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    ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      ES 09.03 - Immunotherapy (ID 7621)

      14:30 - 16:15  |  Author(s): M. Qiao

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.

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    MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)

      11:00 - 12:30  |  Author(s): M. Qiao

      • Abstract
      • Presentation
      • Slides

      Background:
      Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.

      Method:
      Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.

      Result:
      Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways

      Conclusion:
      Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-010 - Impact of Clinicopathological Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients with Previously Treated Non-Small Cell Lung Cancer (ID 8099)

      09:30 - 16:00  |  Author(s): M. Qiao

      • Abstract

      Background:
      The current study aimed to comprehensively investigate the impact of various clinicopathological features on the efficacy of programmed cell death 1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non-small cell lung cancer (NSCLC).

      Method:
      Randomized controlled trials that compared PD-1/PD-L1 inhibitors monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included.

      Result:
      Five trials were included (n = 3025). For all studies, PD-1/PD-L1 inhibitors significantly prolonged overall survival (OS) [hazard ratio (HR) = 0.70; P < 0.001] and progression-free survival (PFS) than chemotherapy (HR = 0.86; P = 0.020). Subgroup analysis showed that anti-PD-1/PD-L1 monotherapy could markedly improve OS in elderly (HR = 0.69; P < 0.001), female (HR = 0.70; P < 0.001), never-smoking (HR = 0.73; P = 0.001) and histology of squamous cell carcinoma (HR = 0.67; P < 0.001) patients but not PFS. Notably, PD-1/PD-L1 inhibitors can not prolong both the OS (HR = 0.76; P = 0.390) and PFS (HR = 0.74; P = 0.210) of patients with central nervous system (CNS) metastasis whereas patients without CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy on OS (HR = 0.71; P < 0.001).

      Conclusion:
      PD-1/PD-L1 inhibitors monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Elderly, female, never-smoking and histology of squamous cell carcinoma patients could also benefit from PD-1/PD-L1 inhibitors monotherapy on OS. However, whether patients with CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy remains further validation.