First-line treatment of savatinib in patients with advanced lung sarcomatoid carcinoma, with rapid onset and 7-month PFS

*For medical professionals to read only for reference to the case sharing of good first-line treatment with MET inhibitors
.

This patient is an advanced lung sarcomatoid carcinoma with MET exon 14 skipping mutation.
The first-line treatment was treated with sivotinib.
Adverse reactions can be tolerated
.

After sevolitinib resistance, cabozantinib was used as the second-line treatment, and crizotinib was used as the third-line treatment.
The disease progression (PD) occurred quickly, and the overall survival (OS) of the patients was 15 months
.

This case was provided by Professor Han Sen of Peking University Cancer Hospital and reviewed by Professor Fang Jian of Peking University Cancer Hospital
.

Case introduction ▎Basic situation: patient, male, 74 years old
.

Chief Complaint: Right chest pain for 5 months
.

Enhanced CT of the chest: a huge soft tissue mass in the upper lobe of the right lung, about 138 × 83 mm in axial plane, about 126 mm in upper and lower diameter, mild enhancement, involving the right 1st to 3rd ribs, and obvious superior vena cava compression, With the establishment of collateral circulation
.

Abdominal and superficial lymph node B-ultrasound: multiple enlarged lymph nodes on the right supraclavicular, considering metastasis
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Whole body bone scan: The salt metabolism of the right 1st and 4th ribs is strong, and the metastasis is possible
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Head MRI: no obvious metastasis
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Mass-occupying biopsy of right upper lobe: (right upper lung) poorly differentiated carcinoma, morphological and immunological markers support non-small cell lung cancer (NSCLC), but cannot clearly differentiate between adenocarcinoma and squamous differentiation
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Immunohistochemistry showed: ALK-Ventana(-), CK5/6(-), NapsinA(-), P 40(-), ROS-1(-), TTF-1(-), Carbine(-), CK(+), Syn(-), CD56(-), CgA(-)
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Clinical diagnosis: stage IV right upper lobe NSCLC (T4N3M1)
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Genetic testing: There is a short deletion in the intron 13 region of the MET gene (NM_000245.
2: c.
2888-35_2888-20del), which leads to the skipping of exon 14 at the mRNA level
.

▎Diagnosis and treatment experience: This elderly patient went to the doctor because of chest pain.
The initial diagnosis was MET exon 14 skipping mutation NSCLC
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On August 31, 2018, the first-line treatment was sivotinib.
The patient complained that the back pain was significantly relieved on the day of the medication, and the pain symptoms were completely relieved after 1 week of medication, and the analgesic drugs were discontinued
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After 6 weeks of treatment, the effect was re-examined.
The enhanced chest CT showed that the mass in the upper lobe of the right lung was reduced to 88 mm, which was 36% smaller than that before treatment
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The overall evaluation is PR
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The superior vena cava compression was completely relieved, and there was no contrast agent filling in the collateral circulation
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The curative effect was confirmed after 12 weeks and 18 weeks of treatment, both maintained PR and the tumor continued to shrink
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Adverse reactions during treatment were tolerable
.

Figure 1.
Review and evaluation of sevolitinib before and during treatment.
On March 8, 2019, the tumor progression was re-evaluated, and the PFS was 7 months
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The patient was asymptomatic.
Considering the clinical benefit, oral savatinib was continued
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A second biopsy was performed to investigate the cause of resistance to savatinib
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Pathological examination of the right upper lung revealed a poorly differentiated carcinoma with necrosis consistent with a sarcoid-like carcinoma
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The results of genetic testing showed that compared with the baseline period, the newly emerged BRAF gene amplification, the MET exon 14 mutation abundance increased from 58.
5% to 69.
8%, and the MET amplification increased from 2.
4-fold to 3.
1-fold
.

The tumor continued to progress.
In June 2019, the patient's second-line treatment regimen was changed to cabozantinib.
After 1 month of treatment, the efficacy evaluation was PD
.

In July 2019, the third-line treatment of crizotinib was changed for more than 1 month, and the efficacy evaluation was PD
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The patient died on October 29, 2019 due to persistent tumor progression, with an OS of 15 months
.

Case provider Professor Han Sen: Make good use of genetic testing to enable precise diagnosis and treatment throughout the entire course of lung cancer.
Studies have shown that driver genes play an extremely important role in the continuous growth, infiltration and metastasis of lung cancer cells, and the inactivation of driver oncogenes Can lead to apoptosis of cancer cells, that is, cancer cells are highly sensitive to inhibitors of driver genes
.

The discovery of driver genes provides a strong theoretical basis for molecular targeted therapy of tumors[1]
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With the development of molecular biology, the detection of gene mutations and the application of corresponding targeted drugs have greatly improved the treatment level of NSCLC
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Today, targeted gene testing is a routine testing item in major hospitals
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MET is considered to be another important molecular therapeutic target for NSCLC after EGFR and ALK.
MET exon 14 skipping mutation accounts for 3%-4% of NSCLC, and accounts for a high proportion of 4.
9% in lung sarcoid-like carcinoma.
-31.
8%; the incidence of MET exon 14 skipping mutation in Caucasian population is slightly higher than that of Japanese and Chinese (3.
0% -4.
9% vs 0.
9% -2.
8%); MET exon 14 skipping in elderly NSCLC patients The incidence of mutations is higher than in younger patients; MET exon 14 skipping mutations are almost always mutually exclusive with other gene mutations, suggesting that it represents an independent tumor driver [2]
.

When the patient was first diagnosed, the genetic test showed that it was a MET exon 14 skipping mutation
.

