AstraZeneca PLC’s Tagrisso (Osimertinib) Shows Potential As A New Standard Of Care In 1st-Line EGFR-Mutated Non-Small Cell Lung Cancer At ESMO 2017 Congress

WILMINGTON, Del. & MADRID--(BUSINESS WIRE)--AstraZeneca today announced the full results of the Phase III FLAURA trial, which support TAGRISSO^®’s (osimertinib) clear potential as a new standard of care (SoC) in the 1st-line treatment of adult patients with locally-advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).

Results of the Phase III FLAURA trial were included at the Presidential Symposium I of the European Society of Medical Oncology (ESMO) 2017 Congress in Madrid, Spain, and demonstrate a superior, clinically-meaningful progression-free survival (PFS) with osimertinib compared to current SoC EGFR tyrosine kinase inhibitors (TKIs) (erlotinib or gefitinib).

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “The FLAURA data are truly exciting. Until now, even with the therapeutic advances offered by the first- and second-generation EGFR inhibitors, less than 20% of EGFR mutation-positive NSCLC patients survive for five years. The FLAURA data suggest early and sustained benefit with TAGRISSO that has the potential to significantly impact long-term patient outcomes and help address the considerable unmet need that remains.”

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA study, from the Winship Cancer Institute of Emory University, Atlanta, GA, said: “The FLAURA data are likely to result in a major paradigm shift in the treatment of patients with EGFR mutation-positive advanced lung cancer. Not only did the trial demonstrate a robust improvement in efficacy with osimertinib when compared to other commonly-used EGFR inhibitors, the side effects profile was also more favorable with osimertinib.”

Summary of key results:

Endpoint		TAGRISSO		SoC		Hazard ratio (HR)/ Odds ratio (OR)
PFS (primary endpoint)		18.9 months (median)		10.2 months (median)		HR 0.46 95% CI, 0.37-0.57, p<0.0001
Overall Survival (OS) at 25% maturity		N/A		N/A		HR 0.63 95% CI, 0.45-0.88, p=0.0068*
Duration of Response (DoR)		17.2 months (median)		8.5 months (median)		N/A
Objective Response Rate (ORR)		80%		76%		OR 1.28 0.85-1.93, p=0.2335

*0.0015 was the threshold required for statistical significance at the current level of maturity. A final OS analysis is planned at a later stage.

Highlights from the FLAURA data presented include:

• Superior PFS (primary endpoint): Patients on osimertinib had less than half the risk of progression or death compared to patients on erlotinib or gefitinib (hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.37, 0.57; p<0.0001). The median PFS was 18.9 months for patients on osimertinib vs. 10.2 months for patients in the comparator arm.
• Clinically meaningful preliminary overall survival (OS) data at 25% maturity: The hazard ratio for OS was 0.63 [95% CI: 0.45, 0.88; P=0.0068] favoring osimertinib. OS data were 25% mature at the time of the interim analysis. (21% of the patients on osimertinib had died and 30% of the patients on the comparator arm had died.) The p-value of 0.0068 was not below the threshold of 0.0015 required for statistical significance at the current level of maturity. A final OS analysis is planned at a later stage.
• PFS improvements consistent across subgroups: Improvements in PFS with osimertinib were consistent across all pre-specified patient subgroups, with at least a 40% reduction in the risk of progression or death, including in patients with/without central nervous system (CNS) metastases at study entry, Asian/non-Asian patients, patients with/without prior smoking history, and patients with Exon 19 deletion/L858R sensitizing mutations.
• Impressive duration of response (DoR) and objective response rate (ORR): Patients treated with osimertinib had more than double the median DoR than those on the comparator arm (17.2 months vs. 8.5 months), and an ORR (a measurement of tumor shrinkage) of 80% vs. 76% with the comparator arm [odds ratio 1.28 (0.85, 1.93), p=0.2335].

