Professor Wu Yilong: "A-T" mode creates the longest OS of EGFR mutation-positive late-stage NSCLC, and treatment tends to be precise.

Professor Wu Yilong deeply interprets the final OS results of nej026 research and the application prospect of "a + T" mode.the appearance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC) with positive EGFR mutation. At the same time, TKI resistance has become a long-term topic that needs to be explored continuously.combined with anti angiogenic therapy is one of the strategies to overcome TKI resistance. The synergistic antitumor effect of bevacizumab combined with erlotinib (a + T) has been confirmed in a number of clinical studies.both the Japanese nej026 study and the domestic ctong1509 study showed that the first-line treatment with a + T regimen can significantly prolong the progression free survival (PFS) of advanced NSCLC patients with EGFR mutation positive.can this mode bring about the overall survival (OS) benefit? At the American Society of Clinical Oncology (ASCO) annual meeting in 2020, the nej026 study released the final OS analysis data."medical community" specially invited Professor Wu Yilong of Guangdong Institute of lung cancer to interpret the results of nej026 clinical study for us, and prospected the future research direction of NSCLC.Click to watch the video of Professor Wu Yilong's interpretation of nej026. The research has reached the main end point and created the longest OS record so far. Medical community: the final OS results of nej026 study were released by ASCO 2020. Can you interpret the research for us? Prof. Wu Yilong: the nej026 study is a phase III clinical trial initiated by Japanese clinical experts. The newly diagnosed advanced NSCLC patients with EGFR mutation positive were divided into two groups. One group was treated with EGFR-TKI alone, and the other group was treated with anti angiogenesis therapy on the basis of EGFR-TKI.there are two main purposes of the study. The first is to explore whether anti angiogenesis therapy can overcome the first generation EGFR-TKI resistance, and the second is to observe whether patients can obtain longer OS.nej026 study confirmed that the combination of bevacizumab and TKI can significantly delay the recurrence time.in clinical practice, the PFS of first generation EGFR-TKI single drug first-line application is about 9-13 months, while the interim analysis results of nej026 study published in 2018 showed that the median PFS of patients receiving a + T treatment reached 16.9 months (control group 13.3 months, P = 0.016), which achieved the first purpose of the study.at this year's ASCO annual meeting, nej026 research released the final OS results.after a median follow-up of 39.2 months, the median OS of group A + t reached 50.7 months (95% CI 37.3 months - not achieved), and 46.2 months (95% CI 38.2 months - not achieved) (HR = 1.00; 95% CI 0.68-1.48), and there was no significant difference between the two groups.Figure 1: the OS results of nej026 study were evaluated mainly on whether the primary endpoint was achieved, because the study did not design the sample size according to the secondary endpoint.the number of patients enrolled in nej026 study can only answer the difference of PFS in primary endpoint, but it is difficult to reveal the difference of OS in secondary endpoint.how should we look at the relationship between OS and PFS? In the nej026 study, the median PFS was 16.9 months, and the median OS was 50.7 months, indicating that the patients survived for a long time after recurrence, even longer than the first stage of treatment, which means that the patients were effectively treated after progression, thus prolonging the OS.however, there were too many influencing factors in the follow-up treatment, resulting in no difference in OS between the two groups.in fact, the a + T model has created the best OS data of patients with EGFR mutation positive NSCLC, so it is of great significance. A + T regimen is more suitable for patients with L858R mutation in exon 21, and the treatment tends to be precise. Medical field: the nej026 study did not show OS benefit in the general population, but there was a trend of OS benefit in some subgroups. combined with the existing research progress of "a + T", what is the application value and Prospect of "a + T" mode in the first-line treatment of advanced NSCLC with EGFR mutation positive? Prof. Wu Yilong: with the development of precision medicine, the current understanding of EGFR is no longer limited to whether there is mutation. For the population with EGFR mutation positive NSCLC, it should be further subdivided into exon 19 deletion, exon 21 L858R mutation and other rare mutations, so as to achieve more accurate treatment