ADAURA Phase III trial data at ESMO
reinforce the proven clinical activity of TAGRISSO in treating
central nervous system metastases
Results from a prespecified exploratory analysis of the positive
ADAURA Phase III trial showed AstraZeneca’s TAGRISSO® (osimertinib)
demonstrated a clinically meaningful improvement in central nervous
system (CNS) disease-free survival (DFS) in the adjuvant treatment
of patients with early-stage (IB, II and IIIA) epidermal growth
factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC),
after complete tumor resection.
While up to 30% of all patients with NSCLC may be diagnosed
early enough to have potentially curative surgery, disease
recurrence is still common in early-stage disease.1-3 CNS
recurrence, when cancer spreads to the brain, is a frequent
complication of EGFRm NSCLC and these patients have an especially
poor prognosis.4,5
Results were presented on September 19, 2020 during the
Presidential Symposium of the European Society for Medical Oncology
(ESMO) Virtual Congress 2020 (abstract #LBA1) and simultaneously
published with the primary results in The New England Journal of
Medicine.
This analysis showed that fewer patients treated with TAGRISSO
in the adjuvant setting had recurrence events or deaths compared to
placebo (11% versus 46%). Among patients whose cancer recurred, 38%
of those treated with TAGRISSO had a metastatic recurrence compared
to 61% of patients on placebo. TAGRISSO showed an 82% reduction in
the risk of CNS recurrence or death (based on a hazard ratio [HR]
of 0.18; 95% confidence interval [CI] 0.10-0.33; p<0.0001).
Median CNS DFS was not yet reached in either arm.
In a post-hoc analysis, the estimated probability of observing
disease recurrence in the brain at 18 months for patients treated
with TAGRISSO was less than 1% versus 9% for placebo among patients
who had not experienced another type of recurrence. On the primary
endpoint of DFS in patients with Stage II and IIIA disease,
TAGRISSO in the adjuvant setting reduced the risk of disease
recurrence or death by 83% (HR 0.17; 95% CI 0.12-0.23;
p<0.0001).
Masahiro Tsuboi, MD, PhD, director of the Department of Thoracic
Surgery and Oncology, National Cancer Center Hospital East in
Japan, and a principal investigator in the ADAURA Phase III trial,
said: “It’s time to change the notion that treatment for
early-stage EGFR-mutated lung cancer ends after surgery, since
recurrence rates are still very high even after adjuvant
chemotherapy. These new data showing low rates of recurrence,
particularly in the brain, combined with the remarkable
disease-free survival benefit, clearly demonstrate that TAGRISSO
provides patients with more time living cancer-free.”
José Baselga, Executive Vice President, Oncology R&D, said:
“Once lung cancer has spread to the brain, outcomes are typically
devastating for patients. We are now seeing TAGRISSO expanding on
its proven efficacy in treating progression in the brain in the
metastatic setting as a result of its ability to cross the
blood-brain barrier. The striking new data show that TAGRISSO
prevents the development of brain metastases in patients with early
disease and reinforce that this medicine is truly transformative
for patients with EGFR-mutated lung cancer. TAGRISSO should become
the standard of care in the adjuvant setting, just as it is for
patients with metastatic disease around the world.”
Summary of exploratory results on CNS recurrence in the
ADAURA Phase III trial
TAGRISSO n=339
Placebo n=343
CNS DFS
HR (95% CI)
0.18 (0.10-0.33);
p-value
p<0.0001
CNS DFS events, patients (%):
6 (2%)
39 (11%)
CNS recurrence
4 (1%)
33 (10%)
Deathi
2 (1%)
6 (2%)
DFS events, patients (%):
37 (11%)
159 (46%)
Type of disease recurrence
n=37
n=157
Local/regional only
23 (62%)
61 (39%)
Distant
14 (38%)
96 (61%)
Deathii
0
2 (1%)
i. Death in absence of CNS disease recurrence, or death within
two visits of baseline where the patient has no evaluable
assessments or no baseline data. ii. Death in the absence of
disease recurrence (any site), or death within two visits of
baseline where the patient has no evaluable assessments or no
baseline data.
