Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?
Authors: Paul A. Bunn, John D. Minna, Alexander Augustyn, Adi F. Gazdar, Youcef Ouadah, Mark A. Krasnow, Anton Berns, Elisabeth Brambilla, Natasha Rekhtman, Pierre P. Massion, Matthew Niederst, Martin Peifer, Jun Yokota, Ramaswamy Govindan, John T. Poirier, Lauren A. Byers, Murry W. Wynes, David G. McFadden, David MacPherson, Christine L. Hann, Anna F. Farago, Caroline Dive, Beverly A. Teicher, Craig D. Peacock, Jane E. Johnson, Melanie H. Cobb, Hans-Guido Wendel, David Spigel, Julien Sage, Ping Yang, M. Catherine Pietanza, Lee M. Krug, John Heymach, Peter Ujhazy, Caicun Zhou, Koichi Goto, Afshin Dowlati, Camilla Laulund Christensen, Keunchil Park, Lawrence H. Einhorn, Martin J. Edelman, Giuseppe Giaccone, David E. Gerber, Ravi Salgia, Taofeek Owonikoko, Shakun Malik, Niki Karachaliou, David R. Gandara, Ben J. Slotman, Fiona Blackhall, Glenwood Goss, Roman Thomas, Charles M. Rudin, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2016)

Despite the paucity of therapeutic advances in SCLC, considerable progress in understanding its biology, molecular biology, model systems, and potential therapeutic targets has been made (Fig. 4 and Table 1). Studies of early lung and neuroendocrine cell development models have provided insights into the cell of origin for SCLC. New GEMMs have illustrated the universal importance of TP53 and RB1 gene mutations in the pathogenesis of SCLC and the potential role of additional genetic changes as well as changes in transcription factor expression. PDXs and CDXs provide new means for preclinical testing of new therapies. Molecular studies have identified the high mutation burden found in SCLC and have identified differences between SCLC, carcinoids, and large cell neuroendocrine tumors. Potential therapeutic targets include EZH2, PARP, cyclin-dependent kinase 1 (CDK1), MCL1, Bcl-2, BIM, sonic Hh, WNT, NOTCH1, Aurora kinase, FGFR, PIK3CA, RET, THZ1, JAK-STAT, FAK, CXCR4, PD-L1, Fuc-GM1, CD56, and CD47. Ongoing and future clinical trials have to show which of these candidates can be translated into an effective targeted therapy. Thus, the future of improving outcomes for patients with SCLC appears promising, but there are still a number of unanswered questions that need to be addressed in the future and these are outlined below.Figure 4Some of the many areas of current therapeutic interest in small cell lung cancer. Cell surface targets include a number of receptor tyrosine kinases implicated in proliferative signaling, invasion, and angiogenesis; factors regulating neuroendocrine differentiation that are being explored as targets for antibody drug conjugates; immunologic regulators; and targets for tumor-specific vaccine strategies. Intracellular pathways of particular interest include metabolic and apoptotic regulators, cell cycle checkpoint controls, developmental signaling pathways, the MYC family of transcriptional regulators, and epigenetic modifiers of histones that affect chromosomal accessibility and gene expression. FAK, focal adhesion kinase; RET, ret proto-oncogene; FGFR1, fibroblast growth factor receptor 1; VEGFR, vascular endothelial growth factor receptor; DLL3, delta-like 3 (Drosophila); CXCR4, chemokine (C-X-C motif) receptor 4; PD-L1, programmed death ligand-1; Fuc-GM1, fucosyl-monosialotetrahexosylganglioside; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; mTOR, mammalian target of rapamycin; BCL2, B-cell lymphoma 2; ASCL1, achaete-scute family bHLH transcription factor 1; NEUROD1, neuronal differntiation 1; DLL4, delta-like 4 (Drosophila); WNT, wingless-type MMTV integration site family