1. First-line therapy for advanced NSCLC in the era of targeted therapy Professor Tony Mok of the Chinese University of Hong Kong, the host of the IPASS study, reviewed the evolution of first-line therapy for advanced non-small cell lung cancer (NSCLC). Since the mid-1990s, first-line treatment of NSCLC has made tremendous progress, and today the latest progression-free survival (PFS) values in the IPASS study are similar to the overall survival (OS) achieved with chemotherapy alone in 1995. With the publication of studies such as IPASS, FLEX and JMDB, the first-line treatment options for NSCLC have been greatly enriched in just a few years. Chen Huiguo, Department of Thoracic Surgery, The Third Hospital of Sun Yat-sen University Among the history of first-line treatment for NSCLC, the ECOG4599 study published in 2005 was epoch-making: the OS of advanced NSCLC exceeded 12 months for the first time after the addition of bevacizumab to platinum-containing two-drug first-line chemotherapy, unveiling the era of targeted first-line treatment for lung cancer. However, there are more conditions that make bevacizumab inappropriate, and elderly patients, patients with squamous cancer, and those with hemoptysis or brain metastases are at higher risk of using the drug. The reason why bevacizumab did not significantly prolong OS in the AVAiL study also remains to be elucidated. With the breakthrough of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib in second- and third-line treatment of lung cancer, their use has begun to expand to first-line treatment. However, in the initial years, studies such as INTACT and TRIBUTE, conducted with EGFR-TKI in combination with first-line chemotherapy regimens, failed to show survival benefit, causing the oncology community to turn to first-line targeted therapies for superior populations. In recent years, a growing number of studies have confirmed that the mutation status of EGFR is a key factor in determining the efficacy of EGFR-TKI first-line therapy, and that groups such as adenocarcinoma, non-smokers, women and Asians have higher EGFR mutation rates and are superior populations for EGFR-TKI first-line therapy. In 2008, the publication of the IPASS study marked a new chapter in the first-line treatment of NSCLC with gefitinib: in the nonsmoking Asian adenocarcinoma patient population, gefitinib monotherapy reduced the risk of disease progression in patients with advanced NSCLC by a significant 26% compared to paclitaxel + carboplatin (PC) chemotherapy, and significantly reduced hematologic adverse events while significantly Stratified analysis showed that EGFR mutation status determined the first-line efficacy of gefitinib: mutation-positive patients had an objective remission rate (ORR) of 71% with gefitinib, significantly higher than the 47% with PC chemotherapy (P<0,0001), with a 52% reduction in the risk of disease progression, while mutation-negative patients had significantly worse PFS and ORR than PC chemotherapy (Figure 1). We stratified the IPASS patient population according to demographic and clinical characteristics, with EGFR mutation rates as high as 47% to 69% in all subgroups, suggesting that this group (non-smokers or light smokers, Asian, adenocarcinoma) represents a superior population for EGFR-TKI therapy. Given that PFS in first-line treatment reflects the therapeutic benefit of new therapies in a more timely manner than OS and is not subject to study bias due to imbalance in subsequent treatment, PFS is now an acceptable study endpoint in several oncology areas. IPASS prolongs PFS in those with EGFR mutations, a result that has the potential to change the framework of first-line treatment in advanced NSCLC. Prof. Shujin Mo concluded: In the IPASS study, gefitinib significantly prolonged PFS compared to chemotherapy in patients with EGFR mutations, and also significantly improved safety and patient quality of life, which is expected to become a new standard of care for first-line treatment of EGFR mutation-positive patients; when the mutation status is unknown, first-line treatment with EGFR-TKI in a superior population based on demographic and clinical characteristics also has a high probability of benefit. probability of benefit. For those with EGFR wild-type or non-dominant clinical characteristics, first-line treatment with EGFR-TKI as maintenance therapy, sequential chemotherapy, or combination of anti-EGFR monoclonal antibody with chemotherapy has also been effective. In the future, individualized therapy is expected to set the standard of first-line treatment for patients with various characteristics of NSCLC. Blogger's note: The efficiency of EGFR wild-type patients treated with gefitinib (1,1%) was significantly lower than in the group of patients with EGFR mutations treated with gefitinib (71,2%), and also lower than in the chemotherapy group (47,3% and 23,5%). 