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AstraZeneca, DxS to Commercialize Companion Dx for Iressa in Europe; US Still Uncharted

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By Turna Ray

DxS is working with AstraZeneca to commercialize its TheraScreen EGFR29 Mutation Kit in Europe as a companion diagnostic for the pharmaceutical firm's non-small cell lung cancer drug Iressa.

According to a statement from the two firms, the EGFR29 test will help doctors determine which NSCLC patients should receive Iressa based on their EGFR oncogene mutation status. EGFR is mutated in between 10 percent and 15 percent of non-Asian lung cancer patients, and between 25 percent and 50 percent of Asian lung cancer patients.

In one clinical trial Iressa has shown to increase progression-free survival in NSCLC patients with EGFR mutations. Iressa, marketed by AstraZeneca, is more commonly known as gefitinib.

"The initial focus is on Europe as this is where there is a label requirement for an EGFR assay," a DxS spokesperson told Pharmacogenomics Reporter this week. The EU approved Iressa last month for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK across all lines of therapy.

However, "the expectation is that the assay will also be made available world-wide to match the distribution of Iressa," the spokesperson added.

DxS already markets its EGFR29 Mutation Kit in the Europe, where it is CE marked. According to the company, its TheraScreen: EGFR29 Mutation Kit is the only CE-marked kit currently available in the EU. The companion diagnostic operates on DxS’ RT-PCR-based platform, ARMS and Scorpions.

AstraZeneca has not announced any plans to commercialize a companion diagnostic for Iressa in the US.

In the US, Iressa is currently indicated for the treatment of locally advanced or metastatic NSCLC in patients who have previously received chemotherapy.

In 2004, AstraZeneca informed the US Food and Drug Administration that a large randomized study, called ISEL, failed to demonstrate a survival advantage for Iressa in NSCLC patients. Based on these findings, the FDA did not take the drug off the market but restricted any new patients from taking Iressa.

"There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival," Iressa's label states. The company provides the drug in the US through an access program.

Based on results of the ISEL study, AstraZeneca also withdrew its application in the EU. However, the company refiled its marketing application with the EU in mid-2008, with data from two Phase III studies, IPASS and INTEREST.

INTEREST (Iressa Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) randomized nearly 1,500 patients with locally advanced or metastatic recurrent NSCLC who had previously received platinum-based chemotherapy to receive either Iressa or docetaxel. The primary endpoint of the Phase III trial was to evaluate whether Iressa was non-inferior to docetaxel in improving survival in study patients. The trial also looked at whether Iressa was superior to docetaxel in patients with EGFR gene amplification as measured by FISH.

In the study, while Iressa's was non-inferior to docetaxel in improving overall survival, the drug was not superior in patients with a high EGFR-gene copy number. Median overall survival in patients receiving Iressa was 7.6 months versus 8 months on docetaxel. Meanwhile, medians survival in patients with a high EGFR-gene copy number was 8.4 months compared to 7.5 months in those receiving docetaxel.

IPASS (IRESSA Pan-ASia Study) was a randomized trial looking the efficacy, safety and tolerability of Iressa versus carboplatin/paclitaxel as first-line treatment in Asian patients. The study enrolled more than 1,200 patients in Asia with advanced NSCLC who had never smoked or where light smokers and who had not received prior chemotherapy. The primary endpoint was progression-free survival.

In subset analysis, researchers compared 261 patients with an EGFR mutation to 176 patients without the mutation. Patients positive for the EGFR mutation had a median PFS of 9.5 months with gefitinib compared to 6.3 months with carboplatin/paclitaxel. However, those who were negative for the EGFR mutation did better with the carboplatin/paclitaxel regimen, with a PFS of 5.5 months, compared to 1.5 months with gefitinib.

This biomarker analysis was presented at the American Society of Clinical Oncology's annual meeting this year in May.

AstraZeneca has agreed to conduct a follow-up study to generate additional data in the caucasian NSCLC patient population and is currently in discussion with the EMEA to finalise the study design and endpoints.

According to a statement from AstraZeneca, there is a rolling program of approvals and license updates for Iressa around the world in a broad second-line population based on data from the INTEREST study. The drug is standard of care therapy for NSCLC in the Asia-Pacific region. In this region, AstraZeneca is in discussions with regulatory authorities about broadening Iressa's indication as a first-line therapy for NSCLC.

DxS has a global distribution deal with Roche Molecular Diagnostics for their TheraScreen brand of diagnostic kits. The UK-based personalized medicine company has also inked deals with Amgen and Merck Serono/Bristol-Myers Squibb to use DxS' TheraScreen KRAS Mutation Kit as a companion diagnostic for colorectal cancer drugs Vectibix and Erbitux.

DxS' KRAS test kit is currently undergoing premarket review at the FDA. The agency recently updated the labels of Vectibix and Erbitux based on retrospective data submitted by Amgen and Merck/BMS showing the drugs are ineffective in patient with KRAS mutations in codon 12 or 13 [see PGx Reporter 07-29-2009].

Separately, Boehringer Ingelheim announced in May that it would use DxS' EGFR Mutation Kit to identify best responders in clinical trials for its investigational NSCLC drug BIBW2992. Under the terms of the agreement, DxS and Boehringer Ingelheim together commercialize a companion diagnostic test kit globally, if BIBW2992 is approved by the FDA. BIBW 2992 is said to be the first dual inhibitor of EGFR and HER2 to reach Phase III development in NSCLC.

Boehringer Ingelheim this week announced it had initiated a Phase III trial looking at BIBW 2992 as first-line treatment in NSCLC patients with EGFR mutations.

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