Last year, there were only one generation of targeted therapy for lung cancer, but recently, the second and third generation drugs have been approved, and while patients are happy, the most frequently asked question is: What is the difference between these drugs? How should I choose? Is there an order for choosing targeted therapy drugs? Which drug has the best efficacy? To answer the above questions, first of all, we need to clarify which drugs are the first, second and third generation drugs and what are the differences. Cancer is essentially a genetic disease and all cancers originate from genetic mutations, which cause cancer cells to appear and grow. Although it is difficult to turn mutated genes into normal genes, it is possible to stop the growth of cancer cells by interrupting their signaling with drugs. This treatment is known as targeted therapy, which means that the drug is like a bullet that is aimed at the target and binds precisely to the target, thus locking it in place. The emergence of targeted therapy has greatly prolonged the life of patients with advanced lung cancer, and the side effects are far less than those of chemotherapy, and the efficacy is also better than that of chemotherapy, which has the effect of enabling patients to live longer and better. The earliest targeted drugs for lung cancer are known as the first generation of targeted therapies, including gefitinib, erlotinib, and erlotinib. These drugs did not bind firmly to their targets and separated after binding for a period of time, so they were called reversible targeted drugs. The second-generation targeted drugs, represented by afatinib, will irreversibly bind to the target, permanently locking the target and preventing it from “doing evil”, while the second-generation has a wider range of targets than the first-generation. Third-generation targeted drugs act on specific genetic mutations (T790M) that are resistant to first- or second-generation targeted drugs, and have a high degree of specific mutation selectivity. First-, second- and third-generation targeted drugs are suitable for different populations, and therefore are not used in a simple order of 1, 2 and 3. First- and second-generation targeted agents have similar populations and are used for the initial treatment of patients. Second-generation targeted agents show better efficacy than first-generation, while third-generation targeted agents are used for patients who have developed specific drug-resistant mutations after receiving treatment with first- or second-generation targeted agents. Professor Wu Yilong, director of Guangdong Lung Cancer Research Institute and director of Guangdong People’s Hospital Cancer Center, a renowned expert in lung cancer treatment in China, emphasized, “Although second-generation targeted therapies are available later than first-generation ones, it is not true that we should use second-generation only when first-generation treatment fails. We can use second-generation drugs from the beginning for patients who are suitable for targeted therapy, because the efficacy of second-generation drugs is very robust, both from clinical study results and from daily treatment, and for the first time, they have been shown to improve overall survival rates. The third-generation drugs should now be used after resistance to first- and second-generation drugs, which mainly target the T790M mutation type.” Clinical studies show that the second-generation targeted drug afatinib can significantly reduce the risk of tumor progression by 26% and the risk of treatment failure by 26% compared with the first-generation drug gefitinib, and the effect of tumor shrinkage is 70% for afatinib and only 56% for gefitinib, which is still a very obvious difference, while the adverse effects of both drugs are similar and there is no significant difference. The above mentioned lung cancer first, second and third generation targeted therapies are briefly summarized as follows: first generation is reversible, second generation is irreversible, third generation is selective; first and second generation are used for initial treatment, while third generation is used after first or second generation. To make an analogy, targeted therapy for lung cancer is like a soccer game, in order to achieve the final victory, the coach will always send the newly introduced strong players on the field first. The third-generation drugs are for the replacement of players in specific positions on the field, and are for the replacement of players in these specific positions when they are physically weak. As for what kind of patients are suitable for targeted therapy, it still depends on the results of genetic testing. Therefore, patients with advanced lung cancer must undergo genetic testing before deciding on a treatment plan, and generation 1 and generation 2 drugs can be used for all patients with positive EGFR gene mutations. Patients should not miss the opportunity because they did not undergo genetic testing.