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The essence of MET excellent cases in September~
The launch of highly selective MET-TKI sevotinib undoubtedly opens up a new path
for targeted therapy for lung cancer.
In order to further promote and improve the standardized diagnosis and treatment of rare mutant tumors, the medical media has launched the "MET Winning Case in Wo - Rare Mutant Tumor MET Inhibitor Sevotenib Treatment Excellent Case Collection Activity", and has collected a large number of classic cases for clinical reference
.
The results of phase II clinical studies of cevotinib [2,3] showed that the survival benefit of cevotinib in the treatment of MET14 exon skipping mutation was obvious, with an objective response rate (ORR) of 49.
2%, a disease control rate (DCR) of 93.
4%, a median overall survival (OS) of 12.
5 months, and a median PFS of 6.
9 months
in the general population.
With its excellent efficacy and safety, the indication of sevotinib for MET exon 14 skipping mutation has been approved in China, bringing a new targeted therapy option
to NSCLC patients with abnormal MET pathway in China.
Not only that, the treatment of MET exon 14 skipping mutation by cervotinib has also been recommended by the 2021 edition of the Chinese Society of Clinical Oncology (CSCO) NSCLC diagnosis and treatment guidelines level II [4], indicating that experts in the field of lung cancer in China recognize and affirm
the efficacy of cevotinib.
In September 2022, the Medical Oncology Channel once again screened and released 5 representative clinical cases, which were provided
by Professor Xin Tian of Liaoning Provincial Cancer Hospital, Professor Jiang Shengli of Tianjin Cancer Hospital, Professor Zhang Lihan of Henan Provincial Cancer Hospital, Professor Anna Li of Guangdong Provincial People's Hospital, and Professor Deng Hanyu of West China Hospital of Sichuan University 。 At the same time, the "medical community" also invited Professor Hu Jie of Zhongshan Hospital affiliated to Fudan University to summarize and comment on the above excellent cases, so as to facilitate clinicians to absorb diagnosis and treatment experience and jointly promote the development of
standardized diagnosis and treatment of MET.
Case highlights review
Case 1: 55-year-old patient with stage IIIB lung cancer with MET exon 14 skipping mutation, due to the presence of MET14 exome skipping mutation, the effect of receiving chemotherapy is not good, and sevotenib 600mg po qd neoadjuvant targeted therapy is selected.
The efficacy was evaluated as partial remission (PR) after 28 days of treatment, and PR
was maintained after 3 months of treatment.
After systematic evaluation, the patient met the conditions for surgical resection and achieved R0 resection
.
Postoperative patients continued oral cevotenib adjuvant therapy and are still benefiting
to this day.
Case 2:
A 68-year-old patient with EGFR L858R positive lung adenocarcinoma with primary MET amplification, the patient received bevacizumab + actinib (A+T) treatment for 2 cycles, the efficacy was evaluated as disease progression (PD), and then the patient was given bevacizumab combined with chemotherapy regimen, and after about 1 month, the patient's tumor shrank, Efficacy was assessed as disease stable (SD).
However, due to the patient's inability to tolerate chemotherapy, the subsequent use of sevotinib + osimertinib treatment, about 1 month later, the patient quickly achieved PR, and the safety was good, and by the time of the last efficacy evaluation, the patient had achieved PR for more than 8 months, and is still in continuous
benefit.
Case 3: A 68-year-old patient with stage IV lung adenocarcinoma with multiple metastases, the patient's first biopsy showed poorly differentiated carcinoma, but due to insufficient specimens, the tissue type could not be identified, and genetic testing was not performed, so the second biopsy was performed and the diagnosis was adenocarcinoma
。 After multidisciplinary team (MDT) consultation, the patient first received "paclitaxel + carboplatin" chemotherapy for 2 cycles, although the tumor obtained PR, the patient refused to continue chemotherapy due to the patient's hypogranulosis and fever (fourth-degree myelosuppression) after chemotherapy
.
In addition, the patient underwent genetic testing using a second biopsy specimen during chemotherapy, which showed primary MET amplification and was switched to cevotenib
.
