Vandetanib improved PFS slightly when combined with paclitaxel and carboplatin

Vandetanib in conjunction with paclitaxel and carboplatin improved PFS for patients with non–small cell lung cancer compared with paclitaxel and carboplatin alone, according to the results of a study conducted in Europe, South Africa and the United States.

In a study sponsored by AstraZeneca, researchers enrolled 181 patients with previously untreated locally advanced or metastatic disease into a randomized phase-2 study. The researchers randomly assigned 56 patients to once-daily 300 mg/mm² vandetanib (Zactima, AstraZeneca) plus paclitaxel and carboplatin and 52 patients to paclitaxel and carboplatin alone. A vandetanib monotherapy arm (n=73) was stopped after meeting discontinuation criteria (HR>1.33 vs. paclitaxel and carboplatin).

The researchers wrote that the study met the primary objective by establishing that risk for progression for patients in the vandetanib group was superior to those in the paclitaxel and carboplatin alone group (HR=0.76). Median PFS for the vandetanib group was 24 weeks compared with 23 weeks in the paclitaxel and carboplatin group.

Progression was the primary cause of death for the 127 of 133 patients who died during the study. The researchers observed four serious events leading to death for patients in the vandetanib group: pulmonary embolism, respiratory failure, respiratory failure with multiorgan failure and sepsis. Only respiratory failure was deemed to be related to study treatment.

OS was not significantly different between the two groups. Median time to death was 10.2 months in the vandetanib group and 12.6 months paclitaxel and carboplatin group. The study team is conducting a correlative analysis of blood-based prognostic/predictive markers and clinical outcome to understand why vandetanib did confer a survival benefit.

Objective response rate for vandetanib was 32% compared with 25% for the paclitaxel and carboplatin group. The rate of disease control was similar, 57% vs. 58% for the paclitaxel and carboplatin group. – by Jason Harris

J Clin Oncol. 2008;26:5407-5415.

Even though the study met its primary endpoint of having a P value <.2 for PFS, the clinical significance of the results of this study are questionable with only a one-week improvement in PFS for the addition of vandetanib to paclitaxel/carboplatin vs. paclitaxel/carboplatin alone. Additionally, there was no improvement in OS, if anything there was a nonstatistically significant detriment.

This compound is a multitargeted tyrosine kinase inhibitor. It inhibits the VEGF receptor, epidermal growth factor receptor and RET receptor. The clinical picture of patients treated with this compound attests to its effects both through the EGFR TK and VEGF receptor TK. Its effects on the EGFR TK are evident because women did better than men, which is typical for gefitinib (Iressa, AstraZeneca); the two patients with mutations who got vandetanib either alone or with chemotherapy did well and rash and diarrhea are the predominant side effects. The presence of hypertension as a side effect attests to effects on VEGF TK.

The role of vandetanib in the treatment of advanced NSCLC remains to be defined. Any further clinical investigation of this compound should occur in a selected population of patients enriched for never smokers or occasional smokers and/or patients with mutations in the EGFR TK domain. The sequential use of this compound after induction chemotherapy could also be explored. Future studies should also address the dose issue of 100 mg vs. the 300-mg dose of vandetanib. In a previous study, when vandetanib was combined with docetaxel, the 100-mg plus docetaxel dose appeared to be similar in efficacy to the 300-mg plus docetaxel dose in previously treated patients with NSCLC.

– George Simon, MD

Director of Thoracic Oncology, Fox Chase Cancer Center