NEW YORK (GenomeWeb) – Following AstraZeneca's December announcement that it is taking steps to reintroduce the EGFR-targeted non-small cell lung cancer drug Iressa (gefitinib) in the US, Qiagen said last week that it would develop a tissue-based molecular diagnostic test to accompany the drug's launch.
On Dec. 2, AstraZeneca announced that the US Food and Drug Administration had accepted its new drug application (NDA) for Iressa. The drug will be advanced with a companion diagnostic that will identify patients with EGFR mutations who are most likely to benefit from treatment. For the CDx, AstraZeneca will work with Qiagen, a company with which it has a long-standing Rx/Dx partnership focused on Iressa, ever since the drug received marketing authorization from the European Commission in 2009. Separately, Qiagen has developed a blood-based test for Iressa for the European market, and recently garnered CE marking for the diagnostic.
AstraZeneca initially received accelerated approval for Iressa from the FDA in 2003, based on data showing that the drug shrank tumors in 10 percent of NSCLC patients who had received standard treatments. But after a confirmatory study failed to show that Iressa-treated patients lived longer compared to placebo, the FDA in 2005 restricted the drug's indication to only those who had received it and were benefiting. The company at that time also withdrew its European marketing application for the drug.
During those early personalized drug development programs, researchers hadn't pinned down the relevant response biomarkers for Iressa. At the time, investigators advancing EGFR inhibiting drugs thought that patients with EGFR over-expression would respond well to these agents, but clinical trials would eventually reveal that patients with EGFR mutations were the best markers to identify best responders.
Further complicating matters was that while Iressa was being developed, the FDA hadn't yet formulated a framework for developing drugs alongside companion diagnostics to home in on subpopulations of best responders. The agency issued draft guidelines on the development of companion diagnostics in 2011 and finalized the guidance just last summer.
Although in 2009 the European Commission granted AstraZeneca marketing authorization for Iressa in patients with EGFR mutations, in 2011 the company decided to pull its accelerated approval status in the US completely. AstraZeneca has never detailed precisely why it decided to withdraw its NDA in the US, but the higher regulatory bar in the US surely influenced its strategy.
The Iressa Pan Asian Study (IPASS) trial, which formed the basis for approval in the EU, showed that NSCLC patients with EGFR mutations experienced improved progression-free survival compared to those treated with chemotherapy, but there was no statistically significant improvement in overall survival. And the lack of a survival advantage was at least one of the reasons that FDA stated for limiting Iressa's indication in 2005. Furthermore, because Iressa's earlier negative trials were so highly publicized, researches may have had trouble recruiting patients into studies.
In withdrawing its US NDA, the firm told US patients taking Iressa and their doctors that "patients currently benefitting from Iressa therapy will be able to continue to receive treatment through a clinical study." However, according to Blair Hains, who was AstraZeneca's director of brand corporate affairs at the time, the trial was not meant to gather data for a new NDA. Rather, the study was aimed at maintaining access to Iressa for the few hundred lung cancer patients in the US who wished to stay on the drug, he said.
Now, based on data from a newly completed study, called the Iressa Follow-Up Measure (IFUM), it seems AstraZeneca has changed its mind, with some encouragement from the FDA. A company spokesperson told GenomeWeb that Caucasian NSCLC patients with EGFR mutations enrolled in the single-arm IFUM trial experienced efficacy with Iressa similar to the response seen in Asian patients enrolled in the IPASS trial.
In IFUM, after screening more than 1,000 NSCLC patients, researchers led by AstraZeneca scientist Tsveta Milenkova enrolled 106 patients with EGFR-mutated tumors. After a median follow-up of 13 months, researchers identified 74 patients as having responded to Iressa and a 70 percent overall response rate. The overall response rate by secondary, central reviewers was 50 percent.
Researchers led by Milenkova noted in a paper published in the British Journal of Cancer that differences in investigator and central reviewer findings aren't uncommon. Post-hoc analysis showed that central review analysis identified 17 patients without measureable disease at baseline, and excluding these patients brought the overall response rate to 60 percent.