Since then, the patient has maintained SD for 12 months and has a good
safety profile.
Case 4: 58-year-old patient with stage IV lung adenocarcinoma with brain metastases with co-EGFR 19del and primary MET amplification
.
Patients received chemotherapy, targeted and whole-brain radiotherapy, and the tumor continued to progress.
Genetic testing again showed that EGFR 19del and MET were amplified, and the FISH test indicated an increase in copy number, and after MDT discussion with osimertinib + sevotinib combination therapy, intracranial and pulmonary lesions reached PR after 1 month, and PR is still continuing, and the progression-free survival (PFS) has reached 54 months
.
Case 5:
A 68-year-old patient with stage IVa lung adenocarcinoma with pleural metastases with M ET14 exon skipping mutation, TP53 and BRAF mutations, after 3 cycles of chemotherapy combined with immunotherapy, The tumor continues to grow.
Subsequently, it was treated with sevotinib for 3 months, and the efficacy was evaluated as PR
.
After evaluation of surgical resection, the patient successfully underwent "general anesthesia through left posterolateral incision + left lower lobe lateral basilar segment resection + pleural implant nodule resection + implant nodule aversion + pleural fixation + thoracic perfusion chemotherapy + systemic lymph node dissection + pleural adhesion caking", and was diagnosed as left lung adenocarcinoma
.
The patient surgically resected the tumor completely and recovered well
after surgery.
(Click to view the full case)
Professor Hu Jie Summary CommentsWith
the launch of the highly selective MET inhibitor sevotinib in June 2021, a new pathway has been opened up for targeted therapy of lung cancer in China.
This not only benefits more lung cancer patients, but also makes people focus on rare targets again and see the potential of
rare target therapy.
In September 2022, 5 excellent cases were released in the "MET Winning Case in Wo - Rare Mutation Tumor MET Inhibitor Sevotinib Treatment Excellent Case Collection Campaign", and many clinical real cases have confirmed the significant efficacy of MET-TKI sevotinib, and it is also exploratory in different variant types, which enlightens
us.
1.
EGFR mutation combined with primary MET amplification, sevotinib combined with osimertinib dual-target therapy shows application prospects
, research data show that about 2%-8% of patients with treatment-new non-small cell lung cancer (NSCLC) have EGFR mutation and MET amplification at the same time [1]
。 Preclinical studies have shown that the presence of EGFR mutations and MET amplification/overexpression in tumors reduces the sensitivity of EGFR-TKIs; It has also been found that EGFR-TKI monotherapy is not effective
in patients with EGFR mutation and MET amplification.
The treatment of EGFR-TKI combined with MET-TKI has become a new direction of exploration, and the significant efficacy of sevotinib combined with osimertinib in individual cases suggests that this combination therapy may bring survival benefits
to these patients.
In the above cases 2 and 4, after EGFR-TKI treatment, the pulmonary lesions reached PR after the use of sevotinib combined with osimertinib, and the brain metastases were also controlled
.
At present, relevant clinical studies exploring the treatment of EGFR mutation with primary MET positive, such as SANOVO study and FLOWERS study, are underway and can be expected
in the future.
2.
Sevotenib targeted therapy is expected to bring the opportunity of radical surgery to some patients, and since NSCLC enters the era of targeted therapy in the future
, there have been many studies [5,6] exploring in patients with positive driver genes, efficacy of neoadjuvant targeted therapy and observed feasibility of neoadjuvant targeted therapy in early to intermediate resectable or potentially resectable patients
.
In the field of MET, neoadjuvant therapy is still availableNo findings have been published, but individual cases have been reported to show their effectiveness
.
The patients with MET exon 14 skipping mutations in case 1 and case 5 were tried to use sevotinib for neoadjuvant therapy, and the results not only obtained PR for the tumor, but also met the surgical criteria, and finally achieved R0 resection
.
In addition, case 1 continued exploratory adjuvant therapy with sevotinib after successful surgical resection, expecting continued benefit
from long-term follow-up.
