With the development of molecular biology, a variety of genetic mutations and expression abnormalities and other molecular mechanisms have been confirmed to be associated with the development and drug resistance of NSCLC. Currently, a variety of molecularly targeted therapeutic agents have been put into clinical use or are under clinical trials.
I. Molecularly targeted therapeutic targets for lung adenocarcinoma
1. Tyrosine kinase inhibitor targets.
The earliest targeted drug targets approved by FDA for the treatment of adenocarcinoma are those with mutations in the tyrosine kinase region of EGFR and those with ALK rearrangements. Both drugs are commonly referred to as tyrosine kinase inhibitors (hereinafter referred to as TKI). Their targets are specified as follows.
(1) EGFR
Mutations occur in approximately 20% of lung adenocarcinoma patients and are prevalent in non-smokers and Asian populations, with up to 60% of Asian patients. The majority of mutations occur in exons 18-21 of the EGFR kinase region, and the major mutations in EGFR are listed in the table below.
The two most common EGFR mutations are exon 19 deletion (15 base pair deletion encoding E746-A750) and mutation L858R in exon 21, which accounts for about 90% of TKI-sensitive adenocarcinomas. Other TKI-sensitive mutations are exon 21 L816Q, exon 18 G719X. exon 20 T790M mutation is associated with TKI Primary and secondary resistance is associated with TKI. In addition, primary resistance to TKI is associated with KRAS mutations and ALK gene rearrangements, and secondary resistance is associated with histological transformation (NSCLC to SCLC, EMT). Another mechanism of resistance is MET amplification, which leads to activation of the PIK3CA/AKT pathway via ERBB3 signaling and occurs in approximately 1% – 2% of lung adenocarcinoma patients and is responsible for 5% -20% of TKI resistance. Other genetic interactions in the tumor, such as mutations in genes downstream of the EGFR signaling pathway, and HER2 amplification, also lead to TKI resistance.
(2) ALK rearrangements and ROS-1 fusions
EML4-ALK fusion occurs in nearly 5% of lung adenocarcinoma patients and results in the fusion of the N-terminal end of the protein encoded by EML4 with the transmembrane signaling portion of the receptor tyrosine kinase encoded by ALK. , never smokers, progressive stage, hypodifferentiated, solid and sieve-type tissue with mucinous and imprinted cell-like features, etc.
A small subgroup of adenocarcinomas has rearrangements of the Ros-1 receptor tyrosine kinase gene, leading to sequential activation of the pathway. The rearrangement is usually manifested as CD74 and SLC 34A2 , this rearrangement occurs in 1% of adenocarcinomas and crizotinib is thought to be active in tumors carrying the ROS-1 fusion gene.
2. Other molecular alterations
(1) KRAS mutation
Present in approximately 30% of lung adenocarcinomas, with poorly differentiated features and a significant correlation with smoking history. No specific treatment is available for the time being.
(2) PIK3CA/AKT/mTOR pathway mutations
These include PIK3CA, AKT, and PTEN mutations, which occur in adenocarcinoma and squamous carcinoma. PIK3CA mutations are oncogenic, are most common in this cohort, and can coexist with other mutations in adenocarcinoma. PIK3CA/AKT/mTOR pathway mutations increase the sensitivity of the mTOR inhibitor everolimus. However, early clinical trials have shown only partial responses to drugs targeting this pathway.
(3) BRAF and HER2 mutations, relative to each other, have a low incidence. Recently, two new alterations have been identified: NTRK1 and NRG1 rearrangements. the NTRK1 fusion gene appears to be present in 3% of adenocarcinoma patients without other mutations, while NRG1 rearrangements appear to be predominantly present in aggressive adenocarcinomas. Both mutations may be specific drug targets.
II. Potential molecularly targeted therapeutic targets in squamous lung cancer
In squamous carcinoma, several putative oncogene drivers were identified. Most include PIK3CA/AKT/mTOR and RAS. preliminary data have confirmed the effectiveness of FGFR inhibitors in FGFR1-amplified squamous lung cancer and squamous cancer carrying the S768R mutation in DDR2. A small group of mutations or amplifications with other potential oncogenes (EGFR 8, MET, PDGFR A, insulin-like growth factor receptor-1) are being studied with inhibitors.
