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• W2898156885 abstract "It is a standard of care to treat patients with non-small cell lung cancer (NSCLC) harboring driver oncogenes with respective tyrosine kinase inhibitors(TKI). The list of the driver genes started with the EGFR gene and now it is further expanding to include ALK, ROS1 and BRAF. Survival of NSCLC patients with EGFR mutations has greatly prolonged since the advent of EGFR-TKI. At the turn of the 21st century, the median survival time of patients with metastatic lung cancer was around on year. However, overall survival of patients with EGFR mutation exceeds 3 years and in some studies, it is close to 4 years. However, acquisition of resistance against EGFR-TKI is almost inevitable and it is exceptional to see patients whose disease are cured. Therefore, although introduction of inhibition of oncogenic tyrosine kinases into lung cancer care was a great progress, it is still on the way from the viewpoint of conquering lung cancer. What is needed for further improving patients’ outcome? Identification of new targets: In addition to above-mentioned driver genes to which each targeted therapy is approved by the regulatory agencies, RET, MET, HER2, NTRK1 gene mutations are emerging molecular targets and clinical trials to test each inhibitor for clinical activities are actively conducted. Gene alterations such as KEAP1/Nrf1 whose mutations are relatively frequent in NSCLC is also sought for possibilities to become a therapeutic target other than receptor tyrosine kinase. Development of strategies to cope with KRAS: Although KRAS gene mutation in NSCLC was found nearly 40 years ago and is frequently mutated in NSCLC especially those occurring Caucasian patients．However despite the fact that KRAS mutation is mutually exclusionary with other driver gene mutations., strategies to treat these lung cancers have been unsatisfactory. For example, recent large-scale, SELECT-1 study failed to show a superiority of addition of selumetinib to docetaxel in patients with KRAS mutation. This is partly because not all KRAS mutated cancer cells are fully addicted to mutated KRAS function. Considering the magnitude of the patient population, efficient strategies to treat KRAS lung cancer including the development of small molecules and immunotherapy are eagerly awaited. Development of mutation-specific and wild-type sparing TKI: Osimertinib is the first third-generation EGFR-TKIs that is active for both activating EGFR mutations as well as T790M resistant mutations yet sparing wild-type EGFR function. As a result, it showed superior activity over chemotherapy for lung cancer with acquired resistance due to T790M. Following this, the Flaura study showed longer PFS compared with gefitinib/erlotinib. OS result is immature but promising. Because of low activity against wild-type EGFR, adverse events are in general less frequent. This will make it easier for this compound to combine with other modality of therapy, although the incidence of interstitial lung disease was high when combined with durvalumab in the Tatton study. In the case of ALK, alectinib showed prominent superiority in terms of PFS to crizotinib in the J-ALEX and ALEX studies, with better tolerability. These facts clearly indicate that newer drugs that have a higher activity against mutated version but not against wild-type version further prolong patient survival. Development of combination strategies: To maximize patients’ benefit, we have to understand the biology of oncogene-driven lung cancer more in detail. When EGFR mutations were initially discovered, NSCLC harboring EGFR mutations were thought to behave similarly in the patients. However, we soon knew that different EGFR mutations may result in different biological/clinical consequences. For example, exon 19 deletion (Del 19) and L858R are sensitizing mutations, exon 20 insertion mutations are resistant against existing TKIs. Other rarer mutations, so-called uncommon mutations are not that as sensitive as Del19. Furthermore, even though with the same EGFR mutation, lung cancer never behaves same in each patient. There is a great heterogeneity in terms of progression-free survival within patients with the same EGFR mutations when treated with EGFR-TKI. This heterogeneity is now being understood as effects of co-occurring genetic alterations (co-drivers). For example, several investigators found that PFS of patients with EGFR mutation plus TP53 mutation has a shorter PFS than those without. These co-occurring alterations that negatively affect PFS include those of CDK2/4, HER2, TP53. Therefore it is clear that EGFR TKI alone will not be able to achieve long-term disease control, necessitating combination strategy. Recently, NEJ009 trial suggested that carboplatin with pemetrexed followed by pemetrexed maintenance plus gefitinib might prolong overall survival up to over 4 years. This illustrates the importance of chemotherapy as well as EGFR-TKI even for patients with driver gene alterations, probably through inhibition of some activities mediated by co-drivers. Role of immunotherapy for NSCLC with driver gene mutations: PD-1 blockade by pembrolizumab is a standard of care for NSCLC with high PD-L1 expression except those with driver mutations. This is because PD-1/L1 antibodies could not derive benefit for the patients with EGFR/ALK alterations over docetaxel, resulting in omission of these patients in the first-line trial except in the case of atezolizumab. IMpower 150 study showed the superiority of carboplatin/paclitaxel/bevacizumab(CPB) plus atezolizumab over CPB not only in wild-type patients but in EGFR/ALK+ cohorts after first-line TKI therapy. It is not very clear this is because of combination with chemotherapy or bevacizumab or both at this point, and also the mechanism of this efficacy is not known. This study re-opened the door to immunotherapy for these patients, which was once almost closed, In this talk, I would like to envision what has to be done in the next 10 years to further improve the outcome of the patients with driver gene and ultimately to cure their disease. Targeted therapy, driver oncogene, combination therapy" @default.
• W2898156885 created "2018-11-02" @default.
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• W2898156885 date "2018-10-01" @default.
• W2898156885 modified "2023-09-25" @default.
• W2898156885 title "PL03.06 The Future of Targeted Therapy" @default.
• W2898156885 doi "https://doi.org/10.1016/j.jtho.2018.08.016" @default.
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