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How to deal with the resistance of osimertinib caused by MET amplification?
The third-generation EGFR-TKI osimtinib is the standard first-line treatment regimen for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) unanimously recommended by domestic and foreign guidelines, with significant survival benefits and good safety, benefiting countless patients
From clinical trials to the real world, the benefits of first-line treatment with osimertinib are clear
With the publication of the RESULTS OF THE FLAURA study, osimatinib has made a strong move to the front line after it was approved for second-line
Figure 1.
Moreover, first-line therapy with osimertinib has significant central nervous system (CNS) benefits, significantly reducing the risk of CNS progression or death by 52 percent and potentially reducing the appearance of new CNS lesions [3,4].
In addition, osimertinib has also shown the same excellent efficacy and safety in
Figure 2.
Both in the total population and in people with CNS metastases, the first-line treatment of osimertinib with positive advanced NSCLC with EGFR mutations has shown similar clinical efficacy to the FLAURA study, with no new safety signals
How many patients develop MET amplification after osimertinib resistance?
Although the benefits of first-line therapy with osimtinib are significant, drug resistance seems to be a "fate"
that the vast majority of patients receiving targeted therapy cannot escape.
MET amplification is considered an important mechanism of resistance to osimertinib therapy, although there is currently a lack of cohort studies
of MET amplification and large samples of osimtinib resistance.
FlaURA studies have shown that MET amplification (15%) is the most common mechanism of resistance after first-line treatment of osimertinib [7].
A small sample size analysis published in 2020 found that the proportion of patients with first-line therapy-acquired MET amplification of osimertinib was as high as 66 percent (tissue-multi-region total exome and RNA sequencing)[8].
A review summarizing the molecular mechanisms (tissue and/or plasma testing) of osimtinib resistance in patients with advanced NSCLC mutations with EGFR mutations showed an incidence of MET amplification after first-line therapy resistance with osimtinib 7 to 15 percent (Figure 3) [9].
Figure 3.
Mechanisms of resistance in the first-line treatment of osimertinib
The Phase II platform studied tumor or plasma samples of patients after first-line osimertinib resistance in ORCHARD, and exploratorily analyzed the drug resistance mechanism of patients through second-generation sequencing (NGS) detection, in which tissue test results found that the incidence of MET amplification was 24%, the most prevalent mechanism of drug resistance [10].
Figure 4.
Frequency of first-line resistance mutations of osimertinib in the ORCHARD study for tumor tissue NGS testing
In addition, it should be noted that MET amplification can also occur after second-line therapy resistance to osimtinib, with an incidence of 5% to 50% [9].
MET amplification is also one of the most important targets in the molecular mechanism of acquired resistance to one/two EGFR-TKI, with an incidence of 5 to 20 percent [11,12].
Therefore, it is important
to master the coping strategies for MET amplification after EGFR-TKI resistance.
Overcoming drug resistance due to MET amplification, EGFR/MET dual-pathway inhibition shows strength
In the past, patients with NSCLC with MET amplification after EGFR-TKI resistance were mainly chemotherapy, but the benefits were limited
.
With the development of MET-TKI, new ideas
have been brought to the treatment of such patients.
Studies have shown that dual-target inhibition of the EGFR and MET pathways may confer synergistic benefits
.
TATTON was a multi-arm, multicenter, open-label, Phase I.
b study with 180 patients
.
Part B1 of the study included patients who failed treatment with three-generation EGFR-TKI (n=69), of which 96% were patients who progressed after the use of third-generation EGFR-TKI in the second line and above, and 52% of patients were enrolled with brain metastases
.
Findings show that for patients with NSCLC with MET amplification after three generations of EGFR-TKI resistance, the ORR of osimertinib plus sivotinib is 33 percent, and the median PFS is 5.
5 months [13].
Figure 5.
TATTON study final analysis results
ORCHARD is an open-label, multicenter, multi-drug, biomarker-guided Phase II clinical trial of advanced EGFR mutations including advanced EGFR mutations after first-line treatment with osimertinib
.
Results showed that 41 percent of patients with osimitinib combined with cevotinib for first-line therapy resistant to osimtinib and with MET amplification (all confirmed partial responses) were present, and all patients with confirmed partial responses are still under treatment [14].
Figure 6.
ORCHARD found that osimettinib + severinib showed activity in first-line osimtinib-resistant patients
SAVANNAH is a single-arm, open-label, Phase II clinical trial
exploring sivatinib combined with osimtinib for patients with progress in the treatment of osimtinib due to MET amplification or overexpression (NCT03778229).
