China Oncology Times: Understanding the specific mechanism of neovascularization in lung cancer is very important to find the appropriate targets to inhibit tumor vasculature and thus develop effective anti-lung cancer therapies. Please give us an overview of the process and mechanism of neovascularization in lung cancer. Director Yuan-Sheng Zang: Lung cancer neovascularization is an important driving factor in the process of lung cancer development and progression. Since Folkman proposed the tumor neovascularization hypothesis in 1971, several breakthroughs have been made in the study of the mechanism of lung cancer neovascularization. First, the generation of lung cancer neovascularization is a complex process involving multiple cells and factors, involving cells such as lung cancer cells, vascular endothelial cells, vascular smooth muscle cells, fibroblasts, pericytes, inflammatory cells, and extracellular matrix, etc. The factors involved include hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) family, and platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) family, fibroblast growth factor (FGF)/FGF receptor (FGFR) family, Delta ligand 4 pathway (DLL4/Notch), etc. The specific process is that the local growth of lung cancer cells leads to local hypoxia, which activates HIF, which further activates the subsequent angiogenesis process; the VEGF/VEGFR cascade plays the main role; PDGF/PDGFR has a role in the integrity and function of neovascularization, and has a synergistic effect on the VEGF family; FGF/FGFR has a role in FGF/FGFR has a role in neovascular integrity, and the DLL4/Notch pathway has a negative feedback effect on neovascularization. Secondly, it is well established that, similar to neovascularization in other tumors, neovascularization in lung cancer differs significantly from normal vessels in terms of morphology and function, showing disorganization, uneven distribution, distorted morphology, poor maturation, lack of supporting cells, and local hypoxia or hypoxia. Once again, progress has been made with drugs that primarily target neovascularization in lung cancer. One of these antibodies, bevacizumab, which targets VEGF, has been shown to have significant benefit in improving progression-free survival (PFS) and overall survival (OS) in lung cancer patients with non-squamous histology, good physical status (PS 0 to 1), no brain metastases, no bleeding or thrombosis, and can be used in combination with platinum-based It can be used in combination with platinum-based first-line chemotherapy or as maintenance therapy for patients with advanced disease. In addition, new antibodies against VEGF, such as Ramucirumab and Aflibercept, are being studied in clinical trials for the treatment of lung cancer, with promising results from initial studies. However, it is worth pointing out that small molecule inhibitors targeting angiogenesis-related factors in lung cancer, such as Sorafinib and Sunitinib, which target VEGFR/PDGFR, Brivanib, which target VEGFR/FGFR, Nintedanib, which target VEGFR/PDGFR/FGFR Vandetanib, etc., targeting VEGF4/EGFR, have not achieved positive study results supporting their clinical application, while only recombinant human vascular endothelial inhibitor Endostadin (Endo), in combination with NP regimen for non-small cell lung cancer (NSCLC), has achieved survival benefit. China Oncology Times: Since the 1960s, screening has been attempted at home and abroad to achieve early diagnosis of lung cancer and thus reduce the death rate of lung cancer. Please talk about the new progress in lung cancer screening in recent years. Director Zang Yongsheng: As it is not yet possible to change the intrinsic factors of tumorigenesis and the extrinsic factors of tumorigenesis in the short term, it has been a hot spot of research in oncology at home and abroad to detect more lung cancer patients at an early stage through screening so that they can have a chance to be cured. In this area, the US Clinical Large-Sample Trial (NLST) published in the New England Journal of Medicine in 2011 found that low-dose spiral CT (LDCT) reduced lung cancer mortality by 20% and all-cause mortality by 6% compared with plain chest radiographs after a 5-year follow-up study of nearly 60,000 people, which has encouraged the oncology community to adopt LDCT to screen for early-stage lung cancer. This has encouraged the oncology community to have confidence in the use of LDCT for early lung cancer screening. At the same time, the study also found that more than 90% of the screened nodules were eventually confirmed as benign lesions, and 0.08% of the subjects died from procedures such as puncture, surgery, and other means to obtain pathological tissue, raising concerns in the oncology community about the potential for overdiagnosis, overtreatment, waste of resources, and psychological fear. With regard to the pros and cons of LDCT screening for early lung cancer, the following points are worth discussing: first, the NLST study was conducted in the United States, and the differences in ethnicity deserve attention; second, air pollution is an important causative factor for lung cancer, and patients with air pollution as the primary cause present more often with small nodular lung lesions than those with smoking as the primary cause, considering the significant differences between China and the United States in terms of air pollution. Again, it is not known what percentage of lung nodules screened by LDCT are benign in different areas of China with different levels of air pollution, whether the same percentage is over 90%, or whether the percentage of benign is inversely related to the air pollution status. Therefore, it is important to conduct relevant studies in China to clarify the answers to the above questions. It should also be noted that the carcinogenic effect caused by air pollution may lag 5 to 10 years, therefore, it is also necessary to update the answers to the above questions dynamically. China Cancer News: Despite the continuous improvement of surgery, chemotherapy, radiotherapy and molecular targeted therapy, the prognosis of patients with advanced lung cancer is still poor; the 5-year survival rate of patients is still only 16.6%, and the search for new strategies for lung cancer treatment has become the focus of research nowadays. With the development of tumor immunology and molecular biology techniques, immunotherapy of tumors has received wide attention. Can you give us your opinion on the latest progress of immunotherapy for lung cancer? Director