MET is the most common biomarker in patients
with EGFR-mutated lung cancer who develop resistance to targeted
therapy
Global SAFFRON Phase III trial evaluating
this combination is underway
Preliminary results from the SAVANNAH Phase II trial showed that
TAGRISSO® (osimertinib) plus savolitinib demonstrated an objective
response rate (ORR) of 49% (95% confidence interval [CI], 39-59%)
in patients with epidermal growth factor receptor-mutated (EGFRm)
non-small cell lung cancer (NSCLC) with high levels of MET
overexpression and/or amplification, defined as IHC90+ and/or
FISH10+, whose disease progressed on treatment with TAGRISSO.
The highest ORR was observed in patients with high levels of MET
who were not treated with prior chemotherapy (52% [95% CI,
41-63%]). In patients whose tumors did not show high levels of MET,
the ORR was 9% (95% CI, 4-18%). These results are being shared at
the International Association for the Study of Lung Cancer 2022
World Conference on Lung Cancer, taking place August 6-9 in Vienna,
Austria.
Savolitinib is an oral, potent, and highly selective MET
tyrosine kinase inhibitor (TKI) being jointly developed and
commercialized by AstraZeneca and HUTCHMED.
While EGFR-targeted therapy can provide a durable survival
benefit to patients with EGFRm NSCLC, most will eventually develop
resistance to their treatment, with MET being the most common
resistance biomarker.1 Among patients screened for enrolment in
SAVANNAH, all of whom experienced disease progression on TAGRISSO,
62% had tumors with MET overexpression and/or amplification, and
more than one-third (34%) met the defined high MET level
cut-off.
Myung-Ju Ahn, MD, PhD, Professor of Hemato-Oncology at the
Department of Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, South Korea, and Principal
Investigator in the SAVANNAH Phase II trial, said: “Acquired
resistance to targeted therapy and disease progression are
difficult realities for most patients with EGFR-mutated non-small
cell lung cancer. These preliminary SAVANNAH results potentially
support a novel approach for identifying patients with MET
overexpression and/or amplification who are most likely to benefit
from a MET-directed therapy, like savolitinib. They also suggest
that with the right biomarker testing strategy, MET may be a more
prevalent target among resistant patients than previously
understood, supporting further investigation of the osimertinib
plus savolitinib regimen.”
Cristian Massacesi, Chief Medical Officer and Oncology Chief
Development Officer, AstraZeneca, said: “The current standard of
care for patients with EGFR-mutated lung cancer who progress on
targeted treatment is chemotherapy. The results from SAVANNAH
suggest savolitinib added to TAGRISSO at the time of disease
progression could possibly provide these biomarker-selected
patients with a potentially less toxic, more effective treatment
option. We look forward to better understanding the potential of
the TAGRISSO plus savolitinib regimen in this trial and in the
SAFFRON Phase III trial.”
Weiguo Su, Chief Executive Officer and Chief Scientific Officer,
HUTCHMED, said: “It is encouraging to see the savolitinib and
TAGRISSO combination regimen progress into a global Phase III
study, SAFFRON, with a well-supported patient selection strategy
that could benefit more patients than previously recognized. The
preliminary results of the SAVANNAH study also affirm the role of
molecular testing prior to initiating subsequent treatment for
non-small cell lung cancer patients who experience disease
progression on an EGFR-targeted therapy. We are aligned in pursuing
a selective, patient-centric approach in development efforts for
savolitinib in this setting.”
In this analysis, patients’ MET overexpression and/or
amplification levels were determined by two tests:
immunohistochemistry (IHC), which detects if cancer cells have a
particular protein or marker on their surface, and fluorescence in
situ hybridization (FISH), which detects a specific DNA sequence
from cancer cells. All patients in this analysis (n=193) had at
least IHC50+ and/or FISH5+ and were treated with savolitinib 300mg
once daily added to TAGRISSO 80mg once daily following disease
progression on TAGRISSO alone.