member; WEE1, WEE1 G2 checkpoint kinase; CHK1, checkpoint kinase 1; PARP1, poly-ADP ribose polymerase 1; MYCL1, v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog; NMYC, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived; MYC, v-myc avian myelocytomatosis viral oncogene homolog; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; LSD1, lysine (K)-specific demethylase 1A; MLL2, myeloid/lymphoid or mixed-lineage leukemia.View Large Image Figure ViewerDownload (PPT)Table 1Therapeutic Agents and Targets in Small Cell Lung CancerAgentTargetTrial PhaseReferencesErismodegib, sonidegib (LDE225)Smoothened (hedgehog antagonist)Preclinical, I57Belani C.P. Dahlberg S.E. Rudin C.M. 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).J Clin Oncol. 2013; 31 ([abstract]): 7508Google ScholarVismodegib (GDC-0449)Smoothened (hedgehog antagonist)Preclinical, I, II58Tai D. Wells K. Arcaroli J. et al.Targeting the WNT signaling pathway in cancer therapeutics.Oncologist. 2015; 20: 1189-1198Crossref PubMed Scopus (1) Google ScholarABT-737Bcl-2, Bcl-xLPreclinical65Hann C.L. Daniel V.C. Sugar E.A. et al.Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer.Cancer Res. 2008; 68: 2321-2328Crossref PubMed Scopus (116) Google Scholar, 69Gardner E.E. Connis N. Poirier J.T. et al.Rapamycin rescues ABT-737 efficacy in small cell lung cancer.Cancer Res. 2014; 74: 2846-2856Crossref PubMed Scopus (8) Google ScholarNavitoclax (ABT-263)Bcl-2, Bcl-xL, Bcl-wPreclinical, I, IIaClinical development halted at the time.66Garnett M.J. Edelman E.J. Heidorn S.J. et al.Systematic identification of genomic markers of drug sensitivity in cancer cells.Nature. 2012; 483: 570-575Crossref PubMed Scopus (550) Google Scholar, 67Faber A.C. Farago A.F. Costa C. et al.Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.Proc Natl Acad Sci U S A. 2015; 112: E1288-E1296Crossref PubMed Scopus (0) Google Scholar, 68Rudin C.M. Hann C.L. Garon E.B. et al.Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.Clin Cancer Res. 2012; 18: 3163-3169Crossref PubMed Scopus (144) Google ScholarSilvestrolEIF4EPreclinical70Wendel H.G. Silva R.L. Malina A. et al.Dissecting eIF4E action in tumorigenesis.Genes Dev. 2007; 21: 3232-3237Crossref PubMed Scopus (233) Google Scholar, 71Wolfe A.L. Singh K. Zhong Y. et al.RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.Nature. 2014; 513: 65-70Crossref PubMed Scopus (43) Google ScholarPHA-680632Aurora kinasesPreclinical74Sos M.L. Dietlein F. Peifer M. et al.A framework for identification of actionable cancer genome dependencies in small cell lung cancer.Proc Natl Acad Sci U S A. 2012; 109: 17034-17039Crossref PubMed Scopus (44) Google ScholarAlisertib (MLN8237)Aurora A kinasePreclinical, I, II74Sos M.L. Dietlein F. Peifer M. et al.A framework for identification of actionable cancer genome dependencies in small cell lung cancer.Proc Natl Acad Sci U S A. 2012; 109: 17034-17039Crossref PubMed Scopus (44) Google Scholar, 76Melichar B. Adenis A. Lockhart A.C. 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: 395-405Abstract Full Text Full Text PDF PubMed Google ScholarBarasertib (AZD1152)Aurora B kinasePreclinical, IaClinical development halted at the time.75Helfrich B. Kim J. Gao D. et al.The Aurora Kinase B Inhibitor AZD1152-HQPA Inhibitor in Small Cell Lung Cancer (SCLC).J Thorac Oncol. 2015; 10: S363Google ScholarMEDI0639DLL4Preclinical, I77Jenkins D.W. Ross S. Veldman-Jones M. et al.MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo.Mol Cancer Ther. 2012; 11: 1650-1660Crossref PubMed Scopus (19) Google ScholarTarextumab (OMP-59R5)Notch 2/3Preclinical, I, II78Ingram I. Tarextumab gets FDA orphