"World Cancer Day" is a public welfare activity jointly initiated by the International Union Against Cancer (UICC) and the World Health Organization (WHO), which is scheduled to be celebrated on February 4 every year. In order to bridge the gap in cancer medical services around the world, UICC launched the theme activity of "Integrating Health Resources, Sharing Medical Care for All" in 2022~2024, and this year is the last year of this theme. As the most common tumor in clinical practice, lung cancer treatment has taken on a new look with the development of precision medicine in recent years, and there are still valuable emerging targets. Do you know enough about mesenchymal epidermal transition factor (MET) as an important part of the attention?
The situation of lung cancer prevention and control is severe, and it is urgent to strengthen "early screening and early diagnosis" and promote precision treatment
Cancer is one of the most important public health problems, and according to data released by the World Health Organization's International Agency for Research on Cancer (IARC) in 2020, lung cancer is the cancer that causes the most deaths worldwide [1]. As a country with a large population, the mainland's cancer data is also not optimistic, ranking first in the world in terms of both new cases and deaths. In 2020, there were 3 million cancer deaths in mainland China, and the top three cancers causing the most deaths were lung cancer, liver cancer, and gastric cancer (Figure 1), of which lung cancer accounted for 710,000 deaths, accounting for 23.8% of the total cancer deaths [1]. Numerous studies have shown that age is one of the main risk factors for cancer. However, it is worrying that by 2040, the proportion of the elderly population aged 65 and above in the mainland will exceed 20% of the total population, and with the deepening of the aging population, the clinical demand for cancer in the mainland will also further increase, which means that our cancer prevention and control work will face greater challenges. Therefore, we must strengthen publicity and education on cancer prevention and control, raise public awareness of cancer prevention, and increase investment in scientific research to promote the innovation and development of cancer prevention and control technologies.
Figure 1. Statistics of cancer deaths in China in 2020[1]
As the number one "killer", lung cancer ranks first in both morbidity and mortality. "Early screening, early diagnosis and early treatment" is the key to improving the overall treatment effect of lung cancer, and through early detection and timely treatment, it can effectively prolong the survival time of patients and improve their quality of life. In addition, with the continuous development of modern medicine, the emergence of precision treatment has also brought a "powerful weapon" to the fight against malignant tumors. In the mode of precision treatment, we are able to tailor personalized treatment plans according to the specific conditions of different patients. This not only significantly improves the treatment effect, but also reduces the occurrence of adverse reactions, bringing a safer and more effective treatment experience to patients.
Precision therapy is developing rapidly, and MET targets are eye-catching
Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for approximately 85 percent of all lung cancers [2]. At present, traditional surgery and chemoradiotherapy can no longer meet the clinical needs. In the face of lung cancer, a complex disease, we need to have a deeper understanding of the molecular mechanisms behind it in order to develop more effective treatment strategies. At present, targeted therapy, as a major revolution in the field of cancer treatment, has greatly improved the quality of life of lung cancer patients and brought a new dawn to lung cancer patients. In recent years, many precision targeted therapy drugs have been developed for well-identified oncogenic driver genes, making the treatment of lung cancer more personalized.
There are many driver genes for lung cancer, including EGFR, ALK, KRAS, MET, ROS1, BRAF, RET, NTRK1/2/3, HER-2, PIK3CA, etc. It is critical for patients to understand these driver genes and their corresponding therapeutics. Patients may be familiar with mutations such as EGFR and ALK, but may not be familiar with mutations such as MET, BRAF, RET, etc. In fact, each mutation has specific clinical features and corresponding therapeutic agents, and only symptomatic treatment can achieve the best therapeutic effect.
Among these driver genes, MET is a very interesting therapeutic target. MET, as a widely expressed cell surface receptor, is able to promote multiple biological processes such as cell growth and proliferation, motility, migration, and angiogenesis. Moreover, patients with MET mutations are not sensitive to existing standard treatments and have a poor prognosis. Therefore, MET gene is considered to be one of the key exploration directions in the field of lung cancer treatment. In recent years, MET gene has become one of the important therapeutic targets in NSCLC after EGFR and ALK.
MET abnormalities: mechanism of action and mutation type
The MET proto-oncogene is capable of synthesizing the c-MET protein, a receptor tyrosine kinase that binds to hepatocyte growth factor (HGF). When HGF binds to the c-MET receptor, it activates its intracellular tyrosine kinase catalytic activity. This process triggers the activation of several key downstream signaling pathways, including RAS/ERK/MAPK, PI3K/AKT, Wnt/β-catenin, and STAT signaling pathways, which promote tumor cell growth and metastasis (Figure 2) [3-4].
