The EMEA's CHMP has issued a positive opinion supporting the approval of AstraZeneca's targeted oral anticancer drug, Iressa (gefitinib), for the treatment of non-small cell lung cancer (NSCLC). Specifically, the CHMP has recommended approval of Iressa for adults with locally-advanced or metastatic NSCLC with activating mutations of EGFr-tyrosine kinase, in all lines of therapy. However, AstraZeneca will be required to conduct a follow-up measure study to generate further data in a Caucasian NSCLC patient population. The company is in discussion with the CHMP to finalise the study design and endpoints.
The opinion was based on a submission package including two pivotal Phase III studies, IPASS (IRESSA Pan-ASia Study) and INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere). The IPASS trial exceeded its primary objective, demonstrating superior progression-free survival (PFS), greater objective response rate (ORR), improved tolerability and significant quality-of-life benefits for Iressa, compared to carboplatin+paclitaxel doublet chemotherapy (CT) in clinically-selected first-line patients in Asia. However, the treatment effect was not constant over time, with the probability of being progression-free in favour of carboplatin+paclitaxel in the first six months and in favour of Iressa in the following 16 months. This was likely due to the different effect of Iressa in subgroups defined by EGFr tumour mutation status. PFS was significantly longer for Iressa than doublet CT in patients with EGFr mutation-positive tumours, and significantly longer for doublet CT than Iressa in patients with EGFr mutation-negative tumours.
The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality-of-life benefits for Iressa, compared to standard CT (docetaxel) in the pretreated setting. Preplanned subgroup analyses showed a significant improvement in PFS and ORR for Iressa over docetaxel in patients with EGFr mutation-positive tumours.
In 2005, AstraZeneca withdrew its EU marketing authorisation application for Iressa following data from the Phase III ISEL (IRESSA Survival Evaluation in Lung cancer) study in pretreated patients not eligible for further CT. ISEL did not meet its primary objective of a statistically significant improvement in OS for Iressa compared to placebo, but did confirm a number of important clinical benefits, including tumour shrinkage and a significant improvement in time-to-treatment failure. The refractory nature of the ISEL population is the most likely explanation for the magnitude of the survival improvement with Iressa, compared to placebo, not reaching statistical significance.
But what sort of a comeback will Iressa be making? Only a day after the CHMP decision, Roche announced that it is collaborating on a trial to investigate Tarceva (erlotinib) in LC patients with genetic mutations in EGFr. The results from the EURTAC trial, if positive, will support a submission by Roche to the EMEA to seek an additional new indication for use of Tarceva, putting it in direct competition with Iressa. Tarceva is already approved, and unlike Iressa, has been shown to benefit all patients, whether or not they have a mutated version of EGFr. Based on this, it looks likely that Iressa will become a niche product. However, a launched product is better for AstraZeneca than one sat on the shelf.
Matthew Dennis - Editor, Cancer Drug News
Showing posts with label gefitinib. Show all posts
Showing posts with label gefitinib. Show all posts
Thursday, April 30, 2009
Thursday, November 27, 2008
Last chance for Iressa?
Results from the Phase III INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study, published in the 22nd November edition of The Lancet (2008;372:1809-1818), have shown that patients with pretreated advanced non-small cell lung cancer (NSCLC) who received the oral anticancer drug, Iressa (gefitinib), had comparable survival to those treated with intravenous docetaxel. In addition, gefitinib had a more favourable tolerability profile than docetaxel and significantly more gefitinib-treated patients had an improvement in quality of life.
These results follow previous disappointing data for the drug in the ISEL (IRESSA Survival Evaluation in Lung cancer) study, where gefitinib failed to demonstrate a survival advantage versus placebo in NSCLC patients. This led to a severe restriction on the use of the drug in the US and also to AstraZeneca withdrawing its MAA in Europe. As such, gefitinib is not currently licensed in the EU, however on 2nd May, AstraZeneca submitted an MAA to the EMEA seeking approval as a treatment for locally-advanced or metastatic NSCLC patients pretreated with platinum chemotherapy (CT). The application is based on data from the INTEREST study and is the first time a targeted therapy, an EGFr tyrosine kinase inhibitor, has proven non-inferiority for overall survival (OS) relative to CT in patients with pretreated advanced NSCLC.
