MET amplification resistance in patients with EGFR-mutant advanced lung cancer after multi-line therapy?

*For medical professionals only for reference Multi-line therapy such as anti-angiogenesis therapy and anti-angiogenesis combined targeting, chemotherapy, immunotherapy, etc.
, eventually developed drug resistance
.

After the detection of MET amplification, the patient was treated with the MET inhibitor sivotinib combined with EGFR-TKI, and the facial edema was significantly improved in just 8 days.
At follow-up, the patient's lung lesions were further reduced, and the benefit was still ongoing
.

The case was provided by Professor Wang Huanqin of the First Affiliated Hospital of Zhengzhou University, and Professor Jin Jianjun of the First Affiliated Hospital of Zhengzhou University was invited to comment
.

Case Introduction Basic information: The patient is female, 40 years old
.

Chief Complaint: (August 29, 2018) Dizziness for more than 10 days, aggravated with headache for 1 day
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History of present illness: dizziness occurred 10 days ago, intermittent blackness, no sense of rotation, no nausea, vomiting, headache, no concern
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1 day ago, dizziness aggravated, with headache, cough, no sputum, and occasional chest tightness
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No chills, no chest pain, no coughing up blood
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To the local traditional Chinese medicine hospital, chest CT showed: 1.
Right upper lobe space-occupying lesion: Considering the possibility of lung cancer; 2.
Enlarged lymph node between trachea and vena cava; 3.
Pericardial effusion
.

Brain MRI scan and enhancement showed: multiple space-occupying lesions in the pons and bilateral cerebral hemispheres, considered: brain metastases, untreated
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For further treatment, she went to our hospital (the First Affiliated Hospital of Zhengzhou University) for treatment.
The outpatient service was admitted to the hospital with "1.
Right lung space occupation; 2.
Brain metastasis?"
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Since the onset of the disease, the patient's spirit, appetite, and sleep were normal, with normal bowel movements and no significant changes in body weight and physical strength
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Past history: no history of hypertension, heart disease, no history of diabetes, cerebrovascular disease, no history of hepatitis, tuberculosis, malaria, unknown history of vaccination, no history of surgery, trauma, blood transfusion, no history of food or drug use
.

Chest CT (August 29, 2018): 1.
Right upper lobe mass; 2.
Mediastinal lymph node enlargement; 3.
Bone destruction of thoracic 2 vertebra and its appendages
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Brain MRI scan and enhancement (August 30, 2018): Multiple space-occupying lesions in the pons and bilateral cerebral hemispheres, consider: brain metastasis
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Genetic testing: EGFR exon 19 deletion mutation
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Diagnosis: right lung adenocarcinoma with brain and bone metastases (cT2N2M1 stage IV)
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Figure 1: The chest CT examination results of the patient before and after treatment with sivotinib Figure 2: The patient's facial edema significantly improved during the treatment of sivotinib Combination therapy with rapid onset and durable benefit MET amplification is a common type of resistance in EGFR-TKI-treated patients
.

Previous studies have shown that about 5% to 21% of patients with first- and second-generation EGFR-TKI resistance have MET amplification [1-3]; the FLAURA study showed that after the third-generation EGFR-TKI first-line treatment acquired resistance, MET amplification occurred.
(15%) is the most common resistance mechanism [4]; AURA3 study shows that the proportion of MET amplification after resistance to second-line treatment of third-generation EGFR-TKI is 19% [5]
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Chemotherapy is a commonly used follow-up treatment for patients with MET amplification and resistance to EGFR-TKI therapy, but the clinical benefit is limited; similarly, single-agent regimens including immune drugs, anti-angiogenic drugs, and targeted drugs are ineffective
.

Dual-target inhibition of the EGFR and MET pathways may bring synergistic therapeutic benefits and reverse resistance to EGFR-TKIs
.

This case is a right lung adenocarcinoma with brain and bone metastases (cT2N2M1 stage IV) with EGFR exon 19 deletion mutation, who has received first-generation EGFR-TKI targeted therapy, anti-angiogenesis combined with targeted therapy, chemotherapy, immunotherapy, etc.
Multiple lines of therapy, and eventually MET amplification resistance occurs
.

Because the patient was allergic to the third-generation EGFR-TKIs osimertinib and almetinib, he received the combination therapy of sivotinib and icotinib
.

The patient previously had facial edema due to superior vena cava tumor compression, but the edema was significantly improved on the 8th day of treatment
.

