Whether at the American Society of Clinical Oncology (ASCO) annual meeting this year or at the recently concluded World Conference on Lung Cancer, the battle cry of individualized therapy has been sung and deeply rooted in people’s hearts, and the selection of chemotherapy regimen based on pathological histological type is no longer a dream. In the journey of individualized therapy, there is a great ambition of “the sound of apes crying on both sides of the river is inexhaustible, and the light boat has already passed ten thousand mountains”. However, when we think about it calmly, our current understanding of individualization is only the tip of the iceberg, and many obstacles have restricted the improvement of efficacy and survival of lung cancer patients, so there is still a long way to go to achieve true individualized treatment. If small molecule tyrosine kinase inhibitors (TKI) are the most active drugs in molecular targeted therapy research in the 21st century, then pemetrexed is the most promising drug in a chemotherapy platform with a history of more than 60 years, and the three studies involved, whether in the first-line JMDB study (pemetrexed/cisplatin vs. (pemetrexed vs. docetaxel) or the maintenance JMEN study (pemetrexed vs. best supportive care), showed superior efficacy of pemetrexed in non-squamous non-small cell lung cancer (NSCLC) compared to previous studies. A Meta-analysis of these three phase III randomized clinical studies by Soagliotti et al. at this year’s World Lung Cancer Congress also showed that the benefit of pemetrexed in patients with non-squamous NSCLC was consistent and reproducible across all lines of treatment. However, throughout the 3 studies, although pemetrexed improved median survival for first- and second-line treatment of nonsquamous NSCLC (11.0 months vs. 10.1 months and 9.3 months vs. 8.0 months, respectively), it still hovered around 1 year, and median survival in the pemetrexed group in the maintenance treatment study, although more prolonged (5 months), was in contrast to the placebo control group rather than the delayed pemetrexed treatment group, a lingering shadow in several maintenance therapy studies to date, including the SATURN trial. If gemcitabine + cisplatin is chosen as first-line treatment according to the JMDB study, progression-free survival is 5.1 months, and when second-line treatment after failure is chosen, pemetrexed from the JMEI study, median survival is 9.3 months, and the two together are 14.4 months, which is close to the overall survival of 15.5 months with pemetrexed maintenance therapy from the JMEN study. Thus, although the discovery of the selectivity of different pathological histological types for treatment options with pemetrexed is a major advance in the treatment of non-small cell lung cancer in recent years, if we were limited to this, we would be in a new therapeutic bottleneck. Therefore, the selection of specific chemotherapy regimens based on the expression status of thymidine synthase (TS), RRM1, ERCC1, etc. may be the real hope to break the chemotherapy bottleneck. We look forward to the emergence of more effective drug target genes, the results of prospective multicenter randomized clinical studies with strict stratification according to the above molecular markers, and the establishment of standardized and routine testing platforms for TS and other drug target genes. Follow-up treatment after failure of first-line TKI therapy: what can we say? The IPASS study has deservedly become a milestone for individualized targeted therapy in NSCLC, and since then, any clinical trial without patient selection will be met with a red light. However, what is the best treatment option for patients with EGFR mutations after failure of TKI therapy? Platinum-containing combination regimens? Single-agent second-line chemotherapy? Chemotherapy combined with targeted therapy? We are in a new dilemma. Perhaps if the IPASS study had alternated between the two regimens (gefitinib and platinum-containing regimens) in the follow-up, the results would have been more valuable. We are now waiting to see the results of the phase III clinical trial (SLCG study) led by Rossel, which randomized patients with EGFR mutations to erlotinib or platinum-containing regimens, and then exchanged the regimens after failure of both. The results answer at least two questions: (1) Which treatment modality is better: TKI→chemotherapy or chemotherapy→TKI for those with EGFR mutations? (2) Which platinum-containing regimen will have better efficacy after TKI failure? We are also looking forward to the results of the clinical study of EGFR mutated patients receiving chemotherapy + anti-tumor vascular agents or cetuximab after failure of TKI treatment. Targeted drugs other than TKI: “target but not target” In recent years, the development of targeted drugs can be said to be incessant, but except for small molecule TKI, the targets of most drugs such as bevacizumab and cetuximab are only theoretical targets, if we cannot find the relationship between the genetic variants of these target sites and the efficacy of the drugs, and effectively screen the appropriate