The majority of study participants, 100 out of 107, experienced one or more adverse reactions during IFUM, most commonly rash, diarrhea, vomiting, asthenia, cough and dry skin, and nausea. Two patients had serious adverse reactions due to the drug and eight had toxicities that caused them to discontinue treatment. Five patients died during the study due to various reasons, but none were related to Iressa, investigators said. One patient suffered from interstitial lung disease related to Iressa treatment but recovered.
"AstraZeneca took the decision to share these data with FDA," the company spokesperson said. "The FDA indicated that IFUM supported by IPASS could form the basis of a new NDA in the US and hence, the resubmission." Currently, according to a US Patent and Trademark Office document, Iressa's patent is slated to expire in 2017.
However, again likely due to the different regulatory environments in the EU and US, AstraZeneca's strategy for growing the market for Iressa is moving at a faster pace across the pond. Not only has Iressa been available to NSCLC patients in Europe alongside Qiagen's Therascreen EGFR mutation kit since 2009, in September last year EU regulators recommended an update to Iressa's label, allowing doctors to use a test that determines the EGFR mutation status of patients based on circulating tumor DNA present in a blood sample.
AstraZeneca has decided to once again work with Qiagen to develop the ctDNA test for Iressa in Europe. Qiagen last week announced that it had garnered CE-IVD self-certification for the EGFR RGQ Plasma PCR kit.
Christoph Menzel, director of global product management MDx at Qiagen, told GenomeWeb that DNA purification will be performed using the QIAamp circulating nucleic acid kit. This kit has been widely studied, and is referenced in more than 200 peer-reviewed publications, Menzel highlighted. "This is also used in non-invasive prenatal testing very heavily," he noted. Then EGFR mutational analysis will be performed using the Therascreen technology and the Rotor-Gene Q PCR platform.
In IFUM, researchers assessed the reliability of Qiagen's ctDNA testing methods to gauge EGFR mutation status. In the trial, mutation detection rate was 13.7 percent with tumor tissue and 10.6 percent in plasma for patients with both types of samples. Concordance between plasma and tissue analysis of EGFR mutations was 94.3 percent. The sensitivity of the ctDNA testing method was 65.7 percent and specificity was 99.8 percent.
Comparatively, in IPASS, the mutation rate was 23.7 percent with ctDNA and 61.5 percent with tumor tissue in a Japanese cohort. However, the false positive rate in IPASS was also 56.9 percent. "The high rate of false negatives reported in IPASS and the differences seen in assay sensitivity between IPASS and the study reported here may be attributed to differences in sample type, DNA extraction kit, and mutation analysis methodology," the IFUM study authors wrote.
There is a need for blood-based diagnostics in settings such as lung cancer, where testing is invasive and approximately 25 percent of patients with locally advanced or metastatic NSCLC don't have sufficient tumor tissue for testing necessary to determine the appropriate course of therapy.
"There is such a clear clinical utility in lung cancer where tissue isn't simply available any longer, so the patients cannot be tested and therefore cannot receive the drug," Menzel said. He estimated that ctDNA testing using plasma enables between 15 percent to 20 percent of patients who otherwise could not be tested by tissue-based diagnostics to be assessed for EGFR status.
Qiagen has numerous companion diagnostic co-development deals with pharma companies, many of which have matured to launching marketed testing products. For example, in 2013, Qiagen co-developed and launched with FDA approval its Therascreen EGFR test as a companion diagnostic for Boehringer Ingelheim's Gilotrif.
Through its pharma partnerships, Qiagen is aware that drugmakers are increasingly interested in using blood-based diagnostics to identify best responders to their therapies, not only in lung cancer, but in all major tumor types, such as breast, prostate, and colorectal cancers. "Without disclosing too much, we are working with a couple of pharma partners to bring such tests … forward in the future," Menzel said.
This article has been corrected from a previous version to reflect that ctDNA testing enables between 15 percent to 20 percent of patients to be assessed for EGFR status that otherwise wouldn't receive testing with tissue-based diagnostics.