Data at WCLC showed patients in the
practice-changing ADAURA Phase III trial maintained their quality
of life based on patient-reported outcomes
New data reinforce the ability of TAGRISSO
to penetrate the blood-brain barrier in patients with central
nervous system metastases
Results from an exploratory analysis of the positive ADAURA
Phase III trial showed AstraZeneca’s TAGRISSO® (osimertinib)
extended disease-free survival (DFS) in patients with epidermal
growth factor receptor-mutated (EGFRm) non-small cell lung cancer
(NSCLC) regardless of prior adjuvant chemotherapy treatment or
stage of disease, building on the unprecedented primary DFS results
for TAGRISSO in the adjuvant setting announced last year. Results
from ADAURA were presented during the 2020 World Conference on Lung
Cancer (WCLC) hosted by the International Association for the Study
of Lung Cancer (IASLC) and featured in the Press Program.
In this exploratory analysis of the overall trial population,
adjuvant TAGRISSO reduced the risk of disease recurrence or death
by 84% in patients who had been treated with prior adjuvant
chemotherapy (based on a hazard ratio [HR] of 0.16, 95% confidence
interval [CI] 0.10-0.26) and by 77% in patients who had not (HR
0.23; 95% CI 0.13-0.40). DFS benefits were similar across each
stage of disease.
In addition, a separate exploratory post-hoc analysis of
patient-reported outcomes in ADAURA showed that patients treated
with TAGRISSO maintained their quality of life, with no clinically
meaningful differences in physical or mental health measures in the
TAGRISSO and placebo arms.
Yi-Long Wu, MD, FACS, Tenured Professor of the Lung Cancer
Institute at Guangdong Provincial People's Hospital and Academy of
Medical Sciences in Guangzhou, China, and a principal investigator
in the ADAURA Phase III trial, said: “The overwhelming disease-free
survival benefit in patients in ADAURA already supported the role
of TAGRISSO as a pioneering therapy in the adjuvant treatment of
EGFR-mutated non-small cell lung cancer. This latest analysis shows
the magnitude of that benefit is consistent with or without prior
adjuvant chemotherapy, and regardless of disease stage, reinforcing
the critical role of TAGRISSO in this setting.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: “These new data show that TAGRISSO provides
transformative benefits independent of prior chemotherapy
treatment, preventing lung cancer from returning while allowing
patients to sustain their quality of life. Following the recent
approval of TAGRISSO in the US in the adjuvant setting, we continue
to work urgently with regulatory authorities globally to bring this
new standard of care to patients with early-stage lung cancer.”
Exploratory DFS analysis with and without chemotherapy
(CTx) OSI: TAGRISSO; PBO: placebo
Stage IB
Stage II
Stage IIIA
Stage IB-IIIA
OSI
PBO
OSI
PBO
OSI
PBO
OSI
PBO
With CTx
n=28
n=30
n=81
n=85
n=94
n=92
n=203
n=207
DFS events patients (%)
4 (14)
11 (37)
6 (7)
36 (42)
12 (13)
56 (61)
22 (11)
103 (50)
DFS HR (95% CI)
NC (NC, NC)
0.15 (0.06, 0.32)
0.13 (0.06, 0.23)
0.16 (0.10, 0.26)
Without CTx
n=78
n=76
n=37
n=33
n=21
n=27
n=136
n=136
DFS events patients (%)
7 (9)
18 (24)
5 (14)
16 (48)
3 (14)
22 (81)
15 (11)
56 (41)
DFS HR (95% CI)
0.38 (0.15, 0.88)
0.20 (0.07, 0.52)
0.10 (0.02, 0.29)
0.23 (0.13, 0.40)
In the ADAURA Phase III trial, chemotherapy use was balanced
across the two treatment arms, with 60% of patients receiving prior
adjuvant chemotherapy. In line with uptake observed in prior
studies and clinical practice, younger patients (<70 years) and
those with more advanced disease were more likely to have prior
adjuvant chemotherapy.1,2 Treatment with chemotherapy did not vary
according to a patient’s performance status.
The safety and tolerability of TAGRISSO was consistent with
previous trials in the metastatic EGFRm NSCLC setting. Adverse
events at Grade 3 or higher from all causes occurred in 20% of
patients in the TAGRISSO arm versus 13% in the placebo arm as
assessed by investigators.
Primary results of ADAURA, which were published in The New
England Journal of Medicine in September 2020, showed adjuvant
treatment with TAGRISSO reduced the risk of disease recurrence or
death by 83% (HR 0.17; 95% CI 0.12-0.23; p<0.0001) among
patients with Stage II and IIIA EGFRm NSCLC and, as shown in a
prespecified exploratory analysis, demonstrated a clinically
meaningful improvement in central nervous system (CNS) DFS compared
to placebo.
Additional TAGRISSO highlights at WCLC
In addition to these ADAURA analyses, several other
presentations and posters for TAGRISSO across lung cancer settings
and in novel combinations were featured during WCLC, including:
- Results from the ODIN BM Phase I trial, which support the
efficacy and uniform brain penetration of TAGRISSO in patients with
CNS metastases as reported in previous clinical trials. This trial
used a micro dose of intravenous TAGRISSO detectable on PET scans,
which showed rapid, high and widespread brain exposure of TAGRISSO
in both the healthy tissue and CNS metastases of four patients with
EGFRm NSCLC. Results also showed that TAGRISSO markedly reduced CNS
metastases in patients following three to four weeks of daily oral
treatment
- Final results from two expansion cohorts of the TATTON Phase Ib
trial, which support the potential of TAGRISSO plus savolitinib, a
selective inhibitor of mesenchymal epithelial transition (c-MET)
factor receptor tyrosine kinase, to overcome MET-based resistance
in patients with NSCLC whose disease has progressed on prior
EGFR-tyrosine kinase inhibitor (TKI) treatment. The safety profile
of TAGRISSO plus savolitinib was consistent with previous reports.
