Lung cancer has long occupied the first place in the incidence and mortality of malignant tumors, which is discolored. With the development of precision medicine, the diagnosis and treatment methods and protocols of lung cancer in China are ushering in profound changes, and more questions are also coming. How to deal with drug resistance after targeted therapy? How does genetic testing work to the maximum? How can immunotherapy benefit lung cancer patients? Recently, Professor Wu Yilong, chief expert of Guangdong Provincial People's Hospital, and Professor Zhou Qing, president of Guangdong Provincial People's Hospital Cancer Hospital, elaborated on the latest changes in the field of lung cancer treatment in an interview.
What to do after targeted therapy resistance?
According to the International Center for Research on Cancer, there were 816,000 new cases of lung cancer in China in 2020. According to the different characteristics of histopathology, it can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which non-small cell lung cancer accounts for about 80%-85% of all lung cancers.
Before 2004, surgery, chemotherapy, radiotherapy, etc. were the main treatment methods for lung cancer. However, the early stage of lung cancer is hidden, about 70% of patients are diagnosed with local advanced stage or metastases, have lost the opportunity for surgery, and radiotherapy and chemotherapy will lead to a large number of normal cells killed during treatment, the side reactions are more serious, and the patient's treatment needs are far from being met.
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"In 2005, the world's first oral targeted drug for lung cancer was listed in China, and the treatment of advanced lung cancer finally had a new choice after radiotherapy and chemotherapy. The discovery of EGFR, the first lung cancer treatment target in 2009, and the promotion of related research mean that targeted therapy has officially opened a new chapter in precision treatment of lung cancer. Professor Wu Yilong said, "Targeted drugs can be specifically combined with some clear carcinogenic sites, so that tumor cells have specific death, not harming the surrounding normal tissue cells, so the systemic side reactions are small, the effect is precise, and the effect is superior." In particular, the study found that about 45.9% of Chinese non-small cell lung cancer patients have EGFR mutations, much higher than Western patients. Therefore, the emergence of EGFR targeted drugs has met the treatment needs of a large number of patients with advanced non-small cell lung cancer in China, and significantly prolonged the survival time of these patients compared with traditional treatment methods. ”
Although the first and second generation of EGFR targeted drugs have good clinical efficacy, with the prolongation of the drug time, about 2/3 of patients will develop drug resistance due to T790M mutation. "At this time, patients mainly present with lesions that are more enlarged than before treatment, or new local or distant metastases. This is because the mutated tumor cells will constantly fight against the targeted drug, resulting in the targeted drug effect is not obvious. Therefore, once drug resistance develops, it is necessary to adjust the treatment regimen in a timely manner. Professor Zhou Qing said, "The third-generation EGFR lung cancer targeted drug listed in 2017 as a first- and second-generation targeted drug resistance post-drug treatment plan better solved this problem, significantly improving the median progression-free survival of this part of the patient." In addition, not only EGFR targets, such as second-generation targeted drugs for ALK targets, have also been listed in recent years, partially solving the problem of drug resistance of a generation of ALK targeted drugs. “
Professor Wu Yilong pointed out that since last year, a new scheme to overcome drug resistance has emerged in the clinic - "antibody-coupled drugs (ADCs)", which are called "biological missiles" to provide a new direction for drug-resistant post-drug treatment. "There are three or four more very revolutionary and innovative treatment options under study in the future. We believe there will be more new breakthroughs on the issue of drug resistance in the future. “
Genetic testing has become a necessity for the diagnosis and treatment of lung cancer
In addition to improving drug resistance, experts have been exploring ways to maximize the clinical benefits of targeted drugs in order to enable patients to achieve longer survival and a higher quality of life.
