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Nagahiro Saijo

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    PL 04 - Closing Plenary: Where We Are Now, and Where We Will Be in 10 Years (ID 587)

    • Event: WCLC 2017
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL 04.02 - Where We Are Now, and Where We Will Be in 10 years: From Asian Perspective (ID 7842)

      16:30 - 17:45  |  Presenting Author(s): Nagahiro Saijo

      • Abstract
      • Presentation
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      Where we are now, and where we will be in 10 years: From Asian Perspective Nagahiro Saijo, MD, PHD, Tokyo Medical University, Kinki University School Medicine Compared with 30 years ago non-small cell carcinoma(NSCLC) became a vast dominant type of lung cancer and majority of clinical trials focus on it. At the end of 20[th] century, effect of platinum doublet containing third generation cytotoxic drugs reached a plateau and thoracic oncologists felt skepticism to achieve the goal in lung cancer treatment. Development of EGFR-TKIs (Gefitinib and Erlotinib) was one of the biggest breakthroughs for rollback of chemotherapy in lung cancer. The EGFR mutation was discovered in 2004 but it took 5 years until there was general agreement that it was an important driver mutation which could predict for response to EGFR-TKI. Evolution of EGFR-TKI proceeds to irreversible 2[nd] (Afatinib and Dacomitinib) and mutation specific 3[rd] generation (Osimertinib) TKIs which can combat the issues of resistance. In Asia more than 50% of adenocarcinoma are EGFR-Mt+ and physicians experienced many long term survivors like surgical treatment in early stage lung cancer. In addition CTONG trial demonstrated that adjuvant EGFR-TKI (Gefitinib) delays recurrence in EGFR-positive surgically resected EGFR-Mt+ NSCLC. WJOG in Japan is conducting exactly the same schedules of trial. There will be a possibility to conduct study of EGFR-TKI combined with chemoradiotherapy in EGFR-Mt+ stage III NSCLC in Asian countries although this strategy was not successful in unselected population. Many driver mutations have been identified and its molecular classification made rapid progress in lung cancer, especially adenocarcinoma. The identification ALK and ROS rearrangement quickly followed by the development of active drugs (Crizotinib, Alectinib, Brigotinib, Lorlatinib ). J-ALEX and ALEX trials clearly showed that Alectinib was extremely active drug against ALK rearranged NSCLC. The Nation Wide Genomic Screening Project (LC-Scrum-Japan) leaded by K Goto has been started on February 2013 in Japan. Under this project many driver mutations have been identified not only in non-squamous cell carcinoma but also in squamous and small cell lung cancer. Many clinical trials are ongoing targeting genomic alterations screened in LC-SCRUM-Japan. Among them LURET trial demonstrated that Vandetanib could show 53% response rate (9/17) in RET+ lung cancer and Crizotinib produced 69% response rate (89/129) in ROS-1+ patients in OxOnc12-01 Asian Global trial. Driver mutation targeted drugs showed dramatic effect compared with standard cytotoxic chemotherapy, however, there is so far no positive data of their combination in spite of clear preclinical synergistic or additive effect. Human RAS oncogenes are the most commonly mutated gene family in Caucasian. About 35% (15% in Asian) of lung cancer are driven by activating mutations of KRAS. RAS is really an oncogenic driver and numerous preclinical studies suggest that KRAS is an excellent and well validated target. However, unlike EGFR, ALK, ROS, there is no effective drugs against KRAS. It will be extremely an important issue to develop KRAS targeting drugs. Robust negative data accumulate in immunotherapy for lung cancer including peptide vaccine therapy. Based on unique idea of Allison J. first immune checkpoint inhibitor, anti-CTLA4 antibody (ipillimumab) produced survival benefit in melanoma. PD-1 was cloned by Honjo T (Japan) on 1992 and antitumor activity of anti-PD-1 antibody was reported on 2002. During past 7 years, immune checkpoint inhibitors have been an exciting new addition to the armamentarium fort lung cancer. Two anti-PD-1 antibodies such as Nivolumab and Pemblolizumab has become a standard for second line treatment of lung cancer based on durable response and marked increase in overall survival. In first line treatment Pemblolizumab prolonged OS and PFS compared with standard chemotherapy in NSCLC with high PD-L1 expression >50% (Keynote024). On the other hand, Nivolumab failed to show PFS benefit compared with cytotoxic agents because of poor patient selection. The most important issue will be how to concentrate responsive population and how to eliminate ineffective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/PFS/OS, responders are experienced even in PD-L1 negative patients. Microsatellite instability has related with response to anti-PD-1 antibody in colorectal cancer. Mutation burden may influence on antigenicity of tumor cells. Infiltration of CD8+ lymphocytes is also considered to be a predictive biomarker but it is too objective for precise quantification. The successful patient selection for immune checkpoint inhibitors may depend on the development of methods for quantitative measurement of tumor specific cytotoxic activity of CD8+ lymphocytes. Can cytotoxic drugs survive as one of the modalities for lung cancer treatment? Combination of cytotoxic drugs and immune checkpoint inhibitors shows promising antitumor activity in lung cancer and gastric cancer. Antibody-drug conjugate (ADC) is a very interesting strategy for effective chemotherapy. DS-8201 targeting HER2, developed by Daiichi-Sankyo showed high response rate and favorable toxicity profile in previously treated HER2 positive gastric and breast cancer. ADC will be a potent strategy in future cytotoxic chemotherapy for lung cancer. Progress in the treatment of small cell lung cancer is very behind because of decrease in absolute number of SCLC patients and no discovery of driver mutations. JCOG conducted serial randomized clinical trials in SCLC. However, treatment result reached a plateau in both of limited and extensive diseases. Discovery of druggable targets in near future may have a significant impact in small cell lung cancer.

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