Summary of efficacy resultsi:
Endpoint
All patients (IHC50+ and/or
FISH5+; n=193)
Patients with high levels of
METii
(IHC90+ and/or
FISH10+)
Patients with lower levels of
METii (n=77)
All
(n=108)
No prior chemo (n=87)
ORR, % (95% CI)
32 (26, 39)
49 (39, 59)
52 (41, 63)
9 (4, 18)
Median DoRiii, months (95%
CI)
8.3 (6.9, 9.7)
9.3 (7.6, 10.6)
9.6 (7.6, 14.9)
6.9 (4.1, 16.9)
Median PFSiv,
months (95% CI)
5.3 (4.2, 5.8)
7.1 (5.3, 8.0)
7.2 (4.7, 9.2)
2.8 (2.6, 4.3)
DCRv, % (95% CI)
61 (53, 68)
74 (65, 82)
75 (64, 83)
43 (32, 55)
i. Analysis data cut-off: 27 August 2021
ii. Eight patients excluded from subgroup analyses due to
invalid or missing test results
iii. DoR, duration of response
iv. PFS, progression-free survival
v. DCR, disease control rate
The safety profile of TAGRISSO plus savolitinib was consistent
with the known profiles of the combination and each treatment
alone. No new safety signals were identified. Less than half (45%)
of patients in this analysis experienced Grade 3 or higher adverse
events (AEs), with those most frequently reported including
pulmonary embolism, dyspnoea, decreased neutrophil count and
pneumonia. AEs attributable to savolitinib and leading to
discontinuation occurred in 13% of patients.
The global SAFFRON Phase III trial will further assess the
TAGRISSO plus savolitinib combination versus platinum-based doublet
chemotherapy in patients with EGFRm, MET-overexpressed and/or
amplified, locally advanced or metastatic NSCLC following TAGRISSO.
Patients are being prospectively selected using the high MET level
cut-off identified in SAVANNAH.
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.
You may report side effects related to AstraZeneca products by
clicking here.
CI, confidence interval; DFS, disease-free survival; EGFRm,
epidermal growth factor receptor mutation positive; HR, hazard
ratio; NE, not estimable; NSCLC, non-small cell lung cancer; OS,
overall survival; PFS, progression-free survival.
Notes
NSCLC and MET aberrations
Lung cancer is the leading cause of cancer death among men and
women, accounting for about one-fifth of all cancer deaths.2 Lung
cancer is broadly split into NSCLC and small cell lung cancer, with
80-85% classified as NSCLC.3 The majority of NSCLC patients
(approximately 75%) are diagnosed with advanced disease and
approximately 10-15% of NSCLC patients in the US and Europe, and
30-40% of patients in Asia, have EGFRm NSCLC.4,5,6,7
MET is a tyrosine kinase receptor that has an essential role in
normal cell development.8 MET overexpression and/or amplification
can lead to tumor growth and the metastatic progression of cancer
cells, and is the primary mechanism of acquired resistance to EGFR
TKIs for metastatic EGFR-mutated NSCLC. 8,9 The prevalence of MET
depends on the sample type, detection method and assay cut-off
used.10
SAVANNAH
SAVANNAH is an ongoing global, randomized, single-arm Phase II
trial studying the efficacy of savolitinib added to TAGRISSO in
patients with EGFRm, locally advanced or metastatic NSCLC with MET
overexpression and/or amplification who progressed following
treatment with TAGRISSO. Patients were treated with savolitinib 300
or 600 mg once-daily (QD) or 300 mg twice-daily, in combination
with oral osimertinib 80 mg QD.
The trial has enrolled 294 patients to date in more than 80
centers globally, including centers in the US, Canada, Europe,
South America and Asia. The primary endpoint is ORR. Key secondary
endpoints include PFS, DoR and safety.
TAGRISSO
TAGRISSO (osimertinib) is a third-generation, irreversible
EGFR-TKI with proven clinical activity in NSCLC, including against
central nervous system metastases. TAGRISSO (40mg and 80mg
once-daily oral tablets) has been used to treat approximately
575,000 patients across indications worldwide and AstraZeneca
continues to explore TAGRISSO as a treatment for patients across
multiple stages of EGFRm NSCLC.
