ORLANDO, Fla., May 30 Data from the Phase III ZODIAC study in advanced non-small cell lung cancer patients, with the investigational drug vandetanib, were presented today at the American Society of Clinical Oncology (ASCO) meeting in Orlando. Results show that the study met its primary endpoint, demonstrating that the addition of vandetanib to docetaxel resulted in a statistically significant improvement in progression-free survival (PFS), the length of time a patient lives without their cancer growing (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; P<0.001. Median PFS: 14.0 weeks vs. 17.3 weeks, favoring vandetanib). Vandetanib is the first oral targeted therapy to show evidence of clinical benefits when added to chemotherapy in a Phase III study in second line advanced NSCLC(1).
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ZODIAC is a randomized, double-blind, placebo-controlled Phase III study evaluating the combination of vandetanib 100mg with docetaxel versus docetaxel alone. The study enrolled 1391 patients previously treated with one prior anti-cancer therapy for advanced NSCLC.
Data from ZEAL(2), a smaller Phase III study also featured on this year's ASCO program, are supportive of ZODIAC although the primary endpoint did not reach statistical significance in the ZEAL study (hazard ratio [HR] 0.86, 97.58% CI 0.69-1.06; P=0.108. Median PFS: 11.9 weeks vs. 17.6 weeks, favouring vandetanib). The combination of vandetanib plus pemetrexed did show a positive trend in prolongation of PFS compared with pemetrexed alone.
ZEAL is a randomized, double-blind, placebo-controlled Phase III study evaluating vandetanib 100mg plus pemetrexed versus pemetrexed alone. The study enrolled 534 patients previously treated with one prior anti-cancer therapy for advanced NSCLC.
Evaluation of secondary endpoints in the ZODIAC and ZEAL studies showed that the addition of vandetanib to chemotherapy significantly improved objective response rate, which is a measurement of tumor shrinkage (ZODIAC: 17% vs. 10%, P<0.001; ZEAL: 19.1% vs. 7.9%, P<0.001), the studies also showed that adding vandetanib to chemotherapy resulted in a significantly longer time to deterioration of disease related symptoms (ZODIAC: HR 0.78, P=0.002, FACT-L Lung Cancer Subscale; ZEAL: HR 0.61, P=0.004, Lung Cancer Symptom Scale). Overall survival in both studies showed a positive trend, although they did not reach statistical significance (ZODIAC Study: HR 0.91, 97.52% CI 0.78-1.07: P=0.196; ZEAL Study: HR 0.86, 97.54% CI 0.65-1.13; p=0.219).
The observed safety profile in both studies was consistent with previous studies with vandetanib in NSCLC. The most common adverse events associated with vandetanib included rash, diarrhea and hypertension (ZEAL); rash, diarrhea and neutropenia (low white blood cell count) (ZODIAC). Incidence of protocol-defined QTc prolongation was <2.0 percent in both studies and was not associated with symptoms.
"There are more deaths from lung cancer alone than from breast, colon, and prostate cancers combined - and it's extremely difficult to treat," said Professor Roy Herbst, M.D., Ph.D., The University of Texas M. D. Anderson Cancer Center, Texas, Principal Investigator on the ZODIAC study. "The ZODIAC study showed adding vandetanib to chemotherapy improved progression-free survival, in patients who have few, if any options for treatment."
Results from a third Phase III study, ZEST(3), were also presented at this year's ASCO. While the primary objective of demonstrating a statistically significant prolongation of PFS for vandetanib was not met in this study, in a pre-planned non-inferiority analysis, vandetanib was shown to have similar efficacy to erlotinib for PFS and OS (PFS: hazard ratio [HR] 0.98, 95.22% CI 0.87-1.10; P=0.721; OS: HR 1.01, 95.08% CI 0.89-1.16; P=0.830). Objective response rate and symptom control were also similar for both treatments (ORR: both 12%; symptoms: pain, HR 0.96, P=0.583; dyspnea, HR 1.08, P=0.333; cough, HR 0.94, P=0.403).
The ZEST study was a randomized, double-blind, Phase III study evaluating the efficacy of vandetanib 300mg versus erlotinib 150mg. The study enrolled 1240 patients with locally advanced or metastatic NSCLC after failure of at least one prior anti-cancer therapy.
The most common adverse events observed in the ZEST study were rash, diarrhea and hypertension. Incidence of protocol-defined QTc prolongation was 5.1 percent in the vandetanib arm.
AstraZeneca plans to submit a regulatory submission for the use of vandetanib 100mg in combination with chemotherapy for patients with advanced NSCLC in the first half of 2009.
Evaluation of vandetanib is ongoing, as monotherapy or in combination with other anti-cancer therapies in a range of tumor types, including thyroid cancer.
Results from the ZEPHYR (300mg monotherapy study in EGFR failures in advanced NSCLC, Phase III) and ZETA (300 mg monotherapy in advanced medullary thyroid cancer, Phase III) studies will be available during the second half of 2009.
ZACTIMA(TM) is a trademark of the AstraZeneca group of companies.
About lung cancer
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The statements contained herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report/Form 20-F for 2008. Nothing contained herein should be construed as a profit forecast.
(1) Herbst, R. et al. Vandetanib plus docetaxel vs docetaxel as 2nd-line treatment for patients with advanced non-small-cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZODIAC). ABS 31495. ASCO. 2009.
(2) De Boer, R. et al. Vandetanib plus pemetrexed vs pemetrexed as 2nd-line therapy in patients with advanced non-small-cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZEAL). ABS 31867, ASCO. 2009.
(3) Natale, R. et al. Vandetanib versus erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) after failure of at least 1 prior cytotoxic chemotherapy: a randomized, double-blind phase III trial (ZEST). ABS 31610. ASCO. 2009.
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