WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca today reported further evidence that Tagrisso® (osimertinib), the potential new standard of care for patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), also shows clinical activity in those patients with disease progression to central nervous system (CNS) metastases. The data, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, June 2-6, are consistent with earlier clinical and preclinical findings showing the potential of osimertinib to penetrate the blood-brain barrier.
In a further analysis of the Phase III AURA3 trial, osimertinib 80mg tablets once-daily demonstrated a median time without disease worsening or death (progression-free survival, PFS) of 11.7 months in patients with EGFR T790M mutation-positive advanced NSCLC with ≥1 measurable and/or non-measurable CNS metastases on baseline brain scan, as measured by Blinded Independent Central Review (BICR). Standard platinum-based doublet chemotherapy demonstrated a PFS of 5.6 months in the same patient population (HR 0.32; 95% confidence interval [CI] 0.15, 0.69). Among patients who were evaluable for response, CNS objective response rate (ORR) was 70% with osimertinib and 31% with chemotherapy (odds ratio [OR], 5.13; 95% CI 1.44, 20.64). In the AURA3 trial, the most common (≥20%) adverse reactions observed in osimertinib-treated patients were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%).
Dr. Marina-Chiara Garassino, the Thoracic Oncology Unit, Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said: “The results of osimertinib in patients with CNS metastases are consistent with what has already been reported in the overall AURA3 population. These data suggest that, like the overall EGFR T790M mutation-positive NSCLC population, patients who have progressed to develop CNS metastases may also be able to benefit from osimertinib.”
Data were also reported from the BLOOM trial on an EGFR mutation-positive, T790M unselected, advanced NSCLC cohort of 21 patients with leptomeningeal metastases (LM) treated with osimertinib at an off-label dose of 160mg po (oral) once daily. The overall LM response by investigator assessment was 43%, and of the 10 patients with an ‘abnormal’ neurological assessment at baseline, seven (70%) had an improvement. The most common adverse events (AEs) were diarrhea (n=13), nausea (n=11), paronychia (n=9) and rash (n=9). All were Grade 1/2, except one case each of diarrhea and nausea (both Grade ≥3). Six patients had dose interruptions, four patients had an AE leading to dose reduction, and four patients had an AE leading to discontinuation. Three patients had an AE leading to death, however no deaths were considered possibly causally-related to osimertinib by the investigator.
Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “Osimertinib’s potential for blood-brain barrier penetration was recognized at an early stage of development, and it is gratifying to see those findings reflected in positive progression-free survival outcomes in patients with CNS metastases in the AURA3 trial and in responses in patients with leptomeningeal metastases in the BLOOM study.”
LM are incurable and notoriously difficult to treat, as existing therapies are often unable to effectively cross the blood-brain barrier, leaving patients with limited treatment options. The use of osimertinib for these patients is not approved and subject to further clinical research.
In March 2017, the US Food and Drug Administration (FDA) granted full approval for Tagrisso 80mg once-daily tablets 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 tyrosine kinase inhibitor (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, and is now approved in 50 countries worldwide.
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%)
TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy.
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 26% of all cancer deaths in the US, more than breast, prostate and colorectal cancers combined. Among patients with NSCLC, up to 40% have brain metastases at some time in the course of their disease. Patients who have EGFR mutation-positive NSCLC, which occurs in 10% to 15% of NSCLC patients in the US and Europe and 30% to 40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signaling pathways that drive the growth of tumor cells. However, tumors almost always develop resistance to treatment, leading to disease progression. Approximately two-thirds of patients develop resistance to approved EGFR-TKIs such as gefitinib and erlotinib due to the secondary mutation, EGFR T790M.
About Tagrisso® (osimertinib)
Tagrisso® (osimertinib) 40mg and 80mg once-daily oral tablet has been approved in 50 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced NSCLC. Eligibility for treatment with Tagrissois dependent on confirmation that the EGFR T790M mutation is present in the tumor.
Tagrisso is a third generation, irreversible EGFR-TKI designed to inhibit both EGFR sensitizing and EGFR T790M resistance mutations, with clinical activity against CNS metastases. Tagrisso is also being investigated in the adjuvant and metastatic first-line settings, including in patients with and without CNS metastases, in leptomeningeal metastases, and in combination with other treatments.
About the AURA3 trial
AURA3 compared the efficacy and safety of osimertinib 80mg once daily and platinum-based doublet chemotherapy in 419 patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC whose disease had progressed on or after treatment with a previous EGFR-TKI. The trial was carried out in more than 130 locations worldwide, including the US, Canada, Europe, China, Japan, Korea, Taiwan and Australia.
The primary endpoint of the trial was PFS, and secondary endpoints included OS, ORR, DoR, DCR, safety and measures of health-related quality of life (HRQoL).
About the BLOOM trial
In the BLOOM trial, patients with EGFR mutation-positive advanced NSCLC who had progressed on prior EGFR-TKI therapy and had leptomeningeal metastases confirmed by positive cerebrospinal fluid cytology received osimertinib off-label dose 160mg once daily. Response was assessed (by investigator) in two cohorts: EGFR T790M unselected and EGFR T790M-positive (by central test). Analyses were based on cerebrospinal fluid (CSF) cytology, brain MRI imaging and neurological examination every six weeks until progression.
About Central Nervous System (CNS) Metastases
Parenchymal brain metastases (BM) and leptomeningeal metastases (LM) are different forms of CNS metastases with a particularly devastating prognosis. While separate conditions, they may occur in parallel and are notoriously difficult to treat. BM are a common complication of advanced cancer and form when primary tumor cells disseminate through the blood stream and proliferate in the brain, while LM is much rarer and occurs when tumor cells spread to the meninges surrounding the brain and spinal cord.
About AstraZeneca in Lung Cancer
AstraZeneca uses ground-breaking science to develop a wide range of therapies for patients with lung cancer. We are pioneering biomarker-guided therapies that aim to eliminate lung cancer by targeting molecular mutations in tumor cells and by boosting 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.
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.