III. Approved molecular targeted drugs.
1. TKI targeting EGFR.
(1) Erlotinib: It is a type 1 human epidermal growth factor receptor/epidermal growth factor receptor tyrosine kinase inhibitor. Its indications are: advanced NSCLC (including locally advanced NSCLC and metastatic NSCLC) after failure of at least one previous chemotherapy regimen (platinum-containing regimen); maintenance therapy for advanced NSCLC in stable disease after four cycles of platinum-based first-line chemotherapy; first-line therapy for advanced NSCLC with EGFR-sensitive mutations.
(2) Gefitinib: a selective EGFR tyrosine kinase inhibitor. Indications: First-line treatment of advanced NSCLC with sensitive mutations in EGFR-TK gene; advanced NSCLC with previous chemotherapy.
(3) Exatinib hydrochloride: a selective EGFR tyrosine kinase inhibitor with full independent property rights in China, first-line treatment of advanced NSCLC with sensitive mutations in EGFR-TK gene; and advanced NSCLC previously treated with chemotherapy, the ICOGEN study is a non-inferiority phase III clinical trial conducted in China, comparing exatinib with gefitinib in second and third line efficacy and safety in treating unselected patients with advanced NSCLC. The study is also the first phase III clinical study in the world to compare head-to-head between two EGFR-TKIs. The results showed that the efficacy of erlotinib was not inferior to that of gefitinib, and the incidence of diarrhea, a common adverse effect, was significantly lower in the erlotinib group compared to the gefitinib group.
(4) Afatinib: It can inhibit the entire HER family, including EGFR and HER-1. It can be used for the first-line treatment of metastatic non-squamous NSCLC with EGFR-sensitive mutations, and also for the second-line treatment of patients progressing after chemotherapy.
2. TKI targeting ALK rearrangement.
(1) Crizotinib: It is a small molecule inhibitor targeting ALK, ROS1 and MET, and is used for advanced NSCLC patients with ALK rearrangement.
(2) Ceritinib: a small molecule inhibitor targeting ALK and IGF-1, used for ALK-positive patients who progress or are intolerant after crizotinib treatment, and certain patients with central metastases respond to it.
3. Other drugs.
(1) Recombinant human vascular endothelial inhibitor: combined with vincristine and cisplatin chemotherapy regimen for the treatment of primary or relapsed stage III/IV NSCLC.
(2) Cetapenem: a selective histone deacetylase inhibitor, belongs to the epigenetic modulator class of targeted antitumor drugs, mainly used for the second-line treatment of peripheral T-cell lymphoma, and clinical trials of this drug in combination with chemotherapeutic drugs for the treatment of lung cancer are underway.
4.Other.
(1) Bevacizumab: a recombinant humanized IgG1 monoclonal antibody that binds to VEGF. It can be used in non-squamous NSCLC without a history of hemoptysis.
(2) Cetuximab: in combination with cisplatin/vincristine, an option for the treatment of advanced NSCLC without EGFR mutations and ALK rearrangements, recommended in NCCN guidelines as a class 2B and not considered clinically relevant by some clinicians.
(3) Nitrozumab: A recombinant humanized EGFR monoclonal antibody that blocks the binding of EGF and TGFα to EGFR and inhibits tyrosine kinase activity; clinical studies are ongoing for the treatment of advanced NSCLC.
(4) Opdivo: PD-1/PD-L1 immunotherapy that has been or is approved in the EU for previously treated advanced or metastatic squamous NSCLC.
(5) Ramucirumab: a humanized anti-VEGFR-2 monoclonal antibody that has been approved by the US FDA for the treatment of advanced NSCLC.
(6) Necitumumab: a humanized anti-EGFR monoclonal antibody that has shown efficacy in combination with gemcitabine and cisplatin for the treatment of squamous carcinoma in a phase III clinical trial, and clinical trials are underway for non-squamous carcinoma.
(7) Panitumumab (panitumumab): the first fully humanized monoclonal antibody targeting EGFR, clinical trials are in progress.
(8) Matuzumab (matuzumab): anti-EGFR: clinical trials are ongoing.