Moreover, the chest CT examination found that the lung lesions shrunk 25 days after the drug, and the lesions were further reduced in the re-examination 3 months later, suggesting that the dual-target therapy of sevolitinib + EGFR-TKI has a rapid onset and can be used for patients.
Bring lasting benefits
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As the first and currently the only highly selective MET-TKI approved in China, sevolitinib fills the gap of domestic MET inhibitors, bringing new treatment options and hope for long-term survival to patients with abnormal MET pathway
.

Expert comments on Professor Jin Jianjun: EGFR-TKI has been used to treat MET-amplified resistant patients, and sivotinib + EGFR-TKI is an effective treatment for MET-amplified NSCLC.
There is still a large demand for treatment.
As an effective treatment option for EGFR-TKI-experienced MET-driven resistance patients
.

TATTON[6] is a multi-arm, multi-center, open-label, four-part (AD), phase Ib study to investigate the effect of osimertinib combined with sivotinib in the treatment of EGFR-TKIs-resistant MET amplification/overexpression Efficacy and safety of patients with EGFR-mutant locally advanced or metastatic non-small cell lung cancer (NSCLC)
.

Among them, part B consists of three groups of patients: B1 patients who have previously received third-generation EGFR-TKI therapy, B2 patients who have not received third-generation EGFR-TKI therapy (T790M negative), and B3 patients who have not received third-generation EGFR-TKI therapy (T790M positive)
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Part D recruited patients who had not been treated with a third-generation EGFR-TKI (T790M negative)
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The results of the study showed that the median progression-free survival (PFS) of osimertinib combined with sivotinib was 9.
0-11.
1 months in patients with MET amplification who were resistant to first- and second-generation EGFR-TKIs, regardless of whether T790M was positive or not.
The objective response rate (ORR) is 62%-67%; for the osimertinib-resistant and MET-amplified population (B1) receiving multi-line therapy, savatinib + osimertinib treatment can still bring about 33% ORR and a median PFS of 5.
5 months
.

In addition, the clinical phase II ORCHARD study group A partial data of patients with MET amplification in patients with osimertinib + osimertinib for first-line treatment resistance to osimertinib showed that savatinib The ORR of the + osimertinib regimen was up to 41% (both confirmed partial responses)
.

Combining part B1 of the TATTON study and the data of the ORCHARD study (post-line vs.
first-line), or prompting clinicians, the earlier the combined therapy is intervened, the better the expected efficacy and the better the patient's safety and tolerability
.

This case received civotinib + EGFR-TKI treatment in the late line, and the facial edema was significantly improved in just 8 days.
After that, the shrinkage of the lung lesions was continuously observed, which confirmed the good tumor shrinking effect of dual-target therapy
.

At present, MET amplification has been recommended by domestic and foreign authoritative guidelines for routine testing after TKI resistance.
In clinical practice, clinicians should conduct genetic testing in patients with TKI resistance as soon as possible, detect MET amplification as early as possible, and conduct dual-target therapy in a timely manner.
, so that patients get greater benefit
.

Case Comments and Expert Profile Professor Jin Jianjun Doctor of Internal Medicine, Chief Physician Member of Pulmonary Embolism and Pulmonary Disease Group of Respiratory Branch of Chinese Medical Association Standing Member of Targeted Therapy Committee of Henan Anti-Cancer Association Standing Committee of Henan Provincial Respiratory Disease Prevention and Control Committee Member, Member of International Association for Lung Cancer Research, PVRI Member, ATS Member, Case Provided Expert Profile Prof.
Wang Huanqin, MD, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Deputy Chief Physician Committee member, member of the infectious group of Henan Allergy Association
.

Won the first prize of Henan Province Medical Science and Technology Progress Award; won the second prize of Henan Province Science and Technology Progress Award
.

3 papers have been included in SCI, and more than 10 papers have been published in core journals and national journals
.

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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.
*This article is only for providing scientific information to medical professionals and does not represent the views of this platformJi-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 AY, 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.
*This article is for scientific information only for medical professionals and does not represent the views of this platformJi-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 AY, 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.
*This article is for scientific information only for medical professionals and does not represent the views of this platform2020;21(3):373-386.
[7].
Helena AY, 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.
*This article is for scientific information only for medical professionals and does not represent the views of this platform2020;21(3):373-386.
[7].
Helena AY, 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.
*This article is for scientific information only for medical professionals and does not represent the views of this platform