1. Choice of chemotherapy regimen and treatment modality in first-line treatment Internal chemotherapy has been the standard treatment for advanced NSCLC. Previous clinical studies and meta-analysis have shown that platinum-based chemotherapy can significantly prolong patient survival, reduce symptoms and improve quality of life compared to the best supportive therapy. Third-generation regimens consisting of two platinum-containing neoplatinum drugs such as PTX + DDP, TXT + DDP, GEM + DDP, PTX + CBP, and NVB + DDP are currently the commonly used first-line chemotherapy regimens for advanced NSCLC, with an efficiency of 25% to 40%, time to progression (TTP) of 4 to 6 months, and median survival time (MST) of about 8 to 10 months. Nevertheless, recent studies suggest that the efficacy of chemotherapy alone in internal medicine seems to have reached a so-called “plateau”, and it is difficult to further improve the efficacy and prognosis regardless of the type of drug, the mode of administration, the intensity of the dose and the adjustment of the treatment course. This seems to be reflected in the ECOG1594 study. Therefore, all of these regimens are available in the NCCN guidelines as first-line options for patients with advanced NSCLC, with the rationale for individualized selection based primarily on the potential impact of differences in toxicities and side effects on patient tolerability. In clinical practice, it is clear that considering individualized therapy solely on the basis of patient tolerability is far from adequate and inevitably highly blinkered relative to the extremely heterogeneous advanced NSCLC population. Rational individualized treatment selection is more important to achieve the best efficacy based on safety. Recent studies have shed some light on the individualized selection of first-line chemotherapy regimens and treatment modalities for advanced NSCLC. First, at the level of the molecular biology of the patient’s tumor itself, pharmacogenomic findings have directly contributed to the selection of chemotherapeutic agents. dan et al. analyzed the gene expression profiles of 55 chemotherapeutic agents after treatment using 39 tumor cell lines and identified 50 genes associated with chemotherapy sensitivity, suggesting that genomic tags can be used as biomarkers to predict the sensitivity of tumor chemotherapeutic agents. 2006 In 2006, Ken A Olaussen et al. studied ERCC1 expression in postoperative specimens from 761 NSCLC patients enrolled in the IALT study, and this retrospective study found that postoperative platinum-containing chemotherapy prolonged survival in those with low ERCC1 expression, but had no significant benefit in those with high ERCC1 expression, and that ERCC1 expression was positively associated with platinum drug resistance. R0SELL et al. studied 100 cases of NSCLC and found that RRM1 was associated with DNA synthesis, repair and gemcitabine metabolism, while ERCC1 was associated with DDP activity, and their expression levels were highly correlated; GP regimens benefited those with low RRM1 MRNA expression or low expression of both RRM1 and ERCC1 MRNA, and median survival was significantly longer (13.7 months vs. 3.6 months). ROSELL et al. concluded that the expression of RRM1 MRNA is an important predictor of patient survival and can be used as a predictor of individualized treatment. Therefore, if some indicators of advanced NSCLC patients’ tumors in terms of pharmacogenomics are obtained in advance, it is highly likely to guide the clinical selection of reasonable first-line treatment regimens. Second, at the level of clinical characteristics of patients, further individualization has been difficult to implement as the focus has been mainly on ECOG behavioral status scores, while the JMDB prospective phase III clinical study was the first to demonstrate significant differences in the efficacy of first-line platinum-containing chemotherapy regimens for different histological types of advanced NSCLC. The study compared the efficacy and safety of first-line treatment of NSCLC with pemetrexed in combination with cisplatin (AC) and gemcitabine in combination with cisplatin (GC). 1725 patients were enrolled, and the results showed no significant difference in overall survival between the two groups, at 10.3 months, with PFS of 4.8 months and 5.1 months in the AC and GC groups, respectively, and RR of 31% and 28%, respectively. However, among the 847 pre-stratified lung adenocarcinoma cases, the median survival was significantly better in the AC group than in the GC group, with 12.6 months and 10.9 months, respectively, showing a statistical difference, while among the 473 cases of squamous lung cancer, 9.4 months in the AC group and 10.4 months in the GC group tended to be better in the latter group but did not show a statistical difference. As seen in the results of this study, patients with advanced lung adenocarcinoma treated with AC achieved a median OS of 12.6 months, which is difficult to achieve in previous studies without the addition of selected chemotherapy alone. Therefore, the implications of the results of this study for the clinical current individualized treatment are very clear. Further, recent clinical studies have shed light on first-line clinical individualized treatment modalities for advanced NSCLC. The JMEN trial compared the efficacy and safety of lipitor and placebo in the maintenance treatment of stage IIIB/IV NSCLC that had not progressed on four cycles of platinum-containing induction chemotherapy, and after completion of four cycles of platinum-containing regimens, patients with tumors in remission or stable were randomized in a 2:1 ratio to two groups, with one group continuing lipitor 500 mg/m2 maintenance chemotherapy in combination with best supportive care. Fidais et al. designed a phase 3 clinical trial comparing first-line chemotherapy (gemcitabine 1000 mg/m2 d1, d8; carboplatin AUC=5) to first-line chemotherapy (gemcitabine 1000 mg/m2 d1, d8; carboplatin AUC=5) in patients with advanced NSCLC. d1; 21 days per cycle, 4 cycles) immediately after doxorubicin administration versus doxorubicin administration after progression in terms of efficacy and adverse effects. The results showed a significant difference between the two groups with PFS of 6.5 months and 2.8 months, respectively (P < 0.0001); however, there was no significant difference in OS, 11.9 months and 9.1 months, respectively (P = 0.078). 