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
Showing posts with label EGFr. Show all posts
Showing posts with label EGFr. Show all posts
Thursday, November 27, 2008
Friday, May 16, 2008
Gender survival differences linked to EGFr variants
A study by researchers at the University of Southern California (USC) and Keck School of Medicine has found evidence that supports gender-related differences in the development and survival of metastatic colorectal cancer (CRC). The study, which was published in the 15th April edition of Cancer Research (2008;68:3037-3042), found that specific gene variants in EGFr linked to the development of CRC resulted in opposite survival outcomes for men and women.
Germline variations in EGFr DNA have been linked with poor prognosis in CRC, however, when researchers looked at EGFr as a prognostic factor, they found that it had opposite implications for men and women. The scientists expected to find that high expression would correlate with a poor prognosis and faster growth of the cancer. What they found, however, was that men followed the expected trend, while women's response was the opposite.
In the study, researchers analysed 318 patients (177 men and 141 women) with metastatic CRC that were treated at the USC/Norris Comprehensive Cancer Center and the LAC+USC Medical Center between 1992 and 2003. The team studied two independent functional polymorphisms of EGFr, one at codon 497 in the extracellular domain of the EGFr gene and the other related to dinucleotide repeats within intron 1. All the patients were exposed to similar chemotherapy treatments. When genomic DNA samples were analysed, the investigators found that women who had specific gene variants linked with high expression of EGFr had higher overall survival (OS) rates, while men with the same variants had lower survival.
Specifically, median OS in men with the Arg/Arg variant of the 497 polymorphism was 10.3 months, while for those with a Lys allele it was 13.7 months. Among women, the corresponding figures were 16.0 and 14.0 months. For the intron polymorphism, a repeat length <20>20. The corresponding survival rates for women were 17.6 and 14.1 months.
According to Dr Heinz-Josef Lenz, Professor of Medicine at the Keck School of Medicine: "This is the first report to show that the prognostic value of EGFr depends on gender. This may suggest that, in the future, molecular markers should be evaluated differently in women and men and that treatment decisions may depend on gender and not only on molecular or clinical findings."
As to mechanisms that might explain these differences, the researchers point out that the colon expresses both oestrogen receptor beta and androgen receptor, and that EGFr interacts with both. Therefore, EGFr may have molecular intermediates that interact in a gender-specific way to effect EGFr pathway activation. Previous research has shown a protective effect of female hormones in CRC survival. The new findings indicate that hormone receptors are important in signal pathways related to the survival of patients. Research will now need to be performed to determine whether men and women respond differently to certain cancer therapies. This may lead to targeted chemotherapy that is tailored to get the best response from male and female patients.
Matthew Dennis - Editor, Cancer Drug News
Germline variations in EGFr DNA have been linked with poor prognosis in CRC, however, when researchers looked at EGFr as a prognostic factor, they found that it had opposite implications for men and women. The scientists expected to find that high expression would correlate with a poor prognosis and faster growth of the cancer. What they found, however, was that men followed the expected trend, while women's response was the opposite.
In the study, researchers analysed 318 patients (177 men and 141 women) with metastatic CRC that were treated at the USC/Norris Comprehensive Cancer Center and the LAC+USC Medical Center between 1992 and 2003. The team studied two independent functional polymorphisms of EGFr, one at codon 497 in the extracellular domain of the EGFr gene and the other related to dinucleotide repeats within intron 1. All the patients were exposed to similar chemotherapy treatments. When genomic DNA samples were analysed, the investigators found that women who had specific gene variants linked with high expression of EGFr had higher overall survival (OS) rates, while men with the same variants had lower survival.
Specifically, median OS in men with the Arg/Arg variant of the 497 polymorphism was 10.3 months, while for those with a Lys allele it was 13.7 months. Among women, the corresponding figures were 16.0 and 14.0 months. For the intron polymorphism, a repeat length <20>20. The corresponding survival rates for women were 17.6 and 14.1 months.
According to Dr Heinz-Josef Lenz, Professor of Medicine at the Keck School of Medicine: "This is the first report to show that the prognostic value of EGFr depends on gender. This may suggest that, in the future, molecular markers should be evaluated differently in women and men and that treatment decisions may depend on gender and not only on molecular or clinical findings."
As to mechanisms that might explain these differences, the researchers point out that the colon expresses both oestrogen receptor beta and androgen receptor, and that EGFr interacts with both. Therefore, EGFr may have molecular intermediates that interact in a gender-specific way to effect EGFr pathway activation. Previous research has shown a protective effect of female hormones in CRC survival. The new findings indicate that hormone receptors are important in signal pathways related to the survival of patients. Research will now need to be performed to determine whether men and women respond differently to certain cancer therapies. This may lead to targeted chemotherapy that is tailored to get the best response from male and female patients.
Matthew Dennis - Editor, Cancer Drug News
Subscribe to:
Posts (Atom)