and enable patients to obtain longer survival. previous studies found that among the two most common mutations, exon 19 deletion and exon 21 L858R mutation, patients with 19 exon deletion had better response and efficacy to TKI treatment, PFS and OS were longer; patients with L858R mutation in exon 21 developed drug resistance more quickly and had shorter OS. however, subgroup analysis of nej026 study found that patients with L858R mutation in exon 21 showed more benefit than patients with deletion of exon 19. Figure 2: OS analysis of nej026 subgroup shows that a + T mode has better effect on L858R mutation in exon 21, so does it mean that L858R mutation in exon 21 is suitable for a + T treatment? In fact, a number of studies, including ctong1509 research conducted in China, have also confirmed that a + T mode has better efficacy in patients with L858R mutation in exon 21. therefore, the a + T mode lays the foundation for more accurate treatment. For patients with L858R mutation in exon 21, using a + T mode may bring more benefits. active response and active change are the important development direction of the treatment of EGFR mutation NSCLC in the future. Medical community: under the situation that traditional radiotherapy and chemotherapy, targeting, immunity and other treatment methods are in full bloom, what are the important research directions for EGFR mutation population in the future? Prof. Wu Yilong: on the way to explore the treatment of NSCLC with EGFR mutation, we need to improve the deficiencies. after TKI resistance, it is necessary to explore the mechanism of drug resistance and find ways to overcome drug resistance. after decades of development, there have been three generations of EGFR-TKI drugs. One of the future development directions is to clarify the drug resistance mechanism and create new compounds to overcome drug resistance after the third generation of TKI resistance. the human struggle against EGFR mutant NSCLC will continue for a long time. By constantly seeking new treatment methods, we can ensure that there are other treatments after one drug resistance, so as to prolong the survival of patients. the second direction is to actively adopt methods to overcome drug resistance in the early stage, such as the development of combination therapy, including targeted anti angiogenesis, targeted combination chemotherapy, etc. this year, the combination of the first generation TKI and the third generation TKI (1 + 3) has also appeared. Since the third generation TKI will have the c797s mutation after resistance, and the c797s mutation is sensitive to the first generation TKI, so the combination of the two is expected to overcome the mutation resistance of c797s. The preliminary research results show that 1 + 3 treatment has a good prospect. the third direction is to develop new drugs for old targets. for example, in recent years, antibody coupled drugs with sudden emergence have played a very important role in some rare mutations. the fourth direction is to apply the most advanced methods such as immunotherapy to EGFR mutation patients. at present, preliminary studies have found that the side effects of simple targeted combined immunotherapy are relatively large, but in the future, we can explore immunotherapy methods for some specific populations, or further seek new immune combination methods, etc. the role of small node a + T mode in delaying EGFR-TKI resistance has been widely recognized. Although the a + T combination therapy in nej026 has no difference in OS compared with erlotinib monotherapy in the general population, it shows a benefit trend in women, non-smokers, and L858R mutation in exon 21, which lays the foundation for stratified treatment of advanced NSCLC with EGFR mutation positive. and the a + T mode achieved a median OS of 50.7 months, which exceeded the OS data of most of the existing first-line treatment schemes. It is a good treatment for EGFR mutation positive patients. for EGFR mutation population, the future development direction includes targeted combined chemotherapy, "1 + 3" combined targeted therapy, antibody coupled drug therapy and immunotherapy, etc., expecting to bring more new breakthroughs. Prof. Wu Yilong, Professor of oncology, doctoral supervisor, winner of IASLC outstanding science award, President of the World Lung Cancer Congress 2020 (wclc), lifelong director of Guangdong Provincial People's Hospital (GGH), honorary director of Guangdong Provincial Institute of lung cancer (glci), director of Guangdong Provincial Key Laboratory of lung cancer translational medicine Chairman, Guangdong clinical trial Association (GACT), chairman of Lung Cancer Society of Guangdong Medical Association, chairman of ctong, former president of CSCO