What is EGFR-TKI resistance?
EGFR-TKI resistance is divided into primary resistance and acquired resistance. Primary resistance means that no benefit is seen after treatment with EGFR-TKI. Tumor driver genes play an important role in tumor development. Mutations in EGFR exons 18~21 (especially exons 19 and 21) are associated with the efficacy of TKI drugs such as erlotinib. Since the rate of EGFR-sensitive mutations in lung adenocarcinoma patients accounts for less than 50%, nearly half of lung adenocarcinoma patients have ineffective TKI therapy, i.e. primary resistance. Secondary resistance is defined as the emergence of efficacy (tumor remission, delayed progression, symptom improvement, etc.) after receiving EGFR-TKI therapy and then deterioration.
Regarding the definition of EGFR-TKI acquired resistance.
1, EGFR-TKI monotherapy is effective.
2. being on EGFR-TKI at the time of disease progression.
3. systemic disease progression excluding the central nervous system (CNS).
The mechanism by which acquired resistance to EGFR TKI occurs is still not fully understood. Available studies have shown that acquired resistance that occurs in about 50% of patients after effective EGFR TKI therapy may be due to secondary mutations in tumor cells. Another bypass activation pathway is also a mechanism, of which about 50% of EGFR-TKI acquired resistance is known to be associated with T790M mutation and another 20% with C-Met gene amplification, while the molecular mechanism of some tumor acquired resistance is still unknown.
What are the principles of treatment after the emergence of drug resistance?
The 10th China Lung Cancer Summit Forum released a consensus on the management of resistance to small molecule EGFR TKIs in non-small cell lung cancer.
1. EGFR mutant lung cancer, it is recommended to test BIM and L747S to detect patients with primary drug resistance. Consensus level: 3
2. For mutant lung cancer resistant to EGFR TKIs, re-biopsy is recommended to clarify the molecular mechanism of resistance, and patients are encouraged to participate in appropriate clinical trials. Consensus level: 2A
3, For asymptomatic slowly progressive mutant lung cancer secondary to resistance to EGFR TKIs, continued use of EGFR TKIs is recommended. consensus level: 2B
4. For EGFR TKIs secondary to resistance that exhibit isolated progression, it is recommended to continue the use of EGFR TKIs in combination with local therapy. The choice of local treatment is based on the principle of minimal trauma.
Consensus level: 2B
5. EGFR mutant patients who benefit from EGFR TKIs and are resistant again after receiving cytotoxic drug therapy can be considered for EGFR TKIs. consensus level: 2B
Consensus level: 2B
Summit consensus level.
Level 1A: Based on high level of evidence (rigorous meta-analysis or RCT results) and unified understanding of the panel.
Level 1B: Based on high level evidence (rigorous meta-analysis or RCT results), with minor controversy in the expert group.
Level 2A: based on low level evidence, with unified understanding of the expert group.
Grade 2B: based on low level evidence, no unified understanding in the expert group, but little controversy.
Grade 3: There is a large controversy in the expert group.
For fulminant or rapidly progressive progression, continued TKI-synchronized chemotherapy may become a valuable treatment strategy. In addition, experts distinguished between failure of EGFR-TKI first-line therapy, second-line therapy, or multiple lines of therapy as.
1. For patients who fail first-line therapy, PS score and histologic type are critical, and platinum-containing two-drug chemotherapy can be used for patients with a PS score of 0 to 1, and single-drug chemotherapy can be used for patients with a PS score of 2.
2. Patients who have failed second-line EGFR-TKI therapy are switched to second-line effective chemotherapeutic agents. A trial of docetaxel, pemetrexed or platinum-containing two-drug combination chemotherapy can usually be considered.
It is especially appropriate for patients treated with EGFR-TKI agents for more than 6 months. However, the decision of single agent or combination chemotherapy should also be based on the patient’s PS score.
3. Patients who have failed third-line EGFR-TKI therapy: Compared to patients who have failed second-line EGFR-TKI therapy, patients who have failed third-line EGFR-TKI therapy have limited options for.
1) PS 0-1 score combination chemotherapy
2) PS 2 score single agent chemotherapy
(3) Multi-target drug therapy such as sorafenib, sunitinib, vandetanib (EGFR, VEGFR and RET tyrosine kinase), afatinib (EGFR and HER2), etc. Clinical studies are being conducted at home and abroad.
(4) Other drugs such as crizotinib (ALK, ROS1), etc.