Experimental approaches to treatment for small cell lung cancer
- Karen Kelly, MD
Karen Kelly, MD
- Professor of Medicine
- University of California Davis Cancer Center
- Section Editors
- Rogerio C Lilenbaum, MD, FACP
Rogerio C Lilenbaum, MD, FACP
- Section Editor — Lung Cancer
- Yale Cancer Center
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
Small cell lung cancer (SCLC) is distinguished from non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of metastases. Although SCLC is highly responsive to both chemotherapy and radiotherapy (RT), it commonly relapses within months despite treatment.
Since SCLC usually presents with disseminated disease, treatment strategies have focused on systemic chemotherapy. Although this has resulted in significant improvements in survival for patients with both limited- and extensive-stage disease, the long-term prognosis remains poor.
Attempts to further improve survival with chemotherapy have included the evaluation of higher-dose therapy including bone marrow transplantation, dose-dense regimens, alternating non-cross resistant treatments and novel cytotoxic agents. However, these approaches have not resulted in major advances in the treatment of SCLC in more than twenty years. (See "Extensive stage small cell lung cancer: Initial management", section on 'Increased dose intensity'.)
Investigational approaches for the treatment of SCLC will be reviewed here. Standard approaches to chemotherapy in patients with SCLC are discussed separately. (See "Extensive stage small cell lung cancer: Initial management" and "Treatment of refractory and relapsed small cell lung cancer".)
Multiple immunotherapy approaches have been studied in patients with SCLC and are discussed in detail elsewhere. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Immunotherapy'.)
- Fontanini G, Faviana P, Lucchi M, et al. A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma. Br J Cancer 2002; 86:558.
- Salven P, Ruotsalainen T, Mattson K, Joensuu H. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 1998; 79:144.
- Gitlitz BJ, Moon J, Glisson BS, et al. Sorafenib in platinum-treated patients with extensive stage small cell lung cancer: a Southwest Oncology Group (SWOG 0435) phase II trial. J Thorac Oncol 2010; 5:1835.
- Sharma N, Pennell N, Halmos B, et al. Phase II trial of sorafenib combined with chemotherapy and as maintenance therapy in extensive stage small cell lung ancer - Final Results. J Thorac Oncol 2012; :7SS337.
- Han JY, Kim HY, Lim KY, et al. A phase II study of sunitinib in patients with relapsed or refractory small cell lung cancer. Lung Cancer 2013; 79:137.
- Schneider BJ, Gadgeel SM, Ramnath N, et al. Phase II trial of sunitinib maintenance therapy after platinum-based chemotherapy in patients with extensive-stage small cell lung cancer. J Thorac Oncol 2011; 6:1117.
- Spigel DR, Greco FA, Rubin MS, et al. Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer. Lung Cancer 2012; 77:359.
- Ready NE, Pang HH, Gu L, 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.
- Ramalingam SS, Belani CP, Mack PC, et al. Phase II study of Cediranib (AZD 2171), an inhibitor of the vascular endothelial growth factor receptor, for second-line therapy of small cell lung cancer (National Cancer Institute #7097). J Thorac Oncol 2010; 5:1279.
- Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 2007; 25:4278.
- Sanborn RE, Patel JD, Masters GA, et al. A randomized double-blind phase II trial of platinum (P) plus etoposide (E) with or without concurrent ZD6474 (Z) in patients (pts) with previously untreated extensive-stage (ES) small cell lung cancer (SCLC): Hoosier Oncology Group LUN06-113 (abstract 7506). 2014 American Society of Clinical Oncology meeting.
- Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011; 29:2215.
- Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 2009; 27:6006.
- Ready NE, Dudek AZ, Pang HH, et al. Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study. J Clin Oncol 2011; 29:4436.
- Tiseo M, Boni L, Ambrosio F, Camerini A. Italian multicenter phase III randomized study of cisplatin-etoposide with or without bevacizumab as first-line treatment in extensive stage small cell lung cancer (SCLC): GOIRC-AIFA FARM6PMFJM trial. J Clin Oncol 2016; 34S: ASCO #8513.
