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A classic case shows that the excellent efficacy of cevotinib combined with osimertinib .
This case is a patient with multiple metastasis of right lung adenocarcinoma with exon EGFR No. 19 mutation (stage IV, T4N3M1). The first-line treatment plan is pemetrexed + loplatin + ametinib (two hospital treatment). Later, due to lung lesions progression (PD), pemetrexed + loplatinib + ecretinib hydrochloride (two hospital treatment) and second-line treatment. Three months later, the lung lesion was PD again, and the patient came to our hospital for Oncology Department and received third-line treatment of anlotinib + osimertinib. After 4 months, the PD was reported after a follow-up examination of lung CT. The patient's PS score was 3 points. The gene test again showed MET amplification, and the patient was treated with four-line sevoctinib + osimertinib. The efficacy evaluation in November 2021 showed that the right lung lesions shrank compared with the previous (October 2021), achieving partial remission (PR), and multiple metastases in both lungs were partially smaller than the previous one; the efficacy evaluation in December 2021 was overall PR, and the patient's PS score was 1 point; the efficacy evaluation in September 2022 was stable disease (SD), and the patient's current PS score was 0 points. So far, the patient's progression-free survival period (PFS) has exceeded 11 months and is still benefiting continuously. The case was provided by , the First Affiliated Hospital of Zhengzhou University, , and , and , the First Affiliated Hospital of Zhengzhou University, was invited to comment.
Case introduction:
Basic situation:
patient female, 66 years old.
main complaint: patient went to the local hospital for treatment due to "cough, coughing, sputum, sputum with blood , accompanied by general fatigue for more than 1 year."
Past history, family history, personal history, etc. are not special.
After admission, chest CT examination: right hilar placeholder, central lung cancer with obstructive atelectasis in the right upper lung; multiple metastasis in both lungs; multiple swollen lymph nodes in the mediastinum , metastasis is considered; low-density in the liver, metastasis is considered.
head MRI: right frontal lobe, left parietal lobe, right ventricular ventricular 5 paratemporal horn, ponsin, multiple abnormal signals. Combined with the medical history, consider metastasis, please combine with clinical dynamic review.
bone scan : multiple bone metabolism active foci throughout the body, consider bone metastasis .
Pathology: Right lung adenocarcinoma.
Diagnosis: right lung adenocarcinoma multiple metastasis (stage IV, T4N3M1), EGFR exon 19 deletion mutation.
case provides expert
Professor Dong Wenjie: PFS has been more than 11 months! Sevotinib combined with osimertinib dual-target therapy brings more treatment opportunities to third-generation EGFR-TKI resistant patients
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, while epidermal growth factor receptor (EGFR) mutation is the most common type of NSCLC mutation gene. EGFR-tyrosine kinase inhibitor (TKI) is the first-line standard treatment for patients with advanced EGFR mutation NSCLC. In recent years, the iteration of drugs has brought longer survival benefits to many patients, but most patients still develop drug resistance, and treatment after drug resistance is a difficult problem that needs to be solved in clinical practice today.
This case is a patient with right lung adenocarcinoma with multiple metastasis (stage IV, T4N3M1) with first-line and second-line chemotherapy combined with EGFR-TKI treatment and re-piercing and genetic testing were performed in parallel, indicating that it is drug resistance caused by MET amplification. Therefore, the third-line treatment was replaced with anlotinib + osimertinib. After 5 months of treatment, the lung lesions were PD again, and the patient's PS score was 3 points at this time. The patient's physical condition was poor and the subsequent treatment challenge was greater.
MET amplification is one of the important mechanisms of acquired resistance to EGFR-TKI treatment that has been clearly defined and belongs to the bypass activation pathway. 5%-20% of patients treated with first- or second-generation EGFR-TKI will develop MET amplification-mediated drug resistance [1]. The proportion of patients treated with third-generation osimertinib, whether for first-line or backline treatment, is roughly the same, accounting for 10%-24% of [2]. There have been many studies in my country that show that sevotinib combined with osimertinib can benefit extremely long-term in patients with NSCLC who have MET amplification after third-generation EGFR-TKI (osimertinib). Therefore, the patient in this case used sevotinib + osimertinib for the fourth line of treatment. At 1 month and 2 months of treatment, the overall evaluation of efficacy was PR; at 11 months of treatment, the evaluation of efficacy was SD.The patient's PFS has been over 11 months and continues to benefit. Not only that, the patient's PS score improved to 1 point at 2 months of treatment, which showed that sevotinib + osimertinib can also improve the patient's physical fitness and ensure the patient's quality of life.
Generally speaking, the clinical treatment effect of sevotinib combined with osimertinib has given NSCLC patients with MET amplification after third-generation EGFR-TKI resistance to see hope. We look forward to more clinical research data in the future, bringing survival benefits to more patients.
