Is MET amplification refractory after EGFR-TKI resistance? Dual targeted therapy with sevotinib combined with osimertinib achieves PR and continues to benefit

*For medical professionals only

One classic case showed excellent efficacy
of sevotinib in combination with osimertinib.

The case was a patient with multiple metastases (stage IV, T4N3M1) of right lung adenocarcinoma with EGFR exon 19 mutation, and the first-line treatment was pemetrexed + lopplatin + ametinib (out-of-hospital treatment), and then the second-line treatment
was replaced by pemetrexed + lopplatin + actinib hydrochloride (out-of-hospital treatment) due to lung lesion progression (PD).
After 3 months, the lung lesion PD again, and the patient came to the oncology department of our hospital to receive third-line treatment
with anlotinib + osimertinib.
After 4 months, lung CT showed PD, the patient's PS score was 3 points, and the genetic test showed MET amplification, and the four-line treatment
was switched to sevotinib + osimertinib.
The efficacy evaluation in November 2021 showed that the right lung lesion was smaller than the previous (October 2021) to achieve partial remission (PR), and the multiple metastases in both lungs were smaller than the previous part.
In December 2021, the efficacy was evaluated as the overall PR, and the patient's PS score was 1 point; In September 2022, the efficacy was evaluated as stable disease (SD), and the patient's current PS score was 0 points
.
The patient's progression-free survival (PFS) has been more than 11 months so far, and the benefits are still continuing
.
The case was provided by Professor Dong Wenjie, the First Affiliated Hospital of Zhengzhou University, and Professor Wu Xin'ai of the First Affiliated Hospital of Zhengzhou University was invited to comment
.

Basic information:

The patient is female, 66 years old
.

Complaint: The patient went to the local hospital for "cough, sputum, bloodshot sputum, accompanied by general fatigue for more than 1 year
".

Past history, family history, personal history, etc.
are not special
.

Chest CT after admission: right hilar mass, consider central lung cancer with right upper pulmonary obstructive atelectasis; Multiple metastases in both lungs; Multiple enlarged lymph nodes in the mediastinum, considering metastasis; Intrahepatic low-density foci, consider metastasis
.

Cranial MRI: multiple abnormal signals in the right frontal lobe, left parietal lobe, right lateral ventricular paratemporal angle, pontine, combined with medical history, consider metastasis, please combine clinical dynamic review
.

Bone scan: multiple bone metabolism-active foci throughout the body, considering bone metastases
.

Pathologies: adenocarcinoma
of the right lung.

Diagnosis: Multiple metastases of right lung adenocarcinoma (stage IV, T4N3M1), EGFR exon 19 deletion mutation
.

Case provides specialists

Professor Dong Wenjie: PFS has been more than 11 months! Dual-target therapy with sevotinib combined with osimertinib 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, and epidermal growth factor receptor (EGFR) mutation is the most common type of NSCLC mutated gene, and EGFR-tyrosine kinase inhibitor (TKI) is the first-line standard of care
for patients with EGFR-mutated advanced NSCLC.
In recent years, the update and iteration of drugs has brought longer survival benefits to many patients, but most patients still develop drug resistance, and post-drug resistance treatment is an urgent problem
to be solved in clinical practice.

This case was a patient with right lung adenocarcinoma with multiple metastases (stage IV, T4N3M1) with EGFR exon 19 deletion mutation, and re-puncture parallel genetic testing after rapid PD after first-line and second-line chemotherapy combined with EGFR-TKI treatment, indicating drug
resistance caused by MET amplification.
Therefore, the third-line treatment was replaced by anlotinib + osimertinib, and after 5 months of treatment, the lung lesion PD again, and the patient's PS score was 3 points at this time, the patient's physical condition was poor, and the follow-up treatment was more
challenging.

MET amplification is one of the important mechanisms of acquired drug resistance in EGFR-TKI treatment that has been identified, and belongs to the bypass activation pathway
.
MET amplification-mediated resistance develops in 5 to 20 percent of patients treated with first- to second-generation EGFR-TKIs [^1], and approximately the same proportion of patients treated with third-generation osimertinib EGFR-TKI, accounting for approximately 10 to 24 percent of patients treated with first- and latter-line EGFR-TKIs ^[2].