In Phase III trials, TAGRISSO is being investigated in the
neoadjuvant resectable setting (NeoADAURA), in the Stage IA2-IA3
adjuvant resectable setting (ADAURA2), in the Stage III locally
advanced unresectable setting following chemoradiation therapy
(LAURA), and in combination with chemotherapy in the advanced
setting (FLAURA2). AstraZeneca is also researching ways to address
tumor mechanisms of resistance through the SAVANNAH and ORCHARD
Phase II trials, and the SAFFRON Phase III trial, which test
TAGRISSO given concomitantly with savolitinib, an oral, potent and
highly selective MET TKI, as well as other potential new
medicines.
Savolitinib
Savolitinib is an oral, potent, and highly selective MET TKI
that has demonstrated clinical activity in advanced solid tumors.
It blocks atypical activation of the MET receptor tyrosine kinase
pathway that occurs because of mutations (such as exon 14 skipping
alterations or other point mutations), gene amplification or
protein overexpression.
Savolitinib is marketed in China under the brand name Orpathys
for the treatment of patients with NSCLC with MET exon 14 skipping
alterations who have progressed following prior systemic therapy or
are unable to receive chemotherapy. It is currently under clinical
development for multiple tumor types, including lung, kidney, and
gastric cancers, as a single treatment and in combination with
other medicines.
AstraZeneca and HUTCHMED collaboration
In 2011, AstraZeneca and HUTCHMED entered a global licensing and
collaboration agreement to jointly develop and commercialize
savolitinib. Joint development of savolitinib in China is led by
HUTCHMED, while AstraZeneca leads development outside of China.
HUTCHMED is responsible for the marketing authorization,
manufacturing and supply of savolitinib in China. AstraZeneca is
responsible for the commercialization of savolitinib in China and
worldwide. Sales of savolitinib are recognized by AstraZeneca.
AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer
to cure through the detection and treatment of early-stage disease,
while also pushing the boundaries of science to improve outcomes in
the resistant and advanced settings. By defining new therapeutic
targets and assessing innovative approaches, the Company aims to
match medicines to the patients who can benefit most.
The Company’s comprehensive portfolio includes leading lung
cancer medicines and the next wave of innovations including
TAGRISSO (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab)
and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab
deruxtecan in collaboration with Daiichi Sankyo; Orpathys
(savolitinib) in collaboration with HUTCHMED; as well as a pipeline
of potential new medicines and combinations across diverse
mechanisms of action.
AstraZeneca is a founding member of the Lung Ambition Alliance,
a global coalition working to accelerate innovation and deliver
meaningful improvements for people with lung cancer, including and
beyond treatment.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care 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 in Oncology, Rare Diseases, and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. Please visit
astrazeneca-us.com and follow the Company on Twitter
@AstraZenecaUS.
References
1. Del MD, et al. Understanding the Mechanisms of Resistance in
EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide
Treatment Strategy. Int J Mol Sci. 2019;20(16): 3951. 2. World
Health Organization. International Agency for Research on Cancer.
All cancers fact sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf.
Accessed July 2022. 3. American Cancer Society. What is Lung
Cancer? Available at:
https://www.cancer.org/cancer/lung-cancer/about/what-is.html.
Accessed July 2022. 4. Knight SB, et al. Progress and prospects of
early detection in lung cancer. Open Biol. 2017;7(9): 170070. 5.
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;2121-27. 6. Zhang Y, et al. The prevalence of
EGFR mutation in patients with non-small cell lung cancer: a
systematic review and meta-analysis. Oncotarget. 2016;7(48). 7.
Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological
and Histological Samples in 11. Non-Small Cell Lung Cancer: a
Polish, Single Institution Study and Systematic Review of European
Incidence. Int J Clin Exp Pathol. 2013:6;2800-12. 8. Uchikawa E, et
al. Structural basis of the activation of c-MET receptor. Nat
Commun. 2021;12(4074). 9. Wang Q, et al. MET inhibitors for
targeted therapy of EGFR TKI-resistant lung cancer. Journal of
Hematology & Oncology. 2019;63. 10. Coleman N, et al. Beyond
epidermal growth factor receptor: MET amplification as a general
resistance driver to targeted therapy in oncogene-driven
non-small-cell lung cancer. ESMO Open. 2019;6(6).
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