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The case was a 58-year-old female patient with adenocarcinoma (T4N3M1a, stage IV) of right upper lung cancer, with an initial gene mutation type of EGFR L858R mutation. After undergoing a triplication of treatment, the patient developed drug resistance due to EGFR L858R with MET amplification. After that, the patient received cevotinib + osimertinib treatment, and the metastases rapidly shrank. The case was provided by Professor Shen Fangfang of Shanxi Cancer Hospital and commented by Guo Wei, Director of Shanxi Cancer Hospital.
Case profile
Fig. 1 CT findings before and during treatment with osimertinib + sivotinib
The case was a patient with adenocarcinoma (T4N3M1a, stage IV) of the right upper lung carcinoma, initially genetically tested for the EGFR L858R mutation. Patients are treated with exetinib on the first line and adjust the treatment regimen several times based on genetic test results after disease progression.
After post-line therapy with osimertinib, the patient's genetic test results were EGFR L858R with MET amplification, so the adjustment protocol was sevotinib + osiminib treatment. At follow-up after 1 month, efficacy evaluation found that the patient's metastases rapidly shrank. And, by the time of the last follow-up in December 2021, the patient was in stable condition and is still under treatment.
Cases are provided by specialists
Professor Shen Fangfang: In the era of precision therapy, dynamic gene testing should be carried out during NSCLC targeted therapy
In the era of precision medicine, the treatment of non-small cell lung cancer (NSCLC) has made rapid progress. However, at present, NSCLC diagnosis and treatment still faces many challenges in clinical practice, especially the problem of secondary drug resistance of targeted drugs. For NSCLC patients with EGFR mutation positivity, the "three generations in the same house" EGFR-TKI bring more options for clinical treatment. However, most patients will inevitably develop drug resistance and disease progression. Understanding the mechanism by which EGFR-TKI develops drug resistance is decisive for guiding further treatment.
The case was initially genetically tested for the EGFR L858R mutation and received multiple lines of therapy. During treatment, the patient first developed a T790M resistance mutation, and after more than 4 months of treatment with three generations of EGFR-TKI osimertinib, the resistance caused by MET amplification recured. After receiving the MET inhibitor sivotinib + osiminib, the metastases were significantly reduced and the condition remained stable at the latest follow-up, which shows that the dual-target regimen has brought significant therapeutic benefits to this patient with advanced lung cancer who is hyper-line therapy.
MET amplification is one of the mechanisms of resistance after EGFR-TKI therapy, with an incidence of 5% to 21% after primary/second-generation EGFR-TKI resistance [1-2] and a prevalence of 15% to 30% after third-generation EGFR-TKI resistance [3-4]. Currently, fluorescence in situ hybridization (FISH) detection is still the standard detection method for MET amplification, but NGS can also be used for MET amplification detection. Compared with FISH, NGS may miss MET polyjumes, but it can detect other variants such as MET mutations and fusions at the same time, and can achieve multigene co-examination, so it is more widely used in clinical practice [5].
Testing for MET amplification is particularly true in EGFR-TKI-resistant populations, where adequate tumor tissue specimens may be prioritized. If the test results are inconclusive, amplification signals are not typical, or are at a critical value, a FISH retest is recommended. Blood NGS can also be used for MET amplification testing, but it should be noted that it has low sensitivity compared to tissue testing, and a negative test does not exclude MET amplification and can only be used as a clinical reference [5].
In short, it is of great clinical value and significance for NSCLC patients with EGFR mutations to undergo tissue biopsies and dynamic gene tests multiple times during treatment.
Expert reviews
Prof. Wei Guo: In patients with EGFR-TKI resistance with MET amplification who have been treated with multiple lines, sivotinib + osiminib benefit significantly
For EGFR-TKI-resistant populations induced by MET amplification, MET-TKI combined with EGFR-TKI is an important treatment strategy. The TATTON study [6] included patients with MET amplification after EGFR-TKI resistance who received sivotinib plus osimertinib. The results showed that for patients with first/ second-generation EGFR-TKI resistance, the objective response rate (ORR) of sivotinib + osimtinib was 64% to 67%, and the median progression-free survival (PFS) was about 10 months, regardless of the T790M mutation. For people who received multi-line therapy with MET amplification of multitreaterated osimertinib in the absence of standard treatment regimens, cevotinib + osiminib treatment still resulted in 30% ORR and a median PFS of 5.4 months. The findings suggest that the two-target regimen of sivatinib + osiminib remains effective after multi-line therapy, and that sivotinib can delay the time of oscitinib resistance.