Figure 2. Schematic diagram of HGF/MET pathway distortion in tumors[4]
MET abnormalities in NSCLC include skipping mutations in exon 14 of the MET gene (MET14 skipping spike), amplification of the MET gene, point mutations in the MET gene (mainly mutations in the kinase region), MET gene fusions, and overexpression of MET protein [5]. These abnormalities may lead to the development and progression of tumors. MET14 exon skipping mutation refers to the mutation of MET14 exon gene caused by MET14 exon skipping mutation during the expression of MET gene, which makes the abnormal protein produced lose the transmembrane domain, which in turn leads to c-MET protein ubiquitination disorder, increased c-MET stability and reduced degradation rate, and keeps the downstream signaling pathway in a state of continuous activation. The incidence of this mutation in all NSCLC is 0.9%~4.0%, in addition, about 0.3%~10.0% of NSCLC patients with MET14 exon skipping mutations have concomitant EGFR mutations, and 6.4%~28.5% of patients have concomitant EGFR gene amplification[5]. It has been established that MET exon 14 skipping mutations are independent oncogenic drivers of NSCLC.
In addition to MET14 exon skipping mutations, there are other forms of MET abnormalities in NSCLC. In NSCLC, the incidence of MET fusion is about 0.5%, the incidence of primary MET gene amplification is 1%~5%, the incidence of secondary MET gene amplification is 5%~50% in patients resistant to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and the incidence rate is about 13% in patients resistant to anaplastic lymphoma kinase TKI. The incidence of MET protein overexpression was 13.7%~63.7%, and the degree of protein overexpression was often related to the stage and degree of malignancy in NSCLC patients[5].
MET abnormalities have many forms, and MET targets are currently receiving extensive attention in the diagnosis and treatment of lung cancer, and related research on this target is also in full swing. It is believed that in the future, with the in-depth understanding of the mechanism of MET abnormalities, it will help to develop more precise and effective treatments, and bring better treatment options and prognosis to NSCLC patients.
To lay a good foundation for precision treatment, MET genetic testing has been written into major authoritative guidelines
In the era of precision medicine, the advancement of detection technology has provided strong support for the individualized treatment of lung cancer. "Precision treatment, detection first" - through appropriate detection methods, as many rare targets as possible is the premise and key to achieve precision treatment in clinical practice. MET14 exon skipping mutations have been identified as lung cancer drivers, and although MET fusions are relatively rare, existing studies have shown that they have potential oncogenic activity in the development and progression of lung cancer. In addition, data show that MET amplification is one of the main causes of drug resistance after EGFR-TKI treatment, and the proportion of MET gene amplification after different generations of EGFR-TKI resistance is different, the proportion of MET gene amplification after first-generation and second-generation EGFR-TKI resistance is 5%~22%, the proportion of MET gene amplification after first-line EGFR-TKI resistance is 7%~15%, and the proportion of MET gene amplification after second-line resistance is 5%~50% after second-line resistance [5]. This means that for patients who have already been treated with EGFR-TKIs, testing the status of the MET gene can help us detect drug resistance in time, so that we can adjust the treatment regimen or choose a new treatment direction. Whether it is to provide guidance for subsequent medication or to provide clues for different TKI-treated patients to find drug resistance factors, MET gene testing is of vital significance.
Based on a large number of clinical research results and evidence-based medical evidence, the 2021 National Comprehensive Cancer Network (NCCN) NSCLC Clinical Practice Guidelines have included MET14 exon skipping mutation and MET gene amplification detection as routine testing items for NSCLC to guide subsequent targeted therapy (Fig. 3) [6]. On the mainland, updates to the relevant guidelines and consensus have followed. The 2022 CSCO Guidelines for the Diagnosis and Treatment of NSCLC (Fig. 4) and the 2022 Chinese Expert Consensus on Clinical Testing of MET for Non-Small Cell Lung Cancer (Fig. 5) both recommend the MET gene as a "required gene variant", emphasizing its important position in the precision diagnosis and treatment of lung cancer [5,7].
Figure 3. 2021NCCN NSCLC Clinical Practice Guidelines Testing Recommendations
Figure 4. 2022 CSCO non-small cell lung cancer diagnosis and treatment guidelines test recommendations
Figure 5. 2022 NSCLC MET Clinical Testing Recommended by Chinese Expert Consensus
In summary, MET genetic testing plays a pivotal role in the precision treatment of lung cancer. The update of relevant guidelines and consensus marks that the application of MET gene testing in clinical practice has entered a new stage, and also promotes the application and practice of precision treatment of lung cancer in mainland China. With the emergence of more research results and the accumulation of clinical practice experience, precision treatment for lung cancer will become more mature and popular, bringing hope for long-term survival to more patients.
In the era of targeted therapy, MET has a drug to follow
With the in-depth study of lung cancer, we have gradually realized the important role of MET gene in the occurrence and development of lung cancer. In recent years, as the mechanism of action of the MET pathway in NSCLC has been gradually revealed, the treatment of MET gene abnormalities has become the key to optimizing the treatment strategy. Prior to the advent of small molecule c-Met kinase inhibitors (Met-TKIs), there was a lack of highly selective targeted therapy drugs for patients with MET14 exon skipping mutations, and standard treatment regimens often failed to meet the treatment needs of patients. In order to change this, many researchers and clinicians are working to find more effective treatments and develop innovative drugs for abnormalities in the MET gene.
