Resistance mechanisms and treatment options for third-generation EGFR and ALK-TKI in the treatment of non-small cell lung cancer

preface

According to the national cancer report released by the National Cancer Center in 2022, there were about 828,000 new lung cancer cases and 657,000 deaths in China in 2016, which is the highest of all cancers and seriously endangers human health

1.

The EGFR mutation is the number one driver gene in NSCLC patients in China, and 51.

ALK, also known as diamond target, the positive rate in NSCLC patients is about 5-7%, was first identified in 1994, 17 years later FDA approved the first crizotinib for ALK mutation, not after the emergence of acquired resistance, so there is a better central permeability, effective for crizotinib refractory patients second-generation ALK inhibitors, such as aletinib, bugatinib, etc.

2.

The resistance mechanism of three generations of ALK-TKI and EGFR-TKI can be divided into two types: on-target resistance and off-target resistance, and target-dependent resistance refers to the mutation of the kinase domain after a period of use, which directly produces steric hindrance or conformational changes to hinder the binding

Non-target-dependent resistance refers to the occurrence of one or more bypass signal activation, upregulation of downstream signaling protein expression, or phenotypic conversion, and tumor sequencing does not necessarily detect this type of resistance

1) Bypass signal activation: When this type of resistance occurs, the use of corresponding signal pathway inhibitors can effectively overcome drug

2) Downstream signaling pathway reactivation: Although the cause of the occurrence has been analyzed, there is no clinical targeted therapy

3) Histological phenotypic shift: This type of resistance needs to be determined by tumor tissue biopsy, including the transition of adenocarcinoma (ADC) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC) phenotype, and epithelial-mesenchymalization (EMT), which can be observed

3.

For resistant patients with systemic progression, different treatment regimens/drugs need to be switched according to the cause of resistance, and patients with target-dependent resistance can switch to a new generation of TKI or new therapies such as ADC, double antibodies, etc.

In order to overcome the drug resistance caused by EGFR and ALK protein mutations, a number of fourth-generation TKIs are under study, and the ATP competitive inhibitors BLU-945 and BLU-701 have shown the potential for drug resistance overcoming before the clinic, which can effectively inhibit the L858R-T790M-C797S triple mutation EGFR, which has entered phase I/II clinical trials; TPX-0131 and NVL-655 are a new generation of ALK-TKI, which are active against a variety of loratinib complex resistance mutations (G1202R+L1196M, G1202R+L1198F and G1202R+G1269A) and have also entered phase I clinical trials

The reuse and combination of older generation TKIs is also a potential means

In addition to these traditional therapies, the development of new modality is another option to overcome drug resistance, such as ADC drugs, double antibodies, PROTAC, therapeutic tumor vaccines, etc.

In general, the current three-generation TKI resistance is still a great challenge in the clinic, the patient's treatment options are limited, the FDA has not approved any fourth-generation ALK/EGFR-TKI and other targeted drugs, but the current four generations of TKI and more new therapies have entered human trials, and have made positive progress in early clinical practice, which is expected to bring dawn

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