- Pujol JL, Lavole A, Quoix E, et al. Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†. Ann Oncol 2015; 26:908.
- Allen JW, Moon J, Redman M, et al. Southwest Oncology Group S0802: a randomized, phase II trial of weekly topotecan with and without ziv-aflibercept in patients with platinum-treated small-cell lung cancer. J Clin Oncol 2014; 32:2463.
- Pujol JL, Breton JL, Gervais R, et al. Phase III double-blind, placebo-controlled study of thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: an intergroup study FNCLCC cleo04 IFCT 00-01. J Clin Oncol 2007; 25:3945.
- Lee SM, Woll PJ, Rudd R, et al. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst 2009; 101:1049.
- Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol 2015; 16:395.
- Pandya KJ, Dahlberg S, Hidalgo M, et al. A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol 2007; 2:1036.
- Nakanishi Y, Mulshine JL, Kasprzyk PG, et al. Insulin-like growth factor-I can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro. J Clin Invest 1988; 82:354.
- Belani CP, Dahlberg SE, Rudin CM, et al. Three-arm randomized phase II study of cisplatin and etoposide (CE) versus CE with either vismodegib (V) or cixutumumab (Cx) for patients with extensive stage-small cell lung cancer (ES-SCLC) (ECOG 1508) (abstract 7508). 2013 American Society of Clinical Oncology meeting.
- Park KS, Martelotto LG, Peifer M, et al. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat Med 2011; 17:1504.
- Schneider BJ, Kalemkerian GP, Ramnath N, et al. Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-Kit-positive, extensive-stage small-cell lung cancer. Clin Lung Cancer 2010; 11:223.
- Miller AA, Pang H, Hodgson L, et al. A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). J Thorac Oncol 2010; 5:380.
- Moore AM, Einhorn LH, Estes D, et al. Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial. Lung Cancer 2006; 52:93.
- Rudin CM, Kozloff M, Hoffman PC, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004; 22:1110.
- Rudin CM, Salgia R, Wang X, et al. Randomized phase II Study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol 2008; 26:870.
- Paik PK, Rudin CM, Pietanza MC, et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer 2011; 74:481.
- Zhang S, Cordon-Cardo C, Zhang HS, et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides. Int J Cancer 1997; 73:42.
- Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 2005; 23:6854.
- Bottomley A, Debruyne C, Felip E, et al. Symptom and quality of life results of an international randomised phase III study of adjuvant vaccination with Bec2/BCG in responding patients with limited disease small-cell lung cancer. Eur J Cancer 2008; 44:2178.
- McCann J, Fossella FV, Villalona-Calero MA, et AL. Phase II trial of huN901-DM1 in patients with relapsed small cell lung cancer (SCLC) and CD56-positive small cell carcinoma (abstract). J Clin Oncol 2007; 25:690s.
- Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res 2006; 12:878.
- Rudin CM, Pietanza MC, Bauer TM, et al. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). J Clin Oncol 2016; 34S: ASCO #LBA8505.
- Lovly CM, Li C, Hutchinson AS, et al. A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (abstract #7094). J Clin Oncol 2012.
- Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012; 44:1104.
- ANGIOGENESIS INHIBITORS
- Oral angiogenesis inhibitors
- Anti-VEGF antibodies
- MOLECULARLY TARGETED THERAPIES
- Aurora A kinase inhibitor
- PARP inhibitors
- Other agents
- PI3K/Akt/mTOR inhibitors
- - IGF-1R inhibitors
- - Hedgehog inhibitors
- - Tyrosine kinase inhibitors
- - Apoptosis modulators
- Other classes of molecular therapies
- Tumor vaccines
- Other immunotherapy approaches
- CYTOTOXIC CHEMOTHERAPY
- Rovalpituzumab tesirine