Expert comments
Professor Wu Xinai: Sevotinib combined with osimertinib dual-target therapy breaks the linear refractory pattern after MET amplification
MET amplification is mainly reflected in two aspects. On the one hand, the patients have primary MET amplification, which is also one of the primary drug resistance mechanisms of EGFR-TKI. But more commonly, patients appear after the first to third generations of EGFR-TKI treatment. MET amplification is one of the most important targets in addition to T790M after EGFR-TKI resistance. Preliminary data from the Phase III FLAURA study showed that the third-generation EGFR-TKI first-line treatment is acquired, and MET amplification (15%) is the most common resistance mechanism [3], and the proportion of MET amplification after the third-generation EGFR-TKI second-line treatment is 19% [4]. However, clinical follow-up treatment is still mainly chemotherapy, and patients have limited benefits, and innovative treatment plans are urgently needed.
Therefore, it is very necessary to explore the treatment of MET-amplified NSCLC patients with MET. TATTON study [5] explored the efficacy and safety of septotinib combined with oseptotinib in NSCLC patients with MET amplification after EGFR-TKI resistance. The study results show that, regardless of whether T790M is positive, the PFS of the main PFS is 9.0-11.1 months, and the objective response rate (ORR) is 62%-67%, and not only has good anti-tumor activity, but also controllable safety.
What is even more surprising is that in the TATTON study, the ORR of patients who have been treated with three generations of EGFR-TKI can still reach 33%, and it brings 5.5 months of PFS, adding new treatment options for patients who are refractory to the backline.
Following the success of the TATTON study, ORCHARD study [6] deeply explored the drug resistance mechanism after the first-line use of osimertinib and determined the feasibility of osimertinib combined with sevotinib in the treatment of MET amplification. Interim analysis of the study found that sevotinib combined with osimertinib showed initial activity in patients with MET amplified NSCLC after first-line osimertinib resistance and was safe and acceptable. SAVANNAH study [7] further explores the efficacy and safety of this combination therapy in patients with MET amplification/overexpression of NSCLC after first-line osimertinib resistance, as well as optimal MET detection methods and thresholds to determine patients most likely to achieve remission. The study found that the ORR of patients treated with osiminib plus sevotinib was 32%, and the median PFS was 5.3 months. In addition, as MET abnormal levels increase, disease response rates tend to increase. In patients who meet the high MET abnormal level threshold (FISH 10+ and/or IHC 90+), osiminib plus sevotinib combined treatment showed better efficacy, with an ORR of 49%, and a median PFS of over 7 months.
These research results gave patients hope. The case used a sevotinib combined with osimertinib in the case of third-line resistance and MET amplification. The efficacy of PR was achieved in 1 month of treatment, and PFS had been more than 11 months. This also confirms the significant efficacy of sevotinib combined with osimertinib, which further demonstrates the efficacy of this combination in patients with EGFR-TKI drug-resistant MET amplified NSCLC. We look forward to the future treatment plan of EGFR-TKI combined with MET-TKI will benefit more patients and continue the light of life.
Comment Expert Profile
Wu Xinai Professor
Chief Physician, Professor, PhD in Oncology, Master's Supervisor, Zhengzhou University First Affiliated Hospital.
Member of the Esophageal Cancer Professional Committee of the Chinese Anti-Cancer Association;
Henan Anti-Cancer Association Member of the Clinical Precision Diagnosis and Treatment Professional Committee of the Tumor
Deputy Chairman of the Henan Provincial Committee of Integrated Tumor Treatment and Palliative Therapy Professional Committee of Integrated Treatment and Palliative Therapy;
Member of the Clinical Chemotherapy Professional Committee of Henan Provincial Anti-Cancer Association;
Member of the Standing Committee of the Henan Provincial Neuroendocrine Oncology Professional Committee
Member of the Oncology Professional Committee of Zhengzhou Association of Integrated Traditional Chinese and Western Medicine.
is currently mainly engaged in clinical and basic research and clinical teaching of oncology medical treatment. He has rich clinical experience in the medical treatment of various advanced malignant tumors. He has participated in a number of topics such as the prediction of chemotherapy sensitivity of malignant tumors, obtained two scientific research results, published more than 40 papers in this major in national and Chinese magazines, and participated in the compilation of three professional works oncology.
case provides expert profile
Dong Wenjie Professor
Department of Oncology, First Affiliated Hospital of Zhengzhou University, Associate Chief Physician, Master's Supervisor
Graduated in July 2010 from Shanghai Jiaotong University School of Medicine
Oncology Department, specializing in the diagnosis and treatment of gastrointestinal malignant tumors, lung cancer and other tumors.
In 2015, I went to Beijing Cancer Hospital for further study for half a year. After work, Published 4 SCI articles related to related majors, and presided over National Natural Science Foundation of Youth and Projects 1
References
[1] Pan Sisi, Wang Na, Song Xia. Research progress on MET amplification mediated acquired drug resistance in advanced non-small cell lung cancer [J]. Chinese Journal of Lung Cancer, 2022, 25(08): 615-621.
[2] Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging treatment paradigms for EGFR-mutant lung cancer progressing on Osimertinib: A rev iew. J Cl in Oncol, 2020, 18: JCO1903123.
[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]Papadimitrakopoulou V, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. 2018 ESMO Abstract LBA51.
[5]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.
[6]H.A. Yu, H. Ambrose, C. Baik, 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. Annals of Oncology (2021) 32 (suppl_5): S949-S1039.
[7]M-j. Ahn, F. De Marinis, L. Bonanno, et al. MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib. 2022WCLC EP08.02-140.
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