2. Recognition and reflection on EGFR-TKI first-line treatment of advanced NSCLC Large-scale phase III clinical studies and Meta-analysis affirmed the place of TKI in second- and third-line treatment of advanced NSCLC [9-11], with similar and slightly superior efficacy and more benefit-risk ratio compared with the standard second-line chemotherapy drug docetaxel TKI in combination with chemotherapy phase III Possible explanations for the negative clinical findings are potential antagonistic effects between TKI and cytotoxic chemotherapeutic agents, as TKI stops cell proliferation in the G1 phase and blocks cells from entering the S and M phases, which are critical for the efficacy of chemotherapeutic agents. In conclusion, the available clinical studies are not sufficient to draw conclusions about the sequential combination of TKI and chemotherapy; except for clinical trials, sequential combination of chemotherapy and TKI is not recommended for routine use in unselected populations. Although, the three published studies of TKI maintenance therapy have all resulted in improved PFS and in some cases even prolonged OS, there are still some questions to be addressed as to whether TKI maintenance therapy can become a new paradigm of clinical treatment. Is there a survival benefit of maintenance therapy compared to the same drug used in second-line therapy? Can patients' quality of life and symptoms be improved while prolonging PFS? Are the benefits of maintenance therapy worth the corresponding increase in treatment costs and adverse effects? In addition, further analysis of these maintenance studies revealed that some subgroups had the most benefit, so it is necessary to further explore the most appropriate groups for TKI maintenance therapy, and individualization remains the direction of development for TKI maintenance therapy. EGFR mutation is a strong predictor of benefit (PFS, ORR) in advanced NSCLC treated with gefitinib in the first line, and this result can be extended to erlotinib and populations outside of Asia; however, for those with unknown mutation status, to quote Professor Simon of Fox Chase Cancer Center, "chemotherapy should be preferred in the first line. "The results of the IPASS study will change the landscape of first-line treatment for advanced NSCLC, which is a milestone. The results of existing clinical trials do not support the first-line preference for EGFR-TKI in unselected patients with PS scores ≥2. Early correlational analyses of clinical trials suggest that TKI efficacy is associated with certain clinical characteristics of NSCLC, and these predictors of treatment effectiveness include female, Asian, no history of smoking, adenocarcinoma and type of bronchoalveolar carcinoma (BAC) component. that there is no significant correlation between EGFR protein expression levels and TKI efficacy [23]. Instead, the gene copy number of EGFR may be a valid predictor of TKI efficacy Several studies have reported that two sensitive mutations, exon 19 deletion and exon 21 missense mutation, are closely associated with the efficacy of EGFR-TKI, and this finding is the most meaningful molecular event in contemporary lung cancer treatment. EGFR-sensitive mutations are the most core-valued biological indicators for predicting TKI efficacy In the first-line treatment of advanced NSCLC, the results of the phase III study of FAST-ACT are worthy of our expectation, except in the nonsmoking population, where simultaneous or sequential combination chemotherapy with EGFR-TKI is not supported. maintenance therapy with TKI brings definite benefits to a wide range of patients, and whether it can become a new paradigm of clinical treatment remains to be time. In patients with EGFR mutations, the most appropriate treatment has not been determined, but based on the data provided by IPASS, first-line use of TKI is appropriate; it should be noted that these patients may have greater benefit from receiving TKI in combination with standard chemotherapy (with or without bevacizumab). In unselected elderly or poor PS score patients, TKI should not be used routinely in first line. EGFR-sensitive mutations are valid predictors of TKI, while KRAS mutations may be counterindicators of TKI therapy, and genotype-guided targeted therapy will be the way forward. 