BARCELONA , Spain , July 6/PRNewswire/ --

First Inhibitor of VEGF (a) and EGF (b) Signalling to Show Anti-Tumour Activity Both as Monotherapy and in Combination With Chemotherapy

AstraZeneca today reported new findings from two Phase II studies, Trials 003 and 006, in the 2nd-line treatment of NSCLC, with ZD6474 (ZACTIMA(TM)), its novel selective inhibitor of key signalling pathways in cancer. Both studies, presented at the 11th World Conference on Lung Cancer (WCLC) in Barcelona , Spain , met their primary endpoints.

The monotherapy study, Trial 003, compared the anti-tumour effects of ZD6474 300mg monotherapy with gefitinib (IRESSA(R)) 250 mg monotherapy in patients with advanced non-small cell lung cancer (NSCLC). Preliminary results from Trial 003 showed that patients receiving ZD6474 had a significant prolongation of progression free survival (PFS) compared with gefitinib (mean PFS of 11.9 weeks compared to 8.1 weeks respectively, HR 0.63; 95% CI 0.44 to 0.90; p=0.011).(1)

Lead Trial 003 investigator, Ronald Natale MD, Cedars-Sinai Outpatient Cancer Center , Los Angeles , USA , commented, "In Trial 003, ZD6474 had a higher objective response rate and improved PFS compared to gefitinib. Given the poor prognosis in lung cancer, any increase in PFS can be meaningful for these patients, making these data very encouraging. With the results of these important Phase II studies we see ZD6474 is the first of this type of novel agent to have both activity as a single agent and when combined with standard chemotherapy in patients with previously treated NSCLC."

The combination therapy study, Trial 006, showed patients receiving ZD6474 100 mg or 300 mg plus docetaxel 75 mg/m2 had an increased median progression free survival (PFS) compared to those receiving docetaxel 75 mg/m2 alone.(2) Patients receiving ZD6474 100mg plus docetaxel had a median PFS of 18.7 weeks (HR 0.64; 95% CI 0.38 to 1.05; p=0.074), and patients Receiving ZD6474 300mg plus docetaxel had a median PFS of 17.0 weeks (HR 0.83; 95% CI 0.50 to 1.36; p=0.416), compared to 12.0 weeks with docetaxel alone.

Trial 006 study investigator John Heymach MD, PhD, Dana-Farber Cancer Institute, Boston , USA , commented, "ZD6474 is one of the next generation of novel agents that targets two established pathways in tumour growth - EGF and VEGF. This means in one orally administered pill we can tackle two different processes needed by tumours to grow and spread. The results of Trials 003 and 006 show it has the potential to increase PFS by a significant amount, as both monotherapy and in combination with chemotherapy. ZD6474 is a very promising novel anti-cancer agent and warrants Phase III investigation."

In both trials, possibly due to the small number of patients involved and the fact that survival data was potentially confounded by subsequent therapies there was no significant effect of ZD6474 on overall survival. Both progression free survival and survival outcomes will be investigated in Phase III trials.

In both studies, ZD6474 was generally well tolerated. Common side effects included rash, diarrhoea and asymptomatic QT prolongation.(1,2)

Further Phase II data for ZD6474 at WCLC

Preliminary results from the run-in phase of Trial 007 demonstrate that a combination of ZD6474 and carboplatin/paclitaxel (CP) chemotherapy as a first-line treatment for patients with advanced or metastatic NSCLC was generally well-tolerated and without mutually additive toxicity compared to ZD6474 alone and CP alone.(3) The randomised phase of the study to evaluate objective tumour response and provide pharmacokinetic assessment of ZD6474 and CP levels is ongoing.

These trial results support the decision to enter Phase III clinical studies of ZD6474 in NSCLC. Patient recruitment for Phase III trials is expected to begin in late 2005.

(a) Vascular Endothelial Growth Factor (VEGF)
b) Epidermal Growth Factor (EGF)

Notes

Lung cancer is the leading cause of cancer death accounting for around 25% of all cancer deaths in women and more than 30% in men. The 5-year relative survival rate for all stages of lung cancer combined is only 15%. Survival from lung cancer has shown little improvement for more than 20 years.

- ZD6474 is a unique once-daily oral therapy that selectively targets key signalling pathways in cancer. ZD6474 inhibits vascular endothelial growth factor receptor signalling, inhibiting tumour angiogenesis, and epidermal growth factor receptor signalling, which may lead to direct inhibition of cancer cell proliferation and survival. ZD6474 also inhibits RET kinase which may be important in certain tumours.

- IRESSA(R) (gefitinib) and ZACTIMA(TM) (ZD6474) are trademarks of the AstraZeneca group of companies.

References

1. Natale R et al. A comparison of the anti-tumour efficacy of ZD6474 and gefitinib (Iressa(TM)) in patients with NSCLC: results of a randomised, double-blind Phase II study. Presented at the 11th World Conference on Lung Cancer, July 2005.

2. Heymach J et al. A randomised, placebo-controlled Phase II trial of ZD6474 plus docetaxel, in patients with NSCLC. Presented at the 11th World Conference on Lung Cancer, July 2005.

3. Johnson B et al. Preliminary Phase II safety evaluation of ZD6474, in combination with carboplatin and paclitaxel, as 1st-line treatment in patients with NSCLC. Presented at the 11th World Conference on Lung Cancer, July 2005.

Source: AstraZeneca

  (7/7/05)