A number of studies in China have shown that sevotinib combined with osimertinib can benefit ultra-long in
patients with MET amplification after third-generation EGFR-TKI (osimertinib) resistance.
Therefore, the patient in this case used sevotinib + osimertinib in the fourth-line treatment, and the overall efficacy evaluation was PR at 1 month and 2 months of treatment; At 11 months of treatment, the efficacy was evaluated as SD.

The patient's PFS has been more than 11 months old and continues to benefit
.
Not only that, after 2 months of treatment, the patient's PS score improved to 1 point, showing that sevotinib + osimertinib can also improve the patient's physical condition and ensure the patient's quality of life
.

In general, the clinical therapeutic effect of sevotinib combined with osimertinib has given hope to patients with MET amplification after third-generation EGFR-TKI resistance, and it is expected that more clinical research data will appear in the future to bring survival benefits
to more patients.

Expert reviews

Prof.
Xin'ai Wu: Dual-target therapy with sevotinib combined with osimertinib breaks the refractory pattern after MET amplification

MET amplification is mainly reflected in two aspects, one is the presence of primary MET amplification in patients, which is also one of the primary resistance mechanisms of EGFR-TKI, but more commonly, patients appear
after one to three generations of EGFR-TKI treatment resistance.
MET amplification is one of
the most important targets other than T790M after EGFR-TKI resistance.
Preliminary data from the Phase III FLAURA study show that MET amplification (15 percent) is the most common mechanism of resistance in the first-line treatment of third-generation EGFR-TKI [^3], and the MET amplification ratio after third-generation EGFR-TKI second-line treatment resistance reaches 19 percent ^[4].

However, at present, clinical follow-up treatment is still mainly based on chemotherapy, and the benefits of patients are limited, and innovative treatment plans are urgently needed
.

Therefore, it is necessary to explore EGFR-TKI combined with MET-TKI in patients with MET amplified NSCLC
.
The TATTON study ^[5] explored for the first time the efficacy and safety of sevotinib combined with osimertinib in patients with MET amplification after EGFR-TKI resistance, and the results showed that osivertinib combined with sevotinib in patients with MET amplification after first/second generation EGFR-TKI resistance, regardless of whether T790M is positive or not, The median PFS was 9.
0-11.
1 months, the objective response rate (ORR) was 62%-67%, and it not only had good anti-tumor activity, but also had a controllable
safety.

What's even more surprising is that the ORR of patients who have been treated with three previous generations of EGFR-TKI in the TATTON study can still reach 33%, and it brings 5.
5 months of PFS, adding a new treatment option
for patients who are refractory to the later line.

Following the success of the TATTON study, the ORCHARD study ^[6] explored the resistance mechanism after first-line use of osimertinib and determined the feasibility
of osimertinib combined with sevotinib in the treatment of MET amplification.
The results of the interim analysis of the study found that sevotinib combined with osimertinib showed preliminary activity in patients with MET amplified NSCLC after first-line osimertinib resistance, and the safety was acceptable
.
The SAVANNAH study ^[7] further explored the efficacy and safety of this combination therapy in patients with MET amplification/overexpression of NSCLC after first-line osimertinib resistance, as well as the optimal MET assay and threshold to determine which patients
are most likely to achieve remission.
The results of the study found that patients treated with osimertinib plus sevotinib had an ORR of 32% and a median PFS of 5.
3 months
.
In addition, as MET abnormalities increased, there was a tendency to
increase disease remission rates.
In patients who met the threshold for high MET abnormal levels (FISH 10+ and/or IHC 90+), the combination of osimertinib + sevotinib showed superior efficacy with an ORR of 49% and a median PFS of over 7 months
.

These findings give hope to patients who were treated with sevotinib plus osimertinib in the presence of third-line resistance and MET amplification, achieving PR efficacy within 1 month of treatment, and PFS for more than 11 months
.
This also confirms the significant efficacy of cevotenib combined with osimertinib, which adds to the efficacy of this combination therapy in EGFR-TKI-resistant MET amplified NSCLC patients
.
It is expected that the treatment plan of EGFR-TKI combined with MET-TKI will benefit more patients in the future and renew the light
of life.