Zang Yongsheng: Immunotherapy for tumor has gone through two strategic stages. The first strategic stage in the early stage is to increase the number of immune attack cells by various means, i.e., to increase the number of “friendly forces”, represented by cytokine-induced killer cell (CIK) technology. The second stage of recent strategy is to dismantle the immune protection mechanism of tumor cells, i.e. to remove the resistance of the “enemy army”, which is represented by Checkpoint blocking technology. After years of research, it is now believed that CIK technology is effective in immune-related tumors, such as melanoma and kidney cancer, while its application in lung cancer is still waiting for stronger evidence-based medical evidence. In recent years, the modulation of immune checkpoints has been a hot topic in lung cancer research, with two “star” focuses: programmed death (PD)-1 receptor (PD1) and its ligand (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In short, both PD1/ PD-L1 and CTLA-4 inhibit the proliferation of tumor antigen-specific T cells and their attack on tumor cells, and the use of corresponding antibodies to block PD1/ PD-L1 and CTLA-4 can reverse this effect. Studies have shown that Nivolumab has an objective effectiveness rate (ORR) of 18% in NSCLC, with an ORR of 12% in non-squamous carcinoma and 33% in squamous carcinoma, and that Nivolumab can prolong the survival of patients with advanced NSCLC. survival of patients with advanced NSCLC and has a better safety profile. Considering that in recent years, both chemotherapy and targeted therapies have made a lot of progress in the treatment of non-squamous lung cancer, Nivolumab may become a new “favorite” after albumin-bound paclitaxel for squamous lung cancer, which is a “lost favorite”. The study also showed that Nivolumab is a new “favorite” for lung cancer. Additional studies have shown that sequential administration of Ipilimumab in addition to paclitaxel in combination with carboplatin in lung cancer significantly improves immune-related progression-free survival (irPFS) and immune-related best overall effective rate (irBORR), significantly better than paclitaxel in combination with carboplatin alone, and even better than paclitaxel in combination with carboplatin in combination with Ipilimumab. Synchronous use. Although the number of published studies on Ipilimumab is relatively small, its application is promising. It should be noted that research on modulating immune checkpoints for lung cancer is still in its infancy, and an optimistic estimate is that this stage of research is similar to the stage of research on EGFR TKI for lung cancer more than a decade ago. Just as recent research on EGFR TKI for lung cancer has answered a large number of questions that we need to know, research on modulated immune checkpoint therapy for lung cancer also needs to answer a large number of questions: when should modulated immune checkpoint therapy be used, should it be first, second or third line? Should it be used alone or in combination? What are the best predictors for targeting population screening and efficacy predictors? What is the bottom line of safety? And so on. A large number of prospective, randomized, controlled studies are needed to answer each question. China Oncology News: In the past two years, maintenance therapy for lung cancer has been a hot topic, what is the status of maintenance therapy for lung cancer? What is the current status of maintenance therapy for lung cancer? Currently, drugs such as pemetrexed and docetaxel are approved for maintenance therapy, can you tell us about the application of these drugs in maintenance therapy? Director Zang Yongsheng: Due to the relatively few effective regimens for small cell lung cancer (SCLC) and their poor efficacy, it is premature to explore maintenance therapy for SCLC patients. Instead, maintenance therapy is a treatment decision problem that a large number of NSCLC patients must face. Maintenance therapy is achieved by continuing to give one chemotherapeutic agent from the original regimen on a cyclical basis, i.e., same drug maintenance therapy, or continuing to give another chemotherapeutic agent on a cyclical basis, i.e., switch maintenance therapy, based on the completion of 4-6 cycles of first-line chemotherapy in NSCLC patients. The purpose of maintenance therapy is to prolong the survival of patients. A large number of lung cancer chemotherapeutic agents have undergone co-drug maintenance studies, culminating in the PARAMOUNT study, which confirmed that pemetrexed co-drug maintenance significantly prolonged PFS and OS in patients with non-squamous lung cancer, while co-drug maintenance with gemcitabine and paclitaxel did not result in a survival benefit for patients. In the area of maintenance with drug switching, the SATURN study confirmed that erlotinib prolonged PFS and OS in patients with non-squamous lung cancer, while the INFORM study, the JMEN study and the Fidias study confirmed that gefitinib, pemetrexed and docetaxel all prolonged PFS in lung cancer patients, respectively, while their prolongation of OS did not reach significant differences despite the dominant data. It is on the basis of these findings that the NCCN guidelines preemptively approved pemetrexed for maintenance treatment with the same drug and erlotinib for maintenance treatment with a switch. It should be added that studies such as E4599 and POINTBREAK conducted in recent years have confirmed that concomitant maintenance therapy with bevacizumab improves PFS in patients with non-squamous lung cancer, with the E4599 study also suggesting that bevacizumab may prolong OS. Despite the many breakthroughs in the field of maintenance therapy for lung cancer, however, the rigor of the study design regarding previous maintenance therapy studies, the However, the rigor and rationality of the study design of previous maintenance studies has been a hot topic of discussion among oncologists. For example, is 4 cycles of first-line chemotherapy sufficient prior to maintenance therapy, and does the completion of 6 cycles of first-line chemotherapy make the survival benefit data for maintenance therapy less “glamorous”? Were the control patients in the maintenance trial adequately treated, especially considering that the control group in the trial had to wait until the lesion progressed according to RECIST criteria before administering the drug, when many patients had already lost chemotherapy due to significant progression and PS deterioration? etc.