Tagrisso extended the length of time
patients with CNS metastases live without disease worsening or
death to 11.7 months and chemotherapy to 5.6 months in the AURA3
trial
Evidence of activity in patients with EGFR
mutation-positive NSCLC and leptomeningeal metastases from the
BLOOM trial
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%)
INDICATION
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 Tagrisso is
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.
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.
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