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Chao Zhao



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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.10 - Loss of T790M Mutation is Associated with Early Progression to Osimertinib in Chinese Advanced NSCLC Patients Harboring EGFR T790M (ID 13645)

      14:35 - 14:40  |  Author(s): Chao Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib has demonstrated striking superior efficacy in non-small cell lung cancer (NSCLC) patients detected acuqired T790M mutation as resistant mechanism to upfront early-generation EGFR-TKIs. However, not all the T790M positive tumors are homogeneously sensitive to osimertinib, and the duration of response often varies. Previous studies suggest that loss of T790M mutation upon progression is related to decreased therapeutic benefit from osimertinib. The aim of this study is to investigate the association of T790M-mutant status and clinical outcomes after osimertinib treatment in Chinese NSCLC patients harboring acquired EGFR T790M mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed the electric medical records of all patients receiving osimertinib monotherapy after detected acquired T790M mutation in rebiopsy after resistant to prior EGFR-TKIs, and underwent re-rebiopsy again upon progression to osimertinib at our hospital. Detailed clinicopathologic characteristics and response data were collected for all patients.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 2014 to December 2016, 230 patients were confirmed T790M mutation positive for acquired resistance to early-generation EGFR-TKIs (gefitinib, erlotinib, afatinib and icotinib). Among them, 90 patients received osimertinib monotherapy as subsequent treatment. Out of the patients, 84 (93.3%) were eligible for osimertinib-resistance analysis, and 31 (34.4%) patients underwent T790M detection in biopsy after disease progression to osimertinib. The most commonly used biopsy sample were tumor tissue, peripheral blood and hydrothorax. 16 patients remained T790M positive, while 15 patients lost T790M mutation in their re-rebiopsy samples. Loss of T790M upon progression was significantly associated with shorter duration of response to osimertinib (median time 5.93 vs 11.87 m, HR:0.325, 95%CI: 0.087 to 0.45, p=0.0005), while overall survival (OS) was not statistically different between T790M-loss and -remain groups. The objective response rates were also similar in two groups (85% and 100%, respectively). In multivariate analysis, T790M mutation loss remained significantly associated with early progression to osimertinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Loss of T790M mutation was associated early progression to osimertinib in Chinese NSCLC patients harboring acquired T790M mutation. Dynamic detection during osimertinib treatment may be a potential strategy to timely reveal disease progression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.05 - Comprehensive Analysis of Treatment Response and Progression Pattern in Chinese Patients with Different ALK Fusion-Variants (ID 13883)

      14:00 - 14:05  |  Author(s): Chao Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      ALK inhibitors and chemotherapy are two major strategies in the treatment of patients with ALK-rearrangements in China. However, the respective treatment response varies and heterogeneous. This study aimed to comprehensively analyze the impact of ALK variants on different treatment response and explore progression pattern respectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed a cohort of 135 patients with determined ALK variants and medical record from January 2013 to July 2017 in Shanghai Pulmonary Hospital.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1.jpgThe most frequent ALK variant was variant 1 in 62 patients (46%), followed by variant 3a/b in 52 patients (38%) and variant 2 (12%). 69 (51.1%) of patients received chemotherapy, whereas 64 (47.4%) were treated with crizotinib and 2 (1.5%) with alectinib.The similar PFS was observed in patients ALK variant 1 and non-variant 1 regardless of first-line treatment strategy (crizotinib: 15.7 vs. 12.8 months, p=0.53; chemotherapy: 5.7 vs. 8.1 months, p=0.098). However, in the subgroup analysis, patients with ALK variant 1 and baseline brain metastasis had significantly shorter PFS in the first-line setting versus non-variant 1 (4.9 vs. 11.3 months, HR=2.96, p<0.01). Additionally, ORR was 21.6% and 50% in variant 1 and non-variant 1 patients with brain metastases, respectively. Moreover, in the analysis of progression pattern, 55 patients with ALK variant 1 and 57 patients with ALK non-variant 1 exhibited PD. As to ALK variant 1, the incidence of CNS relapse in patients treated with crizotinib was significantly higher than patients treated with chemotherapy (39.3% vs. 7.4%, p=0.005). In terms of ALK non-variant 1,the patients treated with chemotherapy had higher incidence of bone progression than patients treated with crizotinib (25% vs. 0%, p=0.021).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results firstly indicate the treatment-naïve patients with ALK variant 1 and baseline brain metastasis have inferior response to initial cancer treatment. Different ALK variants have distinct landscape of progression pattern when treated with crizotinib or chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.10 - EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies (ID 11863)

      14:35 - 14:40  |  Author(s): Chao Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immuneapproach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-111 - EGFR exon20 Insertion Patients Treated with First-Line Chemotherapy in Non-Small Cell Lung Cancer (ID 14323)

      16:45 - 18:00  |  Presenting Author(s): Chao Zhao

      • Abstract

      Background

      Epidermal growth factor receptor exon20 insertion(EGFR 20-ins) is a low frequency mutation among EGFR mutations, and chemotherapy is a major choice for these patients. The outcomes between different types of EGFR 20-ins and with EGFR sensitive mutation and wild type are not well studied.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From Oct 2011 to Feb 2018, EGFR 20-ins was detected using ARMS method. The mutation positive samples were subsequently confirmed by DNA sequencing. Clinicopathological features and outcomes between different kind of EGFR 20-ins patients as well as EGFR 20-ins patients with EGFR sensitive mutation and wild type patients were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      Eighty-four 20-ins patients were detected in this study. Eight were not enough for DNA sequencing, 11 were wild type and 65 were mutation positive. The three major subtypes were: 28 c.2308_2309insCCAGCGTGG, 9 c.2311_2312insGCGTGGACA and 10 c.2319_2320insAACCCCCAC. Of the 45 patients who could access treatment effect in first-line chemotherapy, objective response rate(ORR) was 28.9%(13/45), disease control rate(DCR) was 86.7%(39/45) and median progression-free survival (mPFS) was 5.7 month. There were no significant differences in sex, age, smoking status, pathological types, ORR, DCR and PFS between c.2308_2309insCCAGCGTGG mutation and other 20-ins mutations. We compared the PFS of EGFR sensitive mutation, wild type and 20-ins patients, and found no significant difference(p=0.324).

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR 20-ins is a distinct EGFR mutation. The clinicopathological features and clinical outcome were not significantly different between different EGFR 20-ins subtypes, as well as between EGFR 20-ins, EGFR sensitive mutation and wild type patients. Target drugs for this kind of patients are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53