IRESSA® (gefitinib) Approved by the U.S. Food and Drug Administration for First-Line Treatment of Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer

WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca today announced that the U.S. Food and Drug Administration (FDA) has approved IRESSA® (gefitinib) as a first-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

IRESSA is a once daily oral EGFR-tyrosine kinase inhibitor (TKI), which inhibits the activity that contributes to intracellular signaling pathways implicated in the growth and survival of cancer cells. IRESSA was granted Orphan Drug Designation by the FDA in August 2014 for the treatment of EGFR mutation-positive advanced NSCLC.

“In 2003, IRESSA was the first EGFR-TKI for patients with non-small cell lung cancer. While some patients showed dramatic benefit, the research at that time did not enable us to identify those patients that would benefit the most from this treatment,” said Gregory Keenan, Vice President, Medical Affairs & U.S. Head Medical Officer. “Today, our understanding of molecular mutations and molecular targeting has enabled better decision making in the treatment of NSCLC.”

AstraZeneca has partnered with QIAGEN to provide the FDA-approved therascreen® EGFR companion diagnostic test for IRESSA in the U.S. The test uses a tumor tissue sample to rapidly identify EGFR exon 19 deletions or exon 21 (L858R) substitution mutations status of a lung cancer patient’s tumor. Patients whose tests are positive for the EGFR exon 19 deletions or exon 21 (L858R) substitution mutations may be eligible for treatment with IRESSA.

The FDA approval of IRESSA is based on data from the IFUM (IRESSA Follow-Up Measure) clinical trial which showed an Objective Response Rate (ORR) of 50 and 70% (BICR and investigators, respectively) with a median Duration of Response (DOR) of 6 and 8.3 months. The Confidence Interval (CI) is 49, 59 (BICR) and 61, 78 (investigators).

The IFUM results were supported by the IPASS (IRESSA Pan-ASia Study) study which assessed IRESSA vs. carboplatin/paclitaxel as a first-line treatment in these patients. The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in IFUM and had radiographic scans available for a retrospective assessment by BICR. IPASS showed an ORR of 67% with a median duration of response of 9.6 months in IRESSA-treated patients vs. 41% with a median duration of response of 5.5 months for the carboplatin/paclitaxel group. Progression Free Survival (PFS) was 10.9 months in the IRESSA group vs. 7.4 for the carboplatin/paclitaxel patients, as assessed by BICR. The hazard ratio for PFS favored the IRESSA-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the IRESSA-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR. The safety profile of IRESSA is well established through a large, global clinical program and extensive real world evidence. The most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patients and greater than placebo were skin reactions and diarrhea.

“We are very pleased with this new milestone in our partnership with AstraZeneca. The FDA approval of our therascreen® EGFR test to guide the use of IRESSA in NSCLC patients will offer U.S. physicians insights for decision-making based on a clinically proven companion diagnostic. We look forward to continued progress with our AstraZeneca partners,” said Thierry Bernard, Senior Vice President, Head of the Molecular Diagnostics Business Area and a member of the Executive Committee of QIAGEN.

IRESSA is approved in 91 countries for the treatment of adult patients with metastatic EGFR mutation-positive NSCLC.

NOTES TO EDITORS

Douillard JY et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014 Jan 7; 110, 55-62. doi: 10.1038/bjc.2013.721.

Fukuoka M, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011Jul 20; 29(21):2866-74. doi: 10.1200/JCO.2010.33.4235.

About IRESSA

IRESSA is a targeted monotherapy for the treatment of patients with advanced or metastatic epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC. IRESSA acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus inhibiting the transmission of signals involved in the growth and spread of tumors.

In 2003, IRESSA received accelerated FDA approval as a third-line agent after chemotherapy failure in an unselected population with advanced NSCLC. IRESSA became the first EGFR inhibitor available for advanced NSCLC and ushered in a new era in the science and treatment of this deadly disease.

The FDA approval for IRESSA was conditional upon the results from the Phase III confirmatory trial, IRESSA Survival Evaluation in Lung Cancer (ISEL). ISEL was conducted in an unselected patient population before it was known that the EGFR mutation was the target for IRESSA and showed a benefit in only some of the patients. As a result, AstraZeneca in 2005 stopped commercializing IRESSA and ensured that patients who benefitted from IRESSA could continue to receive the treatment.

AstraZeneca remained committed to following the science to better understand how to identify those patients who could benefit from treatment with IRESSA. In 2009, IPASS became the landmark study that confirmed IRESSA’s efficacy in patients with EGFR mutation-positive advanced NSCLC and demonstrated how a targeted treatment can be used in a targeted way.

Clinical Studies – IPASS & IFUM

The efficacy and safety of IRESSA for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA approved test was demonstrated in two multi-center open-label studies known as IPASS and IFUM.

