The prognosis of patients with early lung cancer is better, but many patients with lung cancer are diagnosed with advanced stage, and the overall five-year survival rate is only about 20%. The traditional treatment method is mainly chemotherapy, the therapeutic effect is poor, and the toxic and side effects are strong. With the continuous development of biological detection technology, it is possible to use gene molecular typing, functional diagnosis and immunotherapy to develop personalized drug use for patients. This paper mainly introduces the current situation and progress of targeted therapy, immunotherapy and individualized drug sensitivity detection of NSCLC.
Before targeted therapy, chemotherapy was the most important treatment for patients with stage III and IV NSCLC), the most common of which was the third generation of new chemotherapeutic drugs combined with platinum, although the 5-year survival rate was increased by 11%. But the median survival time was only 8 to 10 months. Moreover, the use of chemotherapeutic drugs, because the chemotherapeutic drugs can’t distinguish between tumor cells and normal cells, will lead to serious adverse reactions. It was not until the advent of targeted therapy based on molecular typing that the survival time of patients with advanced NSCLC was prolonged to a few years.
NSCLC targeted therapy
According to the latest NSCLC guidelines 2019 V3 published by the National Comprehensive Cancer Network (NCCN), nine genes associated with targeted therapy should be detected, including EGFR, KRAS, HER2, ALK, ROS1, MET, BRAF, RET and NTRK. The following is the development of targeted therapy and immunotherapy for non-small cell lung cancer in the past 20 years.
- EGFR
EGFR is one of the earliest and most in-depth targets. The mutation types mainly include single nucleotide variation (SNV), insertion, deletion and copy number variation (CNV). The mutations were mainly concentrated in exons 18 and 21, and the therapeutic effect of EGFR TKI on exons 19 and 21 was better than that of exons 18 and 20. The most common sensitive mutation is amino acid mutation. When there is a mutation in exon19 and L858R in exon21, the first generation of EGFR-TKI (gefitinib, erlotinib, Eketinib) can be used for treatment. The second generation of EGFR-TKI (afatinib) is targeted at two targets, EGFR and HER2, and it is an irreversible dual inhibitor. In addition, FDA approved afatinib for a number of rare EGFR mutations, such as G719X, L861Q and S768I.
- ALK
Anaplastic Lymphoma Kinase (ALK), like EGFR, is a receptor-type tyrosine kinase. ALK fusion occurs in about 3.5% of NSCLC patients. PROFILE series of clinical studies confirmed that the response rate and disease control time of patients treated with clozotinib were significantly improved compared with chemotherapy. The response rate of clozotinib to ALK fusion positive patients was 60% to 80%, compared with 30% to 40% for chemotherapy. However, patients who take clozotinib for a period of time will inevitably develop recurrent drug resistance. In order to overcome drug resistance, the second generation ALK-TKI (aritinib, seritinib, brigatinib),) was developed. Compared with the first generation ALK-TKI, the second generation ALK-TKI can cross the blood-brain barrier and the curative effect is better. At present, the NCCN guidelines have recommended Alatinib, Seratinib, and brigatinib for first-line treatment in patients with ALK fusion positive.
- ROS1
ROS1 gene is a transmembrane tyrosine kinase gene of insulin receptor family, which is located on chromosome 6 Q21. The frequency of ROS1 rearrangement in NSCLC patients was 1 to 2%, which was common in young non-smoking women, and 5% in EGFR and ALK negative patients. ROS1 rearrangement mainly occurred in exon 32 to 36. Patients with ROS1 positive NSCLC can be treated with clozotinib and Seritinib. The objective remission rate of clozotinib is 72%, and the median response duration is 17.6 months. One problem is that patients with ROS1-positive NSCLC treated with clozotinib may also develop drug resistance, especially (CNS) metastasis in the central nervous system. The common drug resistance mutations are G2032R and D2033N of ROS1. When this mutation occurs, it can be treated with carbotinib and loratinib.
- BRAF
BRAF is not only one of the mechanisms of drug resistance of EGFR-TKI, but also an important driving gene and target of targeted therapy. The most common mutation is V600E. Selective BRAF inhibitors (dalafinib and trimetinib) have been recommended by NCCN for first-and second-line treatment in patients with advanced NSCLC.
- C-MET
MET is a transmembrane receptor with independent phosphorylation activity. Amplification of MET gene or overexpression of C-MET protein is one of the reasons for drug resistance of the first and second generation EGFR-TKI in NSCLC patients. The combination of C-MET inhibitor and EGFR-TKI may be a new idea for the treatment of drug resistance.
- NTRK
NTRK gene fusion occurs mostly in solid tumors in adults and children, accounting for about 23% of non-small cell lung cancer (NSCLC). On November 26, 2018, FDA accelerated the approval of Larotinib for the treatment of locally advanced or metastatic solid tumors in adults and children with NTRK gene fusion, regardless of the area where the cancer occurred. This is the first broad-spectrum cancer targeting drug approved by the FDA.
- Other mutant genes
In addition to the above genes, with the continuous progress of molecular detection technology, some specific subtypes of driving genes have been gradually discovered, and corresponding targeted drugs, such as RET,HER2,KRAS, have been developed.
New individualized treatment of NSCLC
Although there are many new treatments and the introduction of diagnostic techniques, the current 5-year survival rate of lung cancer is still very low. Individualized treatment guided by biomarkers can only benefit a small number of patients because most of the predictive biomarkers currently available occur at a very low frequency. And there are no biomarkers that can predict the efficacy of most first-line drugs in lung cancer. Therefore, some new treatments are in urgent need of development.
References
1. Preusser, M., Winkler, F., Valiente, M., Manegold, C., Moyal, E., Widhalm, G., … & Zielinski, C. (2018). Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO open, 3(1), e000262.
2. Masri, M., McManus, M., & Mudad, R. (2018). Treatment of Advanced Non-Small Cell Lung Cancer in the Era of Targeted Therapy. Current Pulmonology Reports, 7(3), 79-91.