The combination is currently being tested in the ongoing SAVANNAH
and ORCHARD Phase II trials
- The design of a Phase I study exploring TAGRISSO in combination
with patritumab deruxtecan (U3-1402) in patients with locally
advanced or metastatic EGFRm NSCLC who progressed during or after
prior treatment with TAGRISSO alone3
- The design of the NeoADAURA Phase III trial testing the benefit
of treating patients with resectable Stage II-IIIB NSCLC with
neoadjuvant TAGRISSO as monotherapy or in combination with a choice
of standard platinum-based chemotherapies versus chemotherapy with
placebo. Patient recruitment for this trial is ongoing
TAGRISSO was recently approved in the US for the adjuvant
treatment of adult patients with early-stage EGFRm NSCLC after
tumor resection with curative intent based on the ADAURA Phase III
trial. This indication is under priority review in China and
regulatory review in the EU; additional global submission
discussions are ongoing. TAGRISSO is also 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 3.7% of
the 1479 TAGRISSO-treated patients; 0.3% 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 1479 TAGRISSO-treated patients in
clinical trials, 0.8% were found to have a QTc >500 msec, and
3.1% 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 3% of the 1479 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 3.2% of 1233 patients who had baseline and
at least one follow-up LVEF assessment. In the ADAURA study, 1.5%
(5/325) of TAGRISSO-treated patients experienced LVEF decreases
≥10% from baseline and a drop to <50%. 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 1479 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
- Postmarketing cases of cutaneous vasculitis including
leukocytoclastic vasculitis, urticarial vasculitis, and IgA
vasculitis have been reported in patients receiving TAGRISSO.
Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate
for systemic involvement, and consider dermatology consultation. If
no other etiology can be identified, consider permanent
discontinuation of TAGRISSO based on severity
- 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 (≥20%) adverse reactions, including laboratory
abnormalities, were leukopenia, lymphopenia, thrombocytopenia,
diarrhea, anemia, rash, musculoskeletal pain, nail toxicity,
neutropenia, dry skin, stomatitis, fatigue, and cough
INDICATIONS
- TAGRISSO is indicated as adjuvant therapy after tumor resection
in adult patients with 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 first-line treatment of adult
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 adult 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
For additional information, please see the complete
Prescribing Information, including Patient Information.
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.4
Lung cancer is broadly split into NSCLC and small cell lung cancer,
with 80-85% classified as NSCLC.5 The majority of all NSCLC
patients are diagnosed with advanced disease while approximately
25-30% present with resectable disease at diagnosis.6-8
For those with resectable tumors, the majority of patients
eventually develop recurrence despite complete tumor resection and
adjuvant chemotherapy.9 Early-stage lung cancer diagnoses are often
only made when the cancer is found on imaging for an unrelated
condition.10,11
Approximately 10-15% of NSCLC patients in the US and Europe, and
30-40% of patients in Asia have EGFRm NSCLC.12-14 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.15
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 was DFS in Stage II and IIIA
patients and a key secondary endpoint was DFS in Stage IB, II and
IIIA patients. The data readout was originally anticipated in 2022.
The trial will continue to assess overall survival.
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 metastatic NSCLC and
EGFR T790M mutation-positive metastatic 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 LAURA, NeoADAURA,
and FLAURA2 Phase III trials.
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 six scientific platforms -
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response,
Antibody Drug Conjugates, Epigenetics, and Cell Therapies - 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
https://www.astrazeneca-us.com/ and follow us on Twitter
@AstraZenecaUS.
References
- Chouaid C, et al. Adjuvant treatment patterns and outcomes in
patients with stage IB-IIIA non-small cell lung cancer in France,
Germany, and the United Kingdom based on the LuCaBIS burden of
illness study. Lung Cancer. 2018;124:310-316.
- Buck PO, et al. Treatment Patterns and Health Resource
Utilization Among Patients Diagnosed With Early Stage Resected
Non-Small Cell Lung Cancer at US Community Oncology Practices. Clin
Lung Cancer. 2015;16:486-495.
- Trial collaboration with Daiichi Sankyo which maintains
exclusive rights to patritumab deruxtecan.
- World Health Organization. International Agency for Research on
Cancer. Lung Fact Sheet.
https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed January 2021.
- LUNGevity Foundation. Types of Lung Cancer.
https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer.
Accessed January 2021.
- Cagle P, et al. Lung Cancer Biomarkers: Present Status and
Future Developments. Arch Pathol Lab Med. 2013;137:1191-1198.
- Le Chevalier T, et al. Adjuvant Chemotherapy for Resectable
Non-Small-Cell Lung Cancer: Where is it Going? Ann Oncol.
2010;21:196-198.
- Datta D, et al. Preoperative Evaluation of Patients Undergoing
Lung Resection Surgery. Chest. 2003;123:2096-2103.
- Pignon JP, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled
Analysis by the LACE Collaborative Group. J Clin Oncol.
2008;26:3552-3559.
- Sethi S, et al. Incidental Nodule Management – Should There Be
a Formal Process? J Thorac Onc. 2016:8;S494-S497.
- LUNGevity Foundation. Screening and Early Detection.
https://lungevity.org/for-patients-caregivers/lung-cancer-101/screening-early-detection.
Accessed January 2021.
- 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.
- 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;2:2121-2127.
- 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.
- 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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