IFUM studied 106 treatment naïve patients with metastatic EGFR mutation-positive NSCLC who received IRESSA at a dose of 250 mg once daily until disease progression or intolerable toxicity. Major efficacy outcomes were objective response rate (ORR) as evaluated by a Blinded Independent Central Review (BICR) and investigators. Duration of Response (DOR) was also an outcome measure. IFUM showed an ORR of 50% according to BICR, and 70% by investigators with a median DOR of 6 and 8.3 months (BICR and investigators, respectively). The Confidence Interval (CI) is 49, 59 (BICR) and 61, 78 (investigators).

IFUM was supported by IPASS, which was an exploratory analysis of a subset of a randomized, multicenter, open-label trial conducted in patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment. Patients received either IRESSA at a dose of 250 mg once daily or up to 6 cycles of carboplatin/paclitaxel. The subset population consisted of 186 patients with metastatic NSCLC whose tumors have EGFR 19 deletions or exon 21 (L858R) substitution mutations as determined by the same assay used in IPASS as well as radiographic scans available for retrospective analysis by BICR. This subset included 88 IRESSA-treated patients and 98 patients randomized to carboplatin/paclitaxel. The median duration of treatment for the IRESSA group was 9.8 months and the hazard ratio for Progression Free Survival (PFS) was favorable to this group with a median PFS of 10.9 months vs. 7.4 for the carboplatin/paclitaxel patients, as assessed by BICR. The ORR was 67% with a median duration of response of 9.6 months for those treated with IRESSA vs. 41% with a median duration of response of 5.5 months for the carboplatin/paclitaxel group. The hazard ratio for PFS favored the IRESSA-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the IRESSA-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR.

About Qiagen

QIAGEN N.V., a Netherlands-based holding company, is the leading global provider of Sample & Assay Technologies that are used to transform biological materials into valuable molecular information. Sample technologies are used to isolate and process DNA, RNA and proteins from biological samples such as blood or tissue. Assay technologies are then used to make these isolated biomolecules visible and ready for interpretation. QIAGEN markets more than 500 products around the world, selling both consumable kits and automation systems to customers through four customer classes: Molecular Diagnostics (human healthcare), Applied Testing (forensics, veterinary testing and food safety), Pharma (pharmaceutical and biotechnology companies) and Academia (life sciences research). As of March 31, 2014, QIAGEN employed approximately 4,000 people in over 35 locations worldwide. Further information can be found at http://www.qiagen.com.

About therascreen®

The therascreen® EGFR RGQ PCR Kit is an FDA-approved, qualitative real-time PCR assay for the detection of specific mutations in the EGFR oncogene. The kit provides reagents optimized for rapid and sensitive detection of 21 somatic mutations using the QIAamp DSP DNA FFPE Tissue Kit and the Rotor-Gene Q MDx.

About Lung Cancer

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one third of all cancer deaths, more than breast, prostate and colon cancers combined. Lung cancer has a five-year survival rate that is less than 20%. Approximately 85% of all lung cancers in the U.S. are NSCLC; 10% to 15% of these are EGFR mutation-positive in the U.S.

About AstraZeneca in Oncology

Oncology is a therapeutic area in which AstraZeneca has deep-rooted heritage. It will be potentially transformational for the company’s future, becoming the sixth growth platform. Our vision is to help patients by redefining the cancer treatment paradigm and one day eliminate cancer as cause of death. By 2020, we are aiming to bring six new cancer medicines to patients.

Our broad pipeline of next-generation medicines is focused on four main disease areas - ovarian, lung, breast, and hematological cancers. These are being targeted through four key platforms – immuno-oncology, the genetic drivers of cancer and resistance, DNA damage repair and antibody drug conjugates.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit www.astrazeneca-us.com.

Important Safety Information

Limitation of Use: Safety and efficacy of IRESSA have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

• There are no contraindications for IRESSA
• Interstitial Lung Disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening of respiratory symptoms. Discontinue IRESSA if ILD is confirmed
• Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations. Discontinue for severe hepatic impairment
• Gastrointestinal Perforation: Discontinue IRESSA for gastrointestinal perforation
• Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea
• Ocular Disorders including Keratitis: Withhold IRESSA for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis
• Bullous and Exfoliative Skin Disorders: Withhold IRESSA for Grade 3 or higher skin reactions or exfoliative conditions
• Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception
• Advise women to discontinue breast-feeding during treatment with IRESSA
• The most commonly reported adverse drug reactions, reported in more than 20% of the patients and greater than placebo, were skin reactions and diarrhea

Please see accompanying complete Prescribing Information including Patient Information.

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Source: AstraZeneca

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