In the future, it is hoped that further research on neoadjuvantive/adjuvant therapy for MET-TKI can be carried out to optimize the perioperative treatment strategy of patients with abnormal MET, so as to obtain the best surgical resection effect and achieve greater survival benefits
.
3.
Sevotinib has a strong effect on the brain, bringing new hope
to patients with refractory brain metastases, which may benefit from its molecular properties
.
Since cevotenib is not a substrate of P-glycoprotein (P-gp), it is theoretically not easy to be excreted by the blood-brain barrier efflux pump, which can maintain the drug concentration in the brain, which lays a theoretical foundation
for the use of cevotenib in patients with clinical brain metastases.
The phase II clinical study of cevotinib [2,3] included 24.
3% of patients with brain metastases, and the results showed that the median PFS in the brain metastases subgroup was 7.
0 months and the median OS reached 17.
7 months; and after treatment with cevotenib, the tumor response was quite high: ORR was 64.
3%, DCR was as high as 100%.
[2,3]
。
In case 4, stage IV patients with left lung adenocarcinoma with brain metastasis were treated with sevotinib combined with osimertinib on the fifth line, and the lung lesions reached PR for 1 month, and the brain metastases also reached PR, and the subsequent continued benefits
.
This case also suggests that sevotinib has sufficient blood-brain barrier penetration or may provide a new treatment option
for this group of patients with a poor prognosis and few treatment options.
Whether in clinical studies or individual cases, sevotinib has shown good efficacy and safety
for different types of MET pathway abnormalities.
In the future, it is expected that more research results of sevotinib will be released, and evidence-based medical evidence will be continuously enriched, and then new ideas
will be opened up for clinical medication.
Expert profile
Professor Hu Jie
Chief physician of Zhongshan Hospital affiliated to Fudan University and Department of Respiratory and Critical Care Medicine, Shanghai Geriatrics Center
Deputy Director of the Laboratory of Cell and Molecular Biology, Shanghai Institute of Respiratory Diseases
American College of Chest Physicians ACCP Fellow (FCCP)
Member of the Lung Cancer Professional Committee of the Respiratory Disease Branch (CTS) of the Chinese Medical Association
Member and Secretary of the Lung Cancer Professional Committee of the Respiratory Physician Branch (CACP) of the Chinese Medical Doctor Association
Vice Chairman of the Immunotherapy Committee of the China Alliance for the Prevention and Control of Lung Cancer
Member of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Member of the Chemotherapy Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of Lung Cancer Molecular Targeting and Immunotherapy Professional Committee of Shanghai Anti-Cancer Association
Member of the Standing Committee of the Brain Metastases Professional Committee of Shanghai Anti-Cancer Association
Vice Chairman of the Lung Cancer Committee of Shanghai Women Doctors Association
Member of the Lung Cancer Group of the Respiratory Specialty Branch of Shanghai Medical Association
References:
[1] Mi J,Huang Z,Zhang R,et al.
Molecular characterization and clinical outcomes in EGFR-mutant de novo MET-overexpressed advanced non-small-cell lung cancer.
ESMO Open.
2022 Feb; 7(1):100347.
[2] Lu S,Fang J,Li X,et al.
Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations:a multicentre, single-arm,open-label,phase 2 study[J].
Lancet Respir Med.
2021; 9(10):1154-1164.
[3] Lu S et al.
(2022)Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations(METex14+)NSCLC.
ELCC 2022,2MO.
[4] 2021 edition of the Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of non-small cell lung cancer.
[5] Yi-Long Wu,Wenzhao Zhong,Ke-Neng Chen,et al.
CTONG1103:Final overall survival analysis of the randomized phase 2 trial of erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non–small cell lung cancer.
Journal of Clinical Oncology 39,no.
15_suppl(May 20,2021)8502-8502.
[6] Tsuboi M,Weder W,Escriu C,et al.
Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer:NeoADAURA.
Future Oncol.
2021 Nov; 17(31):4045-4055.
*This article is only for providing scientific information to medical professionals and does not represent the views of this platform