The INTEREST study was a randomised, open-label, parallel-group trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally-advanced or metastatic recurrent NSCLC who had previously received platinum-based CT. Patients were randomly assigned to receive gefitinib (250mg/day; n=733) or docetaxel (75mg/m2; n=733). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFr-gene-copy number in the intention-to-treat population.
In the study, 1,433 patients were analysed per protocol (723 in the gefitinib group and 710 in the docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 vs 576 events; hazard ratio [HR]=1.02; 96% CI, 0.905 to 1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFr-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR=1.09; 95% CI, 0.78 to 1.51; p=0.62; median survival 8.4 vs 7.5 months).
Will these new data signal a resurrection for the drug? With such mixed results for gefitinib, it is hard to imagine doctors altering their prescribing habits on the basis of the INTEREST data alone, especially when there are many of other options available for treating LC patients. Tarceva (erlotinib), another EGFr inhibitor, is available, as is Avastin (bevacizumab), with more on the horizon, including Erbitux (cetuximab). One thing that could save gefitinb is the use of pharmacogenomics and a test to predict which patients would be suitable for treatment with the drug. However, this is an expensive and time-consuming undertaking, one that AstraZeneca may not see as financially rewarding or competitive as there are already EGFr inhibitors available, such as cetuximab and Vectibix (panitumumab), that are marketed alongside companion diagnostics. As such, INTEREST could be gefitinib’s final chance of success.
Matthew Dennis - Editor, Cancer Drug News
These results follow previous disappointing data for the drug in the ISEL (IRESSA Survival Evaluation in Lung cancer) study, where gefitinib failed to demonstrate a survival advantage versus placebo in NSCLC patients. This led to a severe restriction on the use of the drug in the US and also to AstraZeneca withdrawing its MAA in Europe. As such, gefitinib is not currently licensed in the EU, however on 2nd May, AstraZeneca submitted an MAA to the EMEA seeking approval as a treatment for locally-advanced or metastatic NSCLC patients pretreated with platinum chemotherapy (CT). The application is based on data from the INTEREST study and is the first time a targeted therapy, an EGFr tyrosine kinase inhibitor, has proven non-inferiority for overall survival (OS) relative to CT in patients with pretreated advanced NSCLC.
The INTEREST study was a randomised, open-label, parallel-group trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally-advanced or metastatic recurrent NSCLC who had previously received platinum-based CT. Patients were randomly assigned to receive gefitinib (250mg/day; n=733) or docetaxel (75mg/m2; n=733). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFr-gene-copy number in the intention-to-treat population.
In the study, 1,433 patients were analysed per protocol (723 in the gefitinib group and 710 in the docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 vs 576 events; hazard ratio [HR]=1.02; 96% CI, 0.905 to 1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFr-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR=1.09; 95% CI, 0.78 to 1.51; p=0.62; median survival 8.4 vs 7.5 months).
Will these new data signal a resurrection for the drug? With such mixed results for gefitinib, it is hard to imagine doctors altering their prescribing habits on the basis of the INTEREST data alone, especially when there are many of other options available for treating LC patients. Tarceva (erlotinib), another EGFr inhibitor, is available, as is Avastin (bevacizumab), with more on the horizon, including Erbitux (cetuximab). One thing that could save gefitinb is the use of pharmacogenomics and a test to predict which patients would be suitable for treatment with the drug. However, this is an expensive and time-consuming undertaking, one that AstraZeneca may not see as financially rewarding or competitive as there are already EGFr inhibitors available, such as cetuximab and Vectibix (panitumumab), that are marketed alongside companion diagnostics. As such, INTEREST could be gefitinib’s final chance of success.
Matthew Dennis - Editor, Cancer Drug News
Subscribe to:
Posts (Atom)