Preliminary results of the SAVANAH study, presented at the 2022 World Congress on Lung Cancer (WCLC), showed that osimtinib combined with cevotinib dual-target therapy showed promising clinical efficacy in people with high-megadistenitating/hyperexpression (IHC 90+ and/or FISH10+), with an ORR of 49%, a median duration of remission (DoR) of 9.
3 months, and a median PFS of 7.
1 months [15].
。
Figure 7.
SAVANNAH study efficacy data
The CHRYSALIS study explored the efficacy and safety of MET-amplified NSCLC after Amifantamab combined with Lazertinib in the treatment of oscitinib-resistant, and found that 45 patients receiving Amifantamab combined with Lazertinib had an ORR of 36%, a median DoR of 9.
6 months, a clinical benefit rate (CBR) of 64%, and a median PFS of 4.
9 months, and a controllable safety[16]
。
In addition, INSIGHT 2 is a two-arm, open-label, phase II clinical trial designed to evaluate the efficacy
of Tepotinib in patients with advanced or metastatic NSCLC who are acquired resistant to osimtinib and expanded with MET.
The findings were presented as LBA at the recent ESMO 2022 conference, and Tepotinib and osimtinib demonstrated high antitumor activity and good tolerance [17].
Expert comments: EGFR/MET dual-pathway inhibition is expected to break through the barrier of drug resistance, making the first-line osimertinib drug resistance after MET amplification treatment worry-free
MET amplification is one of the important mechanisms of EGFR-TKI drug resistance, and how to overcome drug resistance has become a hot academic hotspot
.
EGFR combined with MET dual-pathway inhibition is expected to break through the resistance barrier, reverse the drug resistance process, restore tumor remission, and further improve the survival benefit
of MET amplification patients after EGFR-TKI resistance.
A number of studies have confirmed that MET-TKI combined with EGFR-TKI (such as osimertinib plus sivotinib) has good antitumor activity
.
The National Comprehensive Cancer Network (NCCN) guidelines also recommend MET-TKI in combination with EGFR-TKI for patients with MET amplification after EGFR-TKI resistance [18].
Moreover, more combination treatment options are being explored, which is expected to bring more options
to clinical treatment.
It can be seen that the current NSCLC for MET amplification after osimitinib resistance is no longer "drug-free", so clinicians do not need to worry too much about
the first-line use of osimtinib.
The clinical benefits of first-line treatment with osimertinib have been demonstrated in FLAURA studies and real-world studies, and "good drug first" in clinical practice may bring greater benefits to patients with positive EGFR mutations
.
Professor Lin Yingcheng
Associate Dean, Director of Internal Medicine
Chief Physician, Master Supervisor
Cancer Hospital Affiliated to Shantou University School of Medicine
Vice Chairman of tumor branch of Guangdong Medical Association
Vice Chairman of the Precision Medicine Committee of Guangdong Clinical Medicine Association
Vice President of Guangdong Thoracic Tumor Prevention and Treatment Research Association
Vice Chairman of the Cancer Rehabilitation and Palliative Care Committee of Guangdong Anti-Cancer Association
Vice Chairman of the Tumor Prevention and Treatment Professional Committee of Guangdong Health Management Society
Vice Chairman of the Steering Committee for Breast Cancer Clinical Medication of Guangdong Pharmaceutical Association
Honorary Vice Chairman of the Chemotherapy Professional Committee of Guangdong Anti-Cancer Association
Standing Committee Member of Colorectal Committee of Guangdong Precision Medicine Application Society
Standing Committee Member of the South China Oncology Cooperation Group (CSWOG).
Member of the Chinese Society of Clinical Oncology (CSCO).
Member of the Chemotherapy Professional Committee of the Chinese Anti-Cancer Association
Member of the Special Committee on Cancer Rehabilitation and Palliative Care of the Chinese Anti-Cancer Association
Member of the Surgical MDT Committee of the Chinese Medical Doctor Association
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Soria et al.
N Engl J Med 2018; 378:113-25
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Hartmaier, et al, 2022 AACR, Poster# LB078/3
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Matikas A, et al.
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Lecia V Sequist, et al.
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Helena A Y, et al.
ESMO 2021, Abstract 1239P.
[15].
Ann M J, et al.
WCLC 2022.
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02-140.
[16].
Bauml J, et al.
2021 ASCO.
Abstract 9006.
[17].
Tepotinib + osimertinib for EGFRm NSCLC with MET amplification(METamp) after progression on first-line(1L)osimertinib:Initial results from the INSIGHT 2 study.
2022 ESMO,LBA52.
[18].
NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer.
Version 4.
2022.