With the long-term treatment of sevolitinib, after 7 months of progression-free survival, the patient eventually developed resistance
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New mutations occur in genes in tumor tissue all the time, and various treatment methods may affect the frequency of mutation and the location of mutation
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Therefore, after drug resistance and disease progression, genetic testing needs to be considered again as appropriate to try to find its resistance mechanism
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The second genetic test of this patient found that there was a new BRAF gene amplification, the abundance of MET exon 14 mutations increased, and the MET amplification fold increased
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However, the mechanism of resistance to MET inhibitors is more complicated, and further research is currently underway
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The 2021 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer pointed out that for patients with advanced NSCLC, it is recommended to detect genes such as MET amplification and MET exon 14 skipping mutations.
Next-generation sequencing (NGS), if tissue samples are not available, can be considered to detect cell-free/circulating DNA (cf/ctDNA)
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This recommendation is a class II recommendation, which reflects the great importance attached by domestic lung cancer experts to the detection of MET targets [3]
.

In the era of precision medicine, genetic testing has played a positive guiding role in more accurate and effective clinical diagnosis and treatment
.

We look forward to continuous breakthroughs in genetic testing technology in the future to escort the precise treatment of lung cancer patients
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Expert comments on Professor Fang Jian: Traditional therapy has limited efficacy in lung cancer with MET exon 14 skipping mutation, and patients can benefit from savatinib The treatment options are chemotherapy and immunotherapy, but chemotherapy and immunotherapy have limited efficacy in the past for MET exon 14 skipping mutations
.

The results of a clinical study showed that the median OS of patients with MET exon 14 skipping mutation receiving first-line chemotherapy was only 6.
7 months, which was much lower than that of patients with negative driver genes (11.
2 months) [4]
.

In another clinical study, 24 NSCLC patients with MET exon 14 skipping mutation received immunotherapy, and the results showed that the objective response rate (ORR) of immunotherapy was 17%, the median PFS was only 1.
9 months, and the efficacy was not reached.
Expected [5]
.

This patient has pulmonary sarcoid carcinoma, which is a rare type of NSCLC.
The early stage patients are treated with surgery-based comprehensive treatment.
Unfortunately, pulmonary sarcoid carcinoma is not sensitive to radiotherapy and chemotherapy, and is prone to recurrence.
and metastasis, poor prognosis, and patients' treatment needs are far from being met
.

In 2021, The Lancet Respiratory Medicine published the results of a phase II clinical study of sevolitinib in the treatment of MET exon 14 skipping mutant lung sarcomatoid carcinoma or other NSCLC subtypes: in all 70 patients, independent The ORR of sevolitinib treatment assessed by the review committee was 42.
9%, the disease control rate (DCR) was 82.
9%, the median PFS was 6.
8 months, and the median OS was 12.
5 months [6]
.

Notably, the proportion of patients with sarcomatoid carcinoma of the lung was as high as 36%, and 21% of patients developed brain metastases
.

The results of subgroup analysis showed that the ORR as assessed by the independent review committee was 40.
0% and the median PFS was 5.
5 months in patients with lung sarcoid carcinoma
.

In patients with brain metastases, the extracranial ORR as assessed by an independent review committee was 46.
7%, DCR was 93.
3%, and median PFS was 6.
9 months [6]
.

Based on the research results of savatinib, the 2021 edition of the "CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer" recommends medication for MET exon 14 skipping mutations.
In the class II recommendation, it is pointed out that savatinib (category 3 evidence) is not used as a first-line drug.
The treatment options for targeted therapy patients are the highest recommended among MET-targeted drugs [3]
.

Case review expert, Professor Fang Jian, Peking University Cancer Hospital, Chief Physician of the Second Department of Thoracic Oncology, Master's Tutor, Vice President of Beijing Cancer Prevention Research Association, Chairman of the Lung Cancer Sub-Committee of Beijing Cancer Prevention Research Association, Chinese Gerontological Society Deputy Director of the Molecular Targeting Committee of the Committee Member of the Lung Cancer Committee of the Geriatric Cancer Professional Committee of the Chinese Gerontological Society Member of the CSCO Vascular Targeted Therapy Expert Committee Member of the Chemotherapy Professional Committee of the China Anti-Cancer Association Expert case provider Professor Han Sen, Ph.
D.
, Department of Oncology, Peking University School of Medicine, Chief Physician of the Second Department of Thoracic Oncology, Peking University Cancer Hospital, Member of the Lung Cancer Sub-Committee, Beijing Cancer Prevention and Research Association, American Indiana University-Purdue University Visiting Scholar Several international and domestic multi-center clinical research directions are comprehensive treatment of lung cancer, and more than 30 academic papers have been published.
References: [1] Zou Lili, Ke Qi.
Research progress on targeted genes and their detection in non-small cell lung cancer[J].
Sichuan Journal of Anatomy, 2020, 28(3): 196-200.
[2] Zhou Ye, Yu Yan.
MET14 exon skipping mutation and non-small cell lung cancer [J].
International Journal of Oncology, 2021, 48(6 ):366-369.
[3]2021 edition of "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer".
[4]Gow CH, Hsieh MS, Wu SG, Shih JY.
A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population.
Lung Cancer.
2017;103:82-89.
[5]Sabari JK, Leonardi GC, Shu CA, et al.
PD-L1 expression , tumor mutational burden,and response to immunotherapy in patients with MET exon 14 altered lung cancers.
Ann Oncol.
2018;29(10):2085-2091.
[6]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.
Lancet Respir Med.
2021;9(10):1154-1164.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform