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    MTE 09 - Treatment of Advanced SCLC Including Second Line (Ticketed Session) (ID 61)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Small Cell Lung Cancer
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 - 08:00, 708+710+712
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      MTE09.02 - Treatment of Advanced SCLC Including Second Line (ID 1991)

      07:00 - 08:00  |  Author(s): T. Jiang

      • Abstract
      • Presentation
      • Slides

      Lung Cancer is the leading cause of cancer-related death[1]. Small-cell lung cancer accounts for about 15-20% of lung cancer[2]. Although SCLC is chemosensitive, majority of SCLC patients develop disease progression soon after the first line therapy and need 2[nd] line therapy. However, over the past decades, most studies have failed and there is no substantial progress in second-line therapy for SCLC[3]. Topotecan remains 2[nd] line therapy for SCLC patients with sensitive relapse. 1. Targeted therapy Almost all of the studies focused on the molecular targeted therapy for second-line treatment of SCLC were failed. However, in a recent randomized phase II trial (CALGB 30504) of chemotherapy with or without maintenance sunitinib for untreated extensive-stage SCLC, the primary end point [progression-free survival (PFS)] was met for maintenance sunitinib than placebo [median PFS: 3.7 vs 2.1 months; hazard ratio (HR), 1.62; 95% confidence interval (CI), 1.02 to 2.60; P = 0.02]. Overall survival (OS) in maintenance group was also better than in placebo (median OS: 9.0 vs 6.9 months; HR, 1.28; 95% CI, 0.79 to 2.10; P = 0.16). This result suggested that maintenance sunitinib was safe and improved PFS in extensive-stage SCLC[4]. 2. Topotecan Single-agent chemotherapy such as topotecan, paclitaxel, docetaxel, irinotecan, gemcitabine, ifosfamide, vinorelbine and temozolomide have been studied in 2[nd] line therapy of SCLC. But single agent topotecan is the only second-line therapy approved by the U.S. Food and Drug Administration for the treatment of relapsed SCLC. Both oral and intravenious topotecan could significantly improve PFS and OS compared with placebo. Compared with cyclophosphamide, doxorubicin, and vincristine (CAV) regimen in relapsed SCLC patients (n = 211), topotecan produced comparable efficacy but poorer quality of life [5]. Toxicity of topotecan could not be tolerated in many patients. 3. Amrubicin Anthracyclines, including doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone, have been studied in 2[nd] line therapy of SCLC. Tumor response rate ranged from 0% to 20%. Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, has shown promising activity in SCLC. In ACT-1 trial, amrubicin failed to improve OS compared with topotecan but an improvement in OS was noted in patients with refractory disease treated with amrubicin[6]. 4. Immunotherapy Monoclonal antibodies again immune checkpoint inhibitors including ipilimumab, nivolumab and pembrolizumab have been approved as therapy of some solid tumors including melanoma, non-small cell lung cancer (NSCLC), and also studied in SCLC. In the phase Ib KEYNOTE-028 study, SCLC patients who were failure of or inability to receive standard therapy with PD-L1 positivity received pembrolizumab 10 mg/kg, the overall survival rate (ORR) was 35% and safety profiles were consistent with previous studies[7]. Another two trials to explore the efficacy of combination of pembrozulimab and chemotherap/ radiotherapy for extensive-stage SCLC are ongoing (NCT02359019 and NCT02402920). Ipilimumab is a fully human IgG1 cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) monoclonal antibody[8]. In the phase I/II CheckMate-032 study, SCLC patients with progressive disease after > 1 prior line of therapy received nivolumab + ipilimumab or nivolumab monotherapy. The combination or monotherapy showed activity and durable response in SCLC patients who progressed after > 1 prior line of therapy and safety profile was consistent with other tumor types. Unlike NSCLC, second-line therapy has a little progress in SCLC. Second-line treatment for SCLC should be based on the time of recurrence, the reaction and toxicity of first-line chemotherapy, and performance status (PS). A patient’s response to first-line treatment and the duration of the subsequent progression-free period influences the likelihood that a patient will respond to second-line chemotherapy[9]. Tumors that are refractory to first-line chemotherapy or relapse within 60 to 90 days are considered chemoresistant. Tumors whose response to first-line therapy exceeds 60 to 90 days are considered to be chemosensitive and the recommended second-line therapy is the single agent chemotherapy. Topotecan is the optimal choice. Patients in whom response to first-line therapy is maintained for longer than 180 days are likely to benefit from retreatment with prior etoposide/platinum chemotherapy[10]. Immunotherapy in SCLC is widely studied now. References [1] Siegel R, Ma J, Zou Z and Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29. [2] Arcaro A. Targeted therapies for small cell lung cancer: Where do we stand? Crit Rev Oncol Hematol 2015; [3] Spigel DR and Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thorac Oncol 2013;8:587-98. [4] Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, et al. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). J Clin Oncol 2015;33:1660-5. [5] von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658-67. [6] von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014;32:4012-9. [7] A Potential Immune Therapy for Mesothelioma. Cancer Discov 2015; [8] Sharma P and Allison JP. The future of immune checkpoint therapy. Science 2015;348:56-61. [9] Giaccone G, Donadio M, Bonardi G, Testore F and Calciati A. Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 1988;6:1264-70. [10] Metro G and Cappuzzo F. Emerging drugs for small-cell lung cancer. Expert Opin Emerg Drugs 2009;14:591-606.

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