2. Choice of chemotherapy and biologic targeted therapy in first-line treatment For the treatment of advanced non-small cell lung cancer, the efficacy of chemotherapeutic drugs seems to have reached a therapeutic plateau, and the absolute dominance of traditional chemotherapy is challenged by novel targeted therapies. To break through the current therapeutic bottleneck, the application of novel targeted agents is bound to be favored. Existing clinical studies on biologically targeted therapies have shed much light on clinical individualized treatment in terms of treatment strategies, treatment options, and related advantageous populations. First, is there any benefit of combining traditional chemotherapy with biologically targeted drugs? Although four large studies, INTACT1, INTACT2, TRIBUTE, and TALENT, suggest that concurrent use of tyrosine kinase inhibitors (TKI) of EGFR with chemotherapy is not a good strategy, the FLEX and E4599 studies have achieved success with chemotherapy in combination with monoclonal antibodies for advanced NSCLC. the efficacy and safety of EGFR monoclonal antibodies (cetuximab, cetuximab, Erbitux, Erbitux) in combination with chemotherapy with vincristine/cisplatin (NP) and NP. The study was conducted in EGFR-positive stage IIIB and IV NSCLC, and the primary study endpoint was overall survival. The results showed that the OS in the combined cetuximab group was 11.3 months and the 1-year survival rate was 47%, which was a significant difference compared with 10.1 months and 42% in the chemotherapy control group (P=0.044). The study found that cetuximab in combination with NP significantly improved objective remission rates and overall survival, and a prespecified subgroup analysis showed that the efficacy of the combination regimen was independent of tissue type, but the benefit was greater in Caucasians and less pronounced in Asian populations. The E4599 study was a randomized controlled study of a monoclonal antibody to vascular endothelial growth factor (VEGF) (bevacizumab, Avastin, Avastin) in combination with paclitaxel/carboplatin for the treatment of patients with primary advanced non-squamous cancer. A total of 878 patients were treated with paclitaxel/carboplatin chemotherapy alone in the control group. The median survival time was 12.5 months and 10.2 months (P=0.007), progression-free survival time was 6.4 months and 4.5 months, and overall efficiency was 27.2% and 10% in the two groups, respectively. This study showed that first-line treatment with bevacizumab combined with paclitaxel/carboplatin led to a median survival time of more than 1 year (12.5 months) for the first time in this group. Second, based on the excellent performance of EGFR-TKIs such as gefitinib or erlotinib in second-line therapy in a superior population, what is the value of EGFR-TKIs in first-line therapy for this selected group of patients?IPASS is a randomized, open phase III clinical study from multiple Asian countries and regions A total of 1217 patients with stage IIIB/IV NSCLC were enrolled. All patients had not received chemotherapy, had no history of smoking or had smoked lightly, had an ECOG physical status (PS) score of 0 to 2, and had adenocarcinoma on histological examination. After randomization, 609 patients received gefitinib 250 mg/d and 608 patients received carboplatin + paclitaxel (CP regimen). At 22-month follow-up, PFS was significantly better in the gefitinib group than in the CP regimen [hazard ratio (HR) 0.74, P<0.0001]. Notably, PFS was better in the CP group than in the gefitinib group during the first 6 months of treatment, but significantly better in the gefitinib group than in the CP group during the next 16 months. A partial answer to this seemingly unexplained phenomenon was found by biomarker analysis of tumor tissue specimens from the enrolled patients. This phenomenon may be due to the fact that patients with different epidermal growth factor receptor (EGFR) mutation status responded to the two treatments very differently: PFS was significantly better with gefitinib than with chemotherapy in EGFR mutation-positive patients, whereas PFS was significantly better with chemotherapy than with gefitinib in EGFR wild-type patients (both P<0.0001). This difference was also reflected in the ORR: the efficiency of gefitinib treatment was 71.2% in EGFR mutation-positive patients, whereas it was as low as 1.1% in EGFR wild-type patients; the efficiency of paclitaxel/carboplatin chemotherapy was 47.3% in EGFR mutation-positive patients, compared with 23.5% in wild-type patients. Thus, depending on the epidermal growth factor receptor (EGFR) mutation status, conventional chemotherapy was more effective in patients without EGFR mutation during the first 6 months of treatment, but the efficacy of chemotherapy could not be maintained over time, whereas the efficacy of gefitinib was stable over time, and thus the advantage of gefitinib became apparent over time. The investigators noted that a high proportion of nonsmoking adenocarcinoma patients in Asia have EGFR mutations, and that gefitinib first-line treatment in this group of patients results in better regression. Although gefitinib is currently used only for second-line treatment of advanced NSCLC, the IPASS study makes gefitinib a possible new option for first-line treatment in these selected patients. This study suggests that EGFR mutation status is an important predictor of the efficacy of gefitinib in NSCLC, and that EGFR mutation testing is important for selecting patients who will truly benefit from targeted therapy.