Cancer Treatment Today

With the successful results of the phase II studies, AstraZeneca launched an unprecedented 4 simultaneous large, international phase III trials to determine the role that vandetanib would play in NSCLC. Unfortunatel, the results were mostly negative. These 4 trials included 2 monotherapy trials: the ZEPHYR trial – monotherapy after failure of previous EGFR tyrosine kinase inhibition (14) and the ZEST trial – monotherapy in comparison with erlotinib in the 2nd or 3rd line setting. There were also two 2nd line trials where vandetanib was combined with chemotherapy: the ZODIAC trial (vandetanib plus docetaxel), and the ZEAL trial (vandetanib plus pemetrexed. Unfortunately, the ZEST, ZEAL and the ZEPHYR trials did not meet their primary end points, and whilst the ZODIAC trial demonstrated an improved PFS, this did not translate into an improved overall survival and the PFS benefit was clinically modest.

In the ZEPHYR trial (zactima efficacy trial for NSCLC patients with history of EGFR-TKI- and chemo-resistance), 924 patients who had previously received chemotherapy and an EGFR TKI were randomised 2:1 to receive vandetanib 300 mg or placebo (14). As one might expect considering the entry criteria, the trial population was quite different to the standard late stage NSCLC trial: there were more females than males, more than 50% of patients were of Asian descent, and more than 50% were non-smokers. They were heavily pre-treated patients with more than 60% having had 2-3 lines of chemotherapy for advanced disease, 63% had at least 3 organs involved at study entry and 42% had progressed as their best overall response to the previous TKI use. Also of note was that more than 50% of patients in either study arm went on have further specific anti-cancer therapy following completion of their study treatment. This would have constituted 3rd, 4th or even 5th line therapy, which would be considered unusual in advanced NSCLC.

The study failed to meet its primary end point of superior overall survival with vandetanib. No difference in overall survival was seen at median follow-up of 15.4 months, with an estimated HR of 0.95 (95.2% CI, 0.81-1.11; P=0.527). Median survival was 8.5 months compared with 7.8 months in the placebo arm. One year survival was estimated to be 35.5% with vandetanib compared to 31.7% with placebo. Vandetanib was significantly better than placebo in the secondary end points of PFS, ORR and DCR at 8 weeks. The estimated HR for PFS was 0.63 (95.2% CI, 0.54-0.74; P<0.0001). Only 2.6% of patients receiving vandetanib had objective responses, but 30% of patients had stable disease or better at 8 weeks, compared with 16% of patients receiving placebo (P<0.0001). The toxicity profile was as expected considering results published by the other studies: increased incidence of rash, diarrhea, and hypertension. These side effects were mainly grade 1-2, but did indicate that the agent was hitting its targets.

One must conclude, that at this time, using this drug in lung cancer is experimental, with or without RET positivity.
Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR) Jin Soo Lee, Vera Hirsh, Keunchil Park, Shukui Qin, Cesar R. Blajman, Reury-Perng Perng, Yuh-Min Chen, Laura Emerson, Peter Langmuir, and Christian Manegold. J Clin Oncol 30. © 2012

Richard DeBoer, Vandetanib in advanced non small cell lung cancer: a promise unfulfilled. Transl Lung Cancer Res 2013;2(1)