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N. Murray



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    GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      GR03.01b - Systemic Therapy of Extensive Stage Small Cell Lung Cancer (SCLC): Contrasting Therapeutic Principles for SCLC and Non-small Cell Lung Cancer (NSCLC) in 2015 (ID 1839)

      14:40 - 15:00  |  Author(s): N. Murray

      • Abstract
      • Presentation

      Abstract:
      Since the 1960’s, SCLC has been recognized as a distinct lung cancer subtype with unique sensitivity to chemotherapy and radiotherapy. Indeed SCLC and NSCLC are generally discussed as separate topics. After 50 years of investigation, it may be useful to recognize similarities as well as differences in therapeutic principles for systemic therapy. For metastatic disease, palliative first-line systemic therapy for SCLC and NSCLC patients without a drugable driver mutation is a platinum-based two drug chemotherapy combination. For SCLC, platinum and etoposide has generally prevailed as standard although platinum plus irinotecan is widely used in Asia. The platinum doublet used for first-line chemotherapy for NSCLC has had a more complex evolution with many variations, however, the evidence for improved survival with modern platinum doublets can be questioned, even for non-squamous cancers.(1) In both pathologic types, single agents or dose attenuation with first-line therapy result in inferior outcomes. Three and four drug chemotherapy regimens are not better than two drug regimens. Dose-dense and high dose cytotoxic regimens do not generate superior survival results. Non-platinum regimens are not superior to platinum-based two drug combinations. Four to six cycles of first-line therapy is sufficient for most patients. Maintenance chemotherapy is not recommended for SCLC whereas it is an option for NSCLC that confers a survival advantage if patients fail to receive second-line therapy. Second-line treatment for both types of lung cancer is single agent chemotherapy and the survival benefit is worthwhile but modest. Topoisomerase-1 inhibitors have been extensively investigated and used in SCLC. Docetaxel is standard second-line therapy for squamous cancers whereas docetaxel and pemetrexed have equal efficacy in second-line chemotherapy of non-squamous cancers. For both types of lung cancer, second-line chemotherapy is usually unrewarding for cases progressing on first-line chemotherapy or relapsing within less than three months as these tumors have demonstrated chemotherapy resistant biology with response rates of about 10%. Tumors that are sensitive to first-line chemotherapy with a long time to progression are somewhat more tractable with second-line therapy. Third line chemotherapy is not evidenced-based for either SCLC or NSCLC, but may be a reasonable option in selected patients that have responded to second-line treatment. The survival outcome for metastatic SCLC and metastatic NSCLC (without EGFR or ALK mutations) is similar with a median survival of 11-12 months and a two-year survival of 5-10%. Although the initial response rate of SCLC of 60-70% is about double that of NSCLC, the median time for chemotherapy resistant clones to cause a fatal outcome is about the same for both diseases. Without doubt, the natural history of metastatic lung cancer unrestrained by any chemotherapy is worse for SCLC than NSCLC. With respect to trials of SCLC with new chemotherapy agents, it is important to recognize themes of investigation that have been unrewarding. Generally speaking, analogues of active drugs have failed to show evidence of improved survival compared to the parent compounds. This has been shown for alkylating agents, platinum compounds, vinca alkaloids, epipodophylotoxins, and anthracyclines. Moreover, randomized trials have demonstrated statistically significantly inferior survival outcomes for two novel analogues when compared to regimens considered to be standard-of-care. The folate antagonist pemetrexed was studied in a phase III trial of first-line chemotherapy. The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) randomized pemetrexed/ cisplatin versus etoposide/ cisplatin.(2) Accrual was terminated early by the data safety and monitoring committee. Survival was inferior in the pemetrexed-platinum arm (median survival 8.1 months) compared to 10.6 months for etoposide-cisplatin (p <0.01). Time to progression (TTP) and response rates (RR) were worse as well. The inferior result was not explained by thymidylate synthase expression or other folate pathway biomarkers.(3) Pemetrexed is simply a bad drug for treatment of SCLC. Similarly, the taxane analogue cabizitaxel was tested in the second-line setting against topotecan.(4) Cabizitaxel was signifantly inferior to topotecan for RR, TTP and survival. This result stands as another example of analogue investigation failure and makes one wonder about the use of any taxane in SCLC. The discovery of treatable molecular targets in adenocarcinomas with approved drugs is a conspicuous difference in systemic therapy of NSCLC compared to SCLC. No molecular targets that can be treated with drugs with proven efficacy have as yet been approved for SCLC.(5) This is not due to a lack of trying. A large number of molecular targeted agents have already been studied in SCLC without a signal of sufficient activity to continue development.(6) The roster includes pathways suggested by analysis of the SCLC genome but numerous other molecular targeted drugs of interest in other cancers were also tested. Drugs with better efficacy may be identified by more extensive SCLC genome analysis,(5) but there is no escaping the fact that results reported to date have been disappointing. Data from genome analysis have shown a bewildering array of abnormalities in this tobacco hyper-mutated tumor. Like squamous carcinomas, the SCLC molecular battlefield is bleak and complex with little opportunity for even temporary respite by identification of mutually exclusive oncogenic drivers. An intriguing possibility is that the numerous mutations in SCLC may be an asset for immunotherapy studies. Checkpoint inhibition has already been demonstrated superior to standard of care in second-line therapy of both squamous (8) and non-squamous NSCLC.(9) At ASCO 2015, two phase II studies of immunotherapy in previously treated SCLC were presented and the results are provocative. Nivolumab produced a RR of 18% and nivolumab plus ipilumimab had a RR of 17% in a population unselected for PD-L1 positivity.(10) In patients selected for PD-L1 positivity, pembrolizumab produced responses in 35%.(11) Although data is preliminary, some responses in these immunotherapy studies may be long-lasting. . The therapeutic principles of systemic therapy of SCLC and NSCLC may be converging again with immunotherapy becoming the most exciting advance in both histologic types. References (1) Murray N. Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2014 Feb 10;32(5):482-483. (2) Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2009 October 1;27(28):4787-4792. (3) Smit EF, Socinski MA, Mullaney BP, Myrand SP, Scagliotti GV, Lorigan P, et al. Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Ann Oncol 2012 Jul;23(7):1723-1729. (4) Evans TL, Kim J, Shepherd FA, Syrigos KN, Udud K, Chubenko V, et al. Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. ASCO Meeting Abstracts 2013 June 17;31(15_suppl):TPS7609. (5) Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 Oct;44(10):1111-1116. (6) Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer Sheffield: European Respiratory Society; 2015. p. 234. (7) Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015 May 31. (8) Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2015 June 22;33(18_suppl):LBA109. (9) Antonia SJ, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7503. (10) Ott PA, Fernandez MEE, Hiret S, Kim D, Moss RA, Winser T, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7502.

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    MINI 37 - SCLC Therapy (ID 165)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI37.13 - Discussant for MINI37.10, MINI37.11, MINI37.12 (ID 3446)

      19:40 - 19:50  |  Author(s): N. Murray

      • Abstract
      • Presentation

      Abstract not provided

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