treatment population. If we cannot find the relationship between the genetic variation of these target sites and drug efficacy, effectively screen the suitable treatment population, and select the treatment plan only based on the clinicopathological characteristics or treatment response (such as the appearance of non-squamous cancer, skin rash, hypertension, etc.), it will be difficult to get out of the embarrassing situation of “target but not target”, which is one of the reasons why most of the targeted drugs are ineffective and difficult to “individualize” their use. This is one of the reasons for the poor efficacy of most targeted drugs and the difficulty of “individualized” drug use. Combined detection and multi-target therapy: limited by technology The various signaling pathways in the cell form an intricate signaling network, and blocking one of them will inevitably cause feedback activation or inhibition of other pathways, so the blocking of a single target is not enough. In recent years, some multi-target drugs and combination therapies targeting different targets have emerged, but the efficacy does not seem to be a qualitative leap, which requires sensitivity testing of each target before treatment to select a more suitable therapeutic population, but at present, the sensitivity testing is often limited to a single site before drug administration, making the population screening bias, and it is difficult to achieve the expected efficacy. High-throughput technologies such as gene microarrays, protein microarrays and tissue microarrays have advantages for multi-target testing, but they are expensive and difficult to promote in clinical settings. Peripheral blood testing: an alternative or trap for tissue specimens Currently, tissue specimens are still the main source of tumor-related information, but for patients with advanced disease onset, tissue specimens are often obtained by puncture, and the amount of tissue is small and reflects less information. studies, FLEX studies, etc.). In addition, the biological characteristics of tumors may have changed after a series of treatments, so only tumor information obtained in real time before each treatment can reflect the characteristics of tumor cells more accurately, and it is much more difficult to obtain tissue specimens in real time. How to find a substitute for tissue specimens for testing has become a hot topic of research. In recent years, it has been reported in the literature that the detection of EGFR mutations in serum or plasma can predict the efficacy. The results of EGFR mutation detection in paired tissues and plasma of 230 patients with advanced NSCLC were analyzed by Peking University Clinical Oncology Institute Center, and the agreement was nearly 78%, which is the largest set of sample size reported so far (the article was published in American Journal of Clinical Oncology). This suggests the feasibility of peripheral blood testing. A study published in the New England Journal of Medicine in 2008 analyzed peripheral blood circulating tumor cells and plasma specimens from 12 patients with advanced NSCLC and showed EGFR mutation rates of 92% and 33%, respectively, suggesting that circulating tumor cells may be a better tissue replacement specimen. Results from a group of studies from Spain at this year’s World Lung Cancer Congress showed that the concordance between EGFR mutations in peripheral blood and tissue was 66%, which is lower than what we reported, but EGFR mutations in blood were significantly associated with time to disease progression (TTP) with TKI therapy. It is unclear whether peripheral blood testing can be an alternative to tissue specimens or not, and there are the following problems with its detection: (1) the concordance with tissue EGFR mutation (including mutation, amplification, expression, etc.) detection is reported to be inconsistent, ranging from 60% to 90%, which is yet to be further confirmed by multicenter, large sample, and prospective studies; (2) the sensitivity and specificity of multiple EGFR mutation detection methods are very different, making Therefore, the optimization and standardization of EGFR variant detection methods in peripheral blood is urgent; (3) whether the release of tumor cells or free DNA into blood can represent the biological behavior of tumor in the primary focus and be monitored in real time is yet to be studied in depth. There is no doubt that the door of individualized treatment for lung cancer has been opened, and as human beings learn more about themselves, individualized treatment for lung cancer and all cancers is getting closer and closer to us. Based on the evidence provided by evidence-based medicine, individualized treatment based on proteomic and genomic discoveries will bring a more profound revolution in the field of cancer treatment. It should be said that the future is bright, but the road is winding, and our current understanding of individualized therapy may only be the tip of the iceberg, which needs to be explored and discovered continuously by medical practitioners in order to break through the current dilemma and enter a better tomorrow of individualized therapy.