In addition, at the 2021 Annual Meeting of the European Society of Oncology (ESMO), part of the data [7] of the Clinical Phase II ORCHARD Study Group A of patients with MET amplification were published after the use of sivatinib + osimtinib for first-line treatment resistance. Results showed that the objective response rate (ORR) of the cevotinib + oshitinib regimen was 41% (all partial responses), and all patients who achieved remission continued treatment.
This case is EGFR L858R with MET amplification, and due to the previous lack of highly selective targeted drugs for MET gene variants, most of these patients can only switch to standard chemotherapy, and there are obvious limitations in efficacy and safety. At present, the highly selective MET inhibitor sivotinib has been approved for marketing in China, bringing better treatment options to patients with MET variants. The course of treatment of the case, which was found to have a rapid resolution of lesions after one month of follow-up with sivotinib plus osimtinib, remained stable in the last 3 follow-up visits, and the course of treatment once again validated the benefits of the two-target regimen.
The results of TATTON and ORCHARD studies have preliminarily confirmed the efficacy advantages of sivotinib + osimertinib in patients with MET amplification. It is believed that with the release of more research results, cevoltinib is expected to further expand the indications and provide new treatment strategies for EGFR-TKI-resistant patients.
Case review specialist
Professor Guo Wei
Deputy Director and Chief Physician of the Second Department of Respiratory Medicine, Shanxi Provincial Cancer Hospital
Member of the Standing Committee of the Cancer Chemotherapy Committee of the China Medical Education Association
Member of the Standing Committee of the Lung Cancer Branch Committee of the Beijing Cancer Prevention and Control Research Association
Vice Chairman of the Lung Cancer Diagnosis and Treatment Expert Committee of the Beijing Health Promotion Association
Vice Chairman of the Clinical Precision Medicine Professional Committee of Shanxi Medical Doctor Association
Vice Chairman of the Youth Committee of the Standing Committee of the Tumor Chemotherapy Special Committee of Shanxi Anti-Cancer Association
Vice President of Thoracic Tumor Branch of Shanxi Geriatrics Society
Vice Chairman of the Tumor Multidisciplinary Diagnosis and Treatment Management Committee of Shanxi Hospital Association
Shanxi Provincial Health Commission "100 million health talents" high-end leading talents
Member of the Standing Committee of the Lung Cancer Professional Committee of Shanxi Anti-Cancer Association
Member of the Standing Committee of the Targeted Therapy Professional Committee of Shanxi Anti-Cancer Association
Professor Shen Fangfang
Attending physician of the Second Department of Respiratory Medicine, Shanxi Provincial Cancer Hospital
Member of Thoracic Tumor Branch of Shanxi Geriatrics Association
Member of the Health Care Committee of Shanxi Preventive Medicine Association
Member of the Lung Cancer Professional Committee of Shanxi Anti-Cancer Association
Member of the Clinical Precision Medicine Professional Committee of Shanxi Medical Doctor Association
Member of the Adverse Drug Reaction Management Subcommittee of Beijing Cancer Prevention and Control Research Association
bibliography:
[1] Pasquini G, Giaccone G. C-MET inhibitors for advanced non-small cell lung cancer[J]. Expert Opin Investig Drugs. 2018;27(4):363-375.
[2] Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib[J]. Proc Natl Acad Sci U S A. 2007;104(52):20932-7.
[3] Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. 2018 ESMO Congress. Abstract LBA50.
[4] Wang Y, Li L, Han R, et al. Clinical analysis by next-generation sequencing for NSCLC patients with MET amplification resistant to osimertinib[J]. Lung Cancer. 2018;118:105-110.
Clinical Practice Guidelines for Molecular Pathology Detection of Non-Small Cell Lung Cancer (2021 Edition).
[6] Lecia V Sequist, Ji-Youn Han, et al. 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[J]. Lancet Oncol. 2020;21(3):373-386.
[7] Helena A Y, et al. ORCHARD osimertinib + savolitinib interim analysis: A biomarker-directed phase II platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib. ESMO 2021, Abstract 1239P.
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