3. First-line treatment of advanced NSCLC Gefitinib is significantly better than conventional chemotherapy After "igniting" the European Society of Medical Oncology (ESMO) Congress in September, the IPASS study appeared at this forum and rekindled the enthusiasm for first-line treatment of advanced NSCLC with gefitinib. According to the principal investigator, Prof. Shujin Mo of the Chinese University of Hong Kong, 1217 patients with stage IIIB/IV NSCLC in Asia were randomized to receive first-line treatment with gefitinib (609 patients) or carboplatin + paclitaxel (CP) regimen (608 patients) in this randomized open phase III clinical study. At 22-month follow-up, progression-free survival (PFS) was significantly better in the gefitinib group than in the CP group [hazard ratio (HR) 0,741, P<0,0001]. In addition, the objective effective rate (ORR) in the gefitinib group was significantly higher than that in the CP group (43,0% versus 32,2%, P=0,0001), with better tolerability and significantly better quality of life. OS in the gefitinib group was similar to that in the CP group, but follow-up treatment in both groups may have affected patient survival, and further follow-up is ongoing. As an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), gefitinib should be used as a patient selection criterion for the first-line treatment of advanced NSCLC with EGFR mutation detection results, because PFS was better with gefitinib than with CP in the EGFR mutation population and vice versa in the no-mutation population. However, Prof. Mo emphasized that one of the important implications of IPASS is that the study shows that EGFR-TKI can still be safely used as first-line therapy in a clinically selected group of patients with unknown or undetectable EGFR mutations, because the EGFR mutation rate in this population is more than 60%. 4. Can EGFR-TKI replace chemotherapy in the first-line treatment area? As mentioned earlier, none of the studies of EGFR-TKI in combination with first-line chemotherapy have yielded positive results, and the oncology community has turned its attention to first-line monotherapy with EGFR-TKI guided by clinical features and molecular markers. The IPASS study, conducted with this in mind, was published in 2008 and received a tremendous response from the lung cancer community. The study included more than 1,200 non-smoking or lightly smoking Asian adenocarcinoma patients randomized to first-line treatment with either the PC regimen or gefitinib. Intriguingly, progression-free survival was higher in the PC chemotherapy group than in the gefitinib group during the initial 6 months of the follow-up period, while the PFS curves of the two groups crossed over after 6 months. Stratified analysis of molecular markers showed that PC chemotherapy had similar efficacy in EGFR wild-type and mutant patients, whereas gefitinib showed an advantage over chemotherapy in delaying disease progression only in EGFR mutant patients, while the EGFR wild-type group, which represents 40% of measurable patients, received gefitinib first-line treatment instead, substantially increasing the risk of disease progression. On the other hand, the OS curves of the PC chemotherapy group and first-line targeted therapy largely overlapped, with no significant difference in median OS between the two. The FIRST-SIGNAL study, which used a similar design, reached conclusions that were largely consistent with IPASS. This suggests that first-line treatment with EGFR-TKI based on clinical characteristics such as race, pathological type and smoking history, while providing an overall PFS advantage over EGFR-TKI, is associated with an increased risk of disease progression when EGFR-TKI is given first-line to patients with EGFR wild type. both the IPASS and the recent FIRST-SIGNAL study confirmed that in the advantaged population first-line The overall OS obtained with EGFR-TKI or chemotherapy was comparable, and there was no clear comparison between the two first-line treatment strategies. In addition, a study published in 2008 showed that patients with advanced NSCLC with a physical status (PS) score of 2 randomized to PC chemotherapy or EGFR-TKI first-line treatment resulted in shorter OS in the targeted group compared to the chemotherapy group (6 or 6 months versus 9 or 7 months, P=0,018). This study again suggests that the choice of EGFR-TKI first-line therapy is more blind for patients with unknown EGFR mutation status. Faced with the clinical reality that the EGFR mutation status is unknown in the majority of patients treated for the first time, chemotherapy remains one of the options that must be considered for first-line treatment.