MET is the most common biomarker in patients with EGFR-mutated lung cancer
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
Savolitinib, marketed in
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 tumours with MET overexpression and/or amplification, and more than one-third (34%) met the defined high MET level cut-off.
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 hybridisation (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:
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.
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
MET is a tyrosine kinase receptor that has an essential role in normal cell development.8 MET overexpression and/or amplification can lead to tumour 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, randomised, 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
The trial has enrolled 294 patients to date in more than 80 centres globally, including centres in the US,
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
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).
Savolitinib
Savolitinib is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumours. 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
In 2011,
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
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that
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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.
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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.
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-Cieckiewicz 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.
9. Wang Q, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
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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