The FLAURA safety data for osimertinib was in line with that observed in prior clinical trials, with a low rate of Grade =3 adverse events (AEs). In patients treated with osimertinib, the most common AEs were diarrhea (58%, any grade [2% Grade =3]) and dry skin (32%, any grade [<1% Grade =3]), and in the comparator arm group the most common AEs were diarrhea (57%, any grade [2% Grade =3]) and dermatitis acneiform (48%, any grade [5% Grade =3]). Of the patients on osimertinib, 33.7% had a Grade =3 AE, compared to 44.8% in the comparator arm, and 13.3% of patients on osimertinib had an AE leading to treatment discontinuation compared to 18.1% in the comparator arm.

This indication is not yet FDA approved. AstraZeneca is in discussions with global health authorities regarding regulatory submissions for osimertinib based on the FLAURA data. A status of regulatory submissions is usually provided with the Company’s quarterly results announcement.

TAGRISSO once-daily tablets are approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after an EGFR TKI therapy. TAGRISSO is the first and only approved medicine in the US indicated for NSCLC patients who have tested positive for the EGFR T790M mutation.

TAGRISSO^® (osimertinib) Important Safety Information

• There are no contraindications for TAGRISSO
• Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.5% and was fatal in 0.6% of 833 TAGRISSO-treated patients. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms indicative of ILD (eg, dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD is confirmed
• Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 833 TAGRISSO-treated patients, 0.7% of patients were found to have a QTc > 500 msec, and 2.9% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia
• Cardiomyopathy occurred in 1.9% and was fatal in 0.1% of 833 TAGRISSO-treated patients. Left Ventricular Ejection Fraction (LVEF) decline = 10% and a drop to < 50% occurred in 4% of 655 TAGRISSO-treated patients. Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO
• Keratitis was reported in 0.7% of 833 TAGRISSO-treated patients in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) to an ophthalmologist
• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during TAGRISSO treatment and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose
• The most common adverse reactions (=20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%)

Please see complete Prescribing Information including Patient Information.

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10% to 15% of patients in the US and Europe, and 30% to 40% of patients in Asia have epidermal growth factor receptor mutation-positive (EGFRm) NSCLC. These patients are particularly sensitive to treatment with currently-available EGFR tyrosine kinase inhibitors (TKIs), which block the cell signaling pathways that drive the growth of tumor cells. However, tumors almost always develop resistance to EGFR-TKI treatment, leading to disease progression. Approximately half of patients develop resistance to approved EGFR-TKIs, such as gefitinib and erlotinib, due to the resistance mutation, EGFR T790M. TAGRISSO targets this secondary mutation that leads to disease progression. There is also a need for agents with improved central nervous system efficacy since approximately 25% of patients with EGFRm NSCLC have brain metastases at first diagnosis, increasing to approximately 40% within two years of diagnosis.

About TAGRISSO^® (osimertinib)

TAGRISSO^® (osimertinib) is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to inhibit both EGFR sensitizing and EGFR T790M resistance mutations, with clinical activity against central nervous system (CNS) metastases. TAGRISSO 40mg and 80mg once-daily oral tablets have been approved in more than 50 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer. Eligibility for treatment with TAGRISSO is dependent on confirmation that the EGFR T790M mutation is present in the tumor.

TAGRISSO is also being investigated in the adjuvant and metastatic 1st-line settings, including in patients with and without CNS metastases, in leptomeningeal metastases and in combination with other treatments.

About FLAURA

FLAURA assessed the efficacy and safety of osimertinib 80mg orally once daily vs. standard-of-care epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously untreated patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. The trial was a double-blinded, randomized study, with 556 patients across 30 countries.

The primary endpoint of the trial was progression-free survival, and secondary endpoints included overall survival, objective response rate, duration of response, disease control rate, safety and measures of health-related quality of life.

About AstraZeneca in Lung Cancer

AstraZeneca is using ground-breaking science to develop a wide range of medicines for patients with lung cancer. We are pioneering precision medicines that target molecular mutations in tumor cells, as well as those that aim to boost the power of the immune response against cancer. We are committed to transforming outcomes for patients with lung cancer, whose treatment options are currently limited.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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 and follow us on Twitter @AstraZenecaUS.

US-14134 Last Updated 8/17