Abstract
Introduction
Epidermal growth factor receptor (EGFR) mutations are well-known genetic alterations in advanced non-small cell lung cancer
(NSCLC) which are associated with remarkable survival benefits from first-line treatment
with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, around 30% of patients
exhibit primary resistance to EGFR-TKIs therapy. Co-existing MET amplification/over-expression has showed shorter time to progression on EGFR-TKI
monotherapy. Osimertinib (TAGRISSO, AZD9291) has been recommended in EGFR-mutant advanced NSCLC patients as first-line treatment. Savolitinib (AZD6094, HMPL-504)
is a highly selective MET-TKI which has demonstrated anti-tumor activity in various
cancers with MET alterations.
Methods
This FLOWERS study, a phase II, randomized, open-label, 2-cohort multicenter trial
aimed to evaluate the efficacy and safety of osimertinib with or without savolitinib
as first-line therapy in patients with de novo MET amplified/over-expressed, EGFR-mutant positive, locally advanced or metastatic NSCLC. Approximately 44 patients
will be randomized to receive osimertinib (80 mg once daily) monotherapy or osimertinib
(80 mg once daily) and savolitinib (300 mg twice daily) combination therapy; patients
in osimertinib monotherapy cohort confirmed as MET positive (MET-amplified/over-expressed) after disease progression will have the opportunity to
receive the cross-over combination therapy as second-line treatment. Primary endpoint
will be objective response rate. Key secondary endpoints will be progression-free
survival, duration of response, disease control rate, overall survival, safety and
tolerability.
Conclusion
The results of the study will provide better perspectives on the efficacy and safety
of EGFR-TKI plus MET-TKI combination therapy (osimertinib plus savolitinib) in patients
with de novo MET-amplified/over-expressed, EGFR-mutant positive, treatment naïve, advanced NSCLC and offer a meaningful guidance
in clinical practice (NCT05163249).
Keywords
Abbreviations:
EGFR (Epidermal growth factor receptor), NSCLC (non-small cell lung cancer), EGFR-TKIs (EGFR-tyrosine kinase inhibitors), (EGFRm)-positive (EGFR mutation), MET (mesenchymal-epithelial transition factor), TTP (time to progression), LCO (lung cancer organoids), IHC (immunohistochemistry), ICH-GCP (International Conference of Harmonization Good Clinical Practice Guidelines), IEC (independent ethics committee), IRB (international review board), ct-DNA (cell-free DNA), RECIST 1.1 (Response Evaluation Criteria in Solid Tumours), PFS (Progression Free Survival), DoR (duration of response), DCR (disease control rate), OS (overall survival), CR (complete response), PR (partial response), SD (stable disease), PD (progression of disease), ADR (adverse drug reactions), AESI (adverse event of special interest), ECOG (Eastern Cooperative Oncology Group), eCRF (electronic case report form), DCO (data cut-off), LSI (last subject in), HGF (hepatocyte growth factor), PI3K (phosphoinositide 3-kinase), CNG (copy number gain), TTF (time-to-treatment failure)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Lung CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020.Chin Med J. 2021; 134: 783-791https://doi.org/10.1097/CM9.0000000000001474
- Lung cancer molecular epidemiology in China: recent trends.Transl Lung Cancer Res. 2014; 3: 270-279https://doi.org/10.3978/j.issn.2218-6751.2014.09.01
- Implications of key trials in advanced nonsmall cell lung cancer.Cancer. 2010; 116: 1155-1164https://doi.org/10.1002/cncr.24815
- Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25 (Suppliii): 27-39https://doi.org/10.1093/annonc/mdu199
- Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): A phase 3 randomised trial.Lancet Oncol. 2015; 16: 990-998https://doi.org/10.1016/S1470-2045(15)00121-7
- A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER).J Thorac Oncol. 2014; 9: 154-162https://doi.org/10.1097/JTO.0000000000000033
- Systemic therapy for stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.J Clin Oncol. 2015; 33: 3488-3515https://doi.org/10.1200/JCO.2015.62.1342
- Concomitant genetic alterations with response to treatment and epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR-mutant advanced non-small cell lung cancer.JAMA Oncol. 2018; 4: 739-742https://doi.org/10.1001/jamaoncol.2018.0049
- Presence of Epidermal Growth Factor Receptor Gene T790M mutation as a minor clone in non–small cell lung cancer.Cancer Research. 2006; 66: 7854-7858https://doi.org/10.1158/0008-5472.CAN-06-1951
- Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.Cancer Cell. 2010; 17: 77-88https://doi.org/10.1016/j.ccr.2009.11.022
- Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor–activating mutations.Cancer Research. 2008; 68: 9479-9487https://doi.org/10.1158/0008-5472.CAN-08-1643
- Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naïve Asian NSCLC patients.Int J Cancer. 2013; 132: E74-E84https://doi.org/10.1002/ijc.27813
- Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.Cancer Lett. 2016; 380: 494-504https://doi.org/10.1016/j.canlet.2016.07.021
- Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.Clin Cancer Res. 2018; 24: 3108-3118https://doi.org/10.1158/1078-0432.CCR-17-2961
- Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations.Cancer Commun (Lond). 2019; 39: 7https://doi.org/10.1186/s40880-019-0354-z
- Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer.J Med Chem. 2014; 57: 7577-7589https://doi.org/10.1021/jm500510f
- Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models.Mol Oncol. 2015; 9: 323-333https://doi.org/10.1016/j.molonc.2014.08.015
- First-in-human phase I study of the selective MET inhibitor, savolitinib, in patients with advanced solid tumors: safety, pharmacokinetics, and antitumor activity.Clin Cancer Res. 2019; 25: 4924-4932https://doi.org/10.1158/1078-0432.CCR-18-1189
- Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.Lancet Oncol. 2020; 21 (In press): 373-386https://doi.org/10.1016/S1470-2045(19)30785-5
- Clinical outcomes of EGFR+/METamp+ vs. EGFR+/METamp- untreated patients with advanced non-small cell lung cancer.Thorac Cancer. 2022; 13: 1619-1630https://doi.org/10.1111/1759-7714.14429
- Clonal MET amplification as a determinant of tyrosine kinase inhibitor resistance in epidermal growth factor receptor–mutant non–small-cell lung cancer.JCO. 2019; 37: 876-884https://doi.org/10.1200/JCO.18.00177
- A randomized-controlled phase 2 study of the MET antibody emibetuzumab in combination with erlotinib as first-line treatment for EGFR mutation-positive NSCLC patients.J Thorac Oncol. 2020; 15: 80-90https://doi.org/10.1016/j.jtho.2019.10.003
- MET expression in advanced non-small-cell lung cancer: effect on clinical outcomes of chemotherapy, targeted therapy, and immunotherapy.Clin Lung Cancer. 2018; 19: e441-e463https://doi.org/10.1016/j.cllc.2018.03.010
- Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-mutant lung cancer.Biomark Res. 2019; 7: 27https://doi.org/10.1186/s40364-019-0179-6
- Dramatic response to combination erlotinib and crizotinib in a patient with advanced, EGFR-mutant lung cancer harboring de novo MET amplification.J Thorac Oncol. 2016; 11: e83-e85https://doi.org/10.1016/j.jtho.2016.02.021
Article info
Publication history
Published online: September 29, 2022
Accepted:
September 18,
2022
Received in revised form:
August 30,
2022
Received:
June 28,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
