drug which is currently approved by FDA for treating advanced medullary thyroid cancer. Subgroup analyses as defined by histology (adenocarcinoma or squamous), sex (male or female), smoke status (smokers or nonsmokers) and therapy line (first or second line therapy) did not show significant difference in OS. This indicates that there is a critical need for the identification of biomarkers for patients likely to benefit from vandetanib.
Hanrahan et al
. found that, patients with low baseline plasma VEGF treated with vandetanib 100 mg/d and docetaxel appeared to have longer PFS and OS compared with those treated with docetaxel alone, whereas patients with high baseline VEGF showed similar treatment outcomes in both arms, but no definitive conclusions on the role of VEGF as a predictive biomarker for benefit from vandetanib could be drawn from this study because of its limitation 
. However, the prognostic value of baseline plasma VEGF should be evaluated in the future clinical trials.
Furthermore, EGFR and KRAS are the most frequently mutated proto-oncogenes in NSCLC 
. TKIs targeting EGFR have become important therapeutic options for patients with advanced NSCLC, patients whose tumors harboring a classic EGFR mutation or ALK (anaplastic lymphoma kinase) translocation can substantially benefit from erlotinib or gefitinib 
. Whethere or not EGFR and ALK mutations can predict the benefit of vandetanib need to be investigated. Using KRAS mutation status for selecting treatment with EGFR-TKIs remains controversial. A meta-analysis of 22 studies conducted by Mao et al
. identified KRAS mutation as a negative predictive biomarker for EGFR-TKI treatment in patients with NSCLC 
. However, Guan et al
. found that though KRAS mutation was a factor for poor prognosis, but not an independent predictor of response to EGFR-TKIs or chemotherapy in patients with lung cancer 
. The relationship of KRAS mutation status and from the benefit of vandetanib treatment remains to be clarified.
Several limitations exist in this meta-analysis. First, although the publication bias was not found by funnel plots, the small number of the trials limited the power of the analysis. Second, one study we identified was reported in an abstract form only 
, which made it difficult to extract complete data for analysis, though this study was unlikely to change the overall results because of its small sample size. Furthermore, all the trials included in this analysis used PFS as primary end point. The only trial, conducted by de Boer et al
., had a separate survival follow-up analysis 
In conclusion, Vandetanib has shown activity in NSCLC. The identification of predictive biomarkers is warranted in future trials to select a subset of patients with advanced NSCLC who may benefit from vandetanib.