"Targeted therapy developed from the late stage, so the earliest advances were from the late second line to the late first line, and from the late stage to the early and middle stages. Under the impetus and demonstration of relevant research, the third generation of EGFR targeted drugs has also been approved as indications for advanced first-line treatment in recent years, which not only significantly prolongs the median progression-free survival of patients, delays the occurrence of drug resistance, but also significantly prolongs the overall survival of patients, bringing better survival benefits and better safety to patients. Professor Zhou Qing pointed out, "The purpose of late treatment is to improve the quality of life and prolong life; and after the early surgery, the patient's most concerned question is how to avoid recurrence, or postpone recurrence." Thanks to the progress of targeted therapy-related research, compared with traditional postoperative adjuvant chemotherapy, early patients with EGFR mutations can further reduce the recurrence rate through adjuvant targeted therapy after surgery, and the toxic side effects are mild, and the safety and tolerability are better. ”
In the era of precision medicine, Professor Wu Yilong also emphasized: "Regardless of the specific stage, genetic testing is required before using anti-tumor targeted drugs with clear targets." First, when the patient is diagnosed, genetic testing must be done to determine the classification to determine the treatment plan; second, when drug resistance occurs, it must be done to find the cause of drug resistance to adjust the treatment plan; third, it is recommended that early patients be tested regularly after treatment to check whether there is genetic reproduction and further determine whether relevant intervention is needed. “
Immunotherapy ushered in a new era of lung cancer treatment
Compared with common targets such as EGFR, KRAS, ALK, etc., the incidence of rare targets is low and there is a lack of corresponding drugs, and these patients have been facing the dilemma of being ignored and difficult to cure.
Professor Zhou Qing explained: "At present, the driver genes of non-small cell lung cancer that we know include rare and rare targets such as about 5% ALK and ROS1, which account for about 45% of EGFR targets. However, because the population of lung cancer patients is relatively large, the number of these patients is not large. Moreover, the proportion of common or rare targets is 100% for specific individuals, which is the so-called 'small target, big benefit'. “
Professor Zhou Qing said that in recent years, the development of rare and rare driver gene targeting drugs is very rapid, for example, in 2021, the first targeted drugs for RET targets and MET exon 14 jump mutations have been approved for marketing, so that these patients finally got rid of the dilemma of "no drug available". "It is worth mentioning that the approval of the first China-independently developed MET inhibitor in 2021 means that for the rare mutation of MET, China has independently achieved drug initiation and 'from zero to one' breakthrough, as well as local research and development and international integration, which is of milestone significance."
Although the treatment needs of many lung cancer patients have been met through targeted therapy, a considerable number of Patients of Asian Descent have negative driver genes in NSCLC patients, and SCLC also faces difficulties in the study of related driver genes. Therefore, current targeted therapy cannot meet the treatment needs of this part of the patient. Professor Wu Yilong pointed out: "In recent years, with the wide application of immunosuppressants and anti-angiogenic drugs, more treatment methods have been brought to this part of the patient. The so-called immunotherapy is a series of immune-related treatment methods that destroy tumor cells with the help of the human body's own immune system, which has the characteristics of improving the ability of the immune system to recognize and eliminate tumor cells, and has a slight impact on normal tissues. At present, immunotherapy for lung cancer mostly refers to 'immune checkpoint inhibitors', such as PD-1/PD-L1 inhibitors. From 2018 to 2019, domestic PD-1 inhibitors and PD-L1 inhibitors were successively approved for listing, opening a new era of immunotherapy for lung cancer. “
"Compared with the traditional treatment plan, the efficacy of immunotherapy is long-lasting, the time span is also large, it has a good tailing effect, and the overall incidence of adverse reactions is lower than that of chemotherapy, and most of the immune-related adverse reactions are also reversible." Advanced squamous cell carcinoma and non-squamous non-small cell lung cancer without drive genes, stage III incisive unsectable small cell lung cancer, extensive stage small cell lung cancer and other different types of patients have also had new treatment options because of the emergence of immunotherapy. Professor Wu Yilong added.
[Reporter] Yan Huifang
【Author】 Yan Huifang
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