At present, a number of clinical studies have demonstrated that MET inhibitors have good anti-tumor activity and safety in patients with advanced NSCLC with MET14 exon skipping mutations. In recent years, a number of MET inhibitors have been launched at home and abroad, illuminating the treatment path for patients with MET mutations. At present, there are four main types of MET inhibitors, type Ia small molecule inhibitors (crizotinib), type Ib small molecule inhibitors (capmatinib, texpotinib, savolitinib, beretinib, etc.), type II small molecule inhibitors (cabozantinib, merestinib and Glesatinib), and large molecule MET inhibitor monoclonal antibodies or ADC type bispecific antibodies. The clinical application of MET inhibitors not only significantly improves the treatment efficacy of patients with advanced NSCLC with MET14 exon skipping mutations, but also brings longer survival to patients.
In mainland China, with the launch of our self-developed innovative MET inhibitor drugs (such as savolitinib, glutatinib, rigitinib, etc.), it has brought new hope to the majority of patients. Taking the newly launched britinib as an example, as a MET inhibitor independently developed by mainland China, it performed well in the key registration clinical study KUNPENG study. The results of the study showed that the overall objective response rate (ORR) was 75 percent, the median duration of response (mDOR) was 15.9 months, and the median overall survival (mOS) was 20.7 months, fully demonstrating the efficacy and well-tolerated efficacy of rigetinib [8]. This milestone not only demonstrates the innovative strength of mainland China in the field of precision treatment of lung cancer, but also provides new treatment options and survival opportunities for lung cancer patients around the world. In November 2023, britinib was approved by the National Medical Products Administration (NMPA) for the treatment of patients with locally advanced or metastatic NSCLC with MET exon 14 skipping mutations, enabling more patients with MET exon 14 skipping NSCLC to benefit from precision targeted therapy, resulting in longer survival and better quality of life.
We can see that the continuous development of MET-targeted therapy in recent years has greatly changed the treatment model of MET abnormalities. In the future, with the in-depth research on the molecular mechanism of lung cancer and technological advancement, we are expected to witness the advent of more therapeutic drugs targeting specific gene mutations, bringing more personalized and precise treatment options to lung cancer patients. At the same time, we also look forward to more scientific research results being translated into clinical practice, bringing more hope and gospel to lung cancer patients.
Message from the experts
Professor Shi Meiqi: "The treatment of NSCLC is a "tough battle" that requires the joint efforts of doctors, patients and society, and the current in-depth development of precision medicine has further enriched the therapeutic targets, so that more patients can achieve better efficacy and longer survival. MET targeted therapy has enabled more patients with MET-abnormal NSCLC to get rid of the situation of "no cure", and newly launched MET abnormal targeted therapy drugs such as britinib have provided more new drug options for lung cancer experts and patients, and it is expected that these new drugs can bring more benefits to patients and further promote the progress of lung cancer treatment. At the same time, we also call on both doctors and patients and the whole society to work together to strengthen the awareness of lung cancer prevention and treatment, improve the early diagnosis rate, and provide patients with better treatment conditions and survival opportunities. ”
In conclusion, precision therapy is the future trend of lung cancer treatment. By in-depth study of the molecular mechanisms and types of genetic variants in lung cancer, we are expected to provide patients with more precise and effective treatment options. At the same time, we also need to continuously summarize clinical practice experience, improve treatment strategies, and strengthen multidisciplinary cooperation to further improve the survival rate and quality of life of lung cancer patients. On the annual "World Cancer Day", we hope to raise public awareness of lung cancer and advocate scientific and correct cancer prevention and treatment concepts. Only when the whole society actively participates and works together can the "lung cancer scare" be truly eliminated. Let's work together to overcome the challenges and overcome the global health challenge of lung cancer!
Resources:
[ 1 ] https://www.iarc.fr/faq/latest-global-cancer-data-2020-qa/
[ 2 ] LUN Gevity Foundation. Types of Lung Cancer. Available at https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. (2023.06.09)
[ 3 ] Remon J, Hendriks LEL, Mountzios G,et al.. MET alterations in NSCLC-Current Perspectives and Future Challenges. J Thorac Oncol. 2023 Apr; 18（4）:419-435.
[ 4 ] Fatemeh Moosavi , Elisa Giovannetti , Godefridus J Peters, et al. Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer. Crit Rev Oncol Hematol
. 2021 Apr:160:103234. doi: 10.1016/j.critrevonc.2021.103234.
[ 5 ] Chinese Society of Pathology, National Center for Pathological Quality Control, Lung Cancer Group, Chinese Society of Oncology, et al.Chinese Expert Consensus on Clinical Detection of Non-small Cell Lung Cancer[J].Chinese Journal of Pathology, 2022, 51(11):1094-1103.
[ 6 ] NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®)Non-Small Cell Lung Cancer.Version 1.2021.
[ 7 ] Chinese Society of Clinical Oncology Guidelines Working Committee.Chinese Society of Clinical Oncology (CSCO) NSCLC Diagnosis and Treatment Guidelines 2022.Beijing:People's Medical Publishing House,2022.
[8]https://oncologypro.esmo.org/meeting-resources/esmo-congress/preliminary-results-of-phase-ii-kunpeng-study-of-vebreltinib-in-patients-pts-with-advanced-nsclc-harboring-c-met-alterations.