The safety and tolerability of TAGRISSO in this trial was
consistent with previous trials in the metastatic EGFRm NSCLC
setting. Adverse events at Grade 3 or higher from all causes
occurred in 10% of patients in the TAGRISSO arm versus 3% in the
placebo arm as assessed by investigators.
TAGRISSO is not currently approved in the adjuvant setting in
any country. TAGRISSO received Breakthrough Therapy Designation in
July 2020 for the adjuvant treatment of patients with early-stage
EGFRm NSCLC after complete tumor resection with curative intent.
TAGRISSO is approved for the 1st-line treatment of patients with
metastatic EGFRm NSCLC and for the treatment of metastatic EGFR
T790M mutation-positive NSCLC in the US, Japan, China, the EU and
many other countries around the world.
TAGRISSO IMPORTANT SAFETY INFORMATION
- There are no contraindications for TAGRISSO
- Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of
the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal.
Withhold TAGRISSO and promptly investigate for ILD in patients who
present with worsening of respiratory symptoms which may be
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 1142 TAGRISSO-treated patients in
clinical trials, 0.9% were found to have a QTc >500 msec, and
3.6% 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 2.6% of the 1142 TAGRISSO-treated
patients; 0.1% of cardiomyopathy cases were fatal. A decline in
left ventricular ejection fraction (LVEF) ≥10% from baseline and to
<50% LVEF occurred in 3.9% of 908 patients who had baseline and
at least one follow-up LVEF assessment. Conduct cardiac monitoring,
including 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, permanently discontinue
TAGRISSO
- Keratitis was reported in 0.7% of 1142 patients treated with
TAGRISSO 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
- Postmarketing cases consistent with Stevens-Johnson syndrome
(SJS) and erythema multiforme major (EMM) have been reported in
patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is
suspected and permanently discontinue if confirmed
- Verify pregnancy status of females of reproductive potential
prior to initiating TAGRISSO. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with TAGRISSO 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
- Most common adverse reactions (≥20%) were diarrhea, rash, dry
skin, nail toxicity, stomatitis, fatigue and decreased
appetite
INDICATIONS
- TAGRISSO is indicated for the first-line treatment of patients
with metastatic non-small cell lung cancer (NSCLC) whose tumors
have epidermal growth factor receptor (EGFR) exon 19 deletions or
exon 21 L858R mutations, as detected by an FDA-approved test
- TAGRISSO is indicated 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 EGFR
tyrosine kinase inhibitor (TKI) therapy
Please see complete Prescribing Information, including
Patient Information.
About Lung cancer
Lung cancer is the leading cause of cancer death among both men
and women, accounting for about one-fifth of all cancer deaths.6
Lung cancer is broadly split into NSCLC and small cell lung cancer,
with 80-85% classified as NSCLC.7 The majority of all NSCLC
patients are diagnosed with advanced disease while approximately
25-30% present with resectable disease at diagnosis.1-3
For those with resectable tumors, the majority of patients
eventually develop recurrence despite complete tumor resection and
adjuvant chemotherapy.8 Early-stage lung cancer diagnoses are often
only made when the cancer is found on imaging for an unrelated
condition.9,10
Approximately 10-15% of NSCLC patients in the US and Europe, and
30-40% of patients in Asia have EGFRm NSCLC.11-13 These patients
are particularly sensitive to treatment with EGFR-tyrosine kinase
inhibitors (TKIs) which block the cell-signaling pathways that
drive the growth of tumor cells.14
About ADAURA
ADAURA is a randomized, double-blinded, global,
placebo-controlled Phase III trial in the adjuvant treatment of 682
patients with Stage IB, II, IIIA EGFRm NSCLC following complete
tumor resection and adjuvant chemotherapy as indicated. Patients
were treated with TAGRISSO 80 mg once-daily oral tablets or placebo
for three years or until disease recurrence.
The trial enrolled in more than 200 centers across more than 20
countries, including the US, in Europe, South America, Asia and the
Middle East. The primary endpoint is DFS in Stage II and IIIA
patients and a key secondary endpoint is DFS in Stage IB, II and
IIIA patients. The data readout was originally anticipated in 2022.
The trial will continue to assess OS.
About TAGRISSO
TAGRISSO® (osimertinib) is a third-generation, irreversible
EGFR-TKI with clinical activity against central nervous system
metastases. TAGRISSO 40 mg and 80 mg once-daily oral tablets have
received approval in the US, Japan, China, the EU and many
countries around the world for 1st-line EGFRm advanced NSCLC and
EGFR T790M mutation-positive advanced NSCLC.
AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and
potential new medicines in late-stage development for the treatment
of different forms of lung cancer spanning different histologies,
several stages of disease, lines of therapy and modes of
action.
AstraZeneca aims to address the unmet needs of patients with
EGFRm tumors as a genetic driver of disease with the approved
medicines gefitinib and TAGRISSO and its ongoing Phase III trials
LAURA, NeoADAURA and FLAURA2.
AstraZeneca is committed to addressing tumor mechanisms of
resistance through the ongoing Phase II trials SAVANNAH and
ORCHARD, which test TAGRISSO in combination with savolitinib, a
selective inhibitor of c-MET receptor tyrosine kinase, along with
other potential new medicines.
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 seven
new medicines launched between 2014 and 2020, and a broad pipeline
of small molecules and biologics in development, the Company is
committed to advance oncology as a key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers.
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
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 therapy areas - Oncology, Cardiovascular, Renal &
Metabolism and Respiratory & Immunology. 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.
References
1. Cagle P, et al. Lung Cancer Biomarkers: Present Status and
Future Developments. Arch Pathol Lab Med. 2013;137:1191-1198. 2. Le
Chevalier T. Adjuvant Chemotherapy for Resectable Non-Small-Cell
Lung Cancer: Where is it Going? Ann Oncol. 2010;21:196-198. 3.
Datta D, et al. Preoperative Evaluation of Patients Undergoing Lung
Resection Surgery. Chest. 2003;123:2096–2103. 4. Rangachari D, et
al. Brain Metastases in Patients with EGFR-Mutated or
ALK-Rearranged Non-Small-Cell Lung Cancers. Lung Cancer.
2015;88:108–111. 5. Ali A, et al. Survival of Patients with
Non-small-cell Lung Cancer After a Diagnosis of Brain Metastases.
Curr Oncol. 2013;20(4):e300-e306. 6. World Health Organization.
International Agency for Research on Cancer. Lung Fact Sheet.
Available at
http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed September 2020. 7. LUNGevity Foundation. Types of Lung
Cancer. Available at
https://www.lungevity.org/about-lung-cancer/lung-cancer-101/types-of-lung-cancer.
Accessed September 2020. 8. Pignon JP et al. Lung Adjuvant
Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative
Group. J Clin Oncol. 2008;26:3552-3559. 9. Sethi S, et al.
Incidental Nodule Management – Should There Be a Formal Process? J
Thorac Dis. 2016;8:S494-S497. 10. LUNGevity Foundation. Screening
and Early Detection. Available at:
https://lungevity.org/for-patients-caregivers/lung-cancer-101/screening-early-detection#1.
Accessed September 2020. 11. Szumera-Ciećkiewicz A, et al. EGFR
Mutation Testing on Cytological and Histological Samples in
Non-Small Cell Lung Cancer: a Polish, Single Institution Study and
Systematic Review of European Incidence. Int J Clin Exp Pathol.
2013;6:2800-2812. 12. Keedy VL, et al. American Society of Clinical
Oncology Provisional Clinical Opinion: Epidermal Growth Factor
Receptor (EGFR) Mutation Testing for Patients with Advanced
Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine
Kinase Inhibitor Therapy. J Clin Oncol. 2011;29:2121-2127. 13.
Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of
Available Methods and Their Use for Analysis of Tumour Tissue and
Cytology Samples. J Clin Pathol. 2013;66:79-89. 14. Cross DA, et
al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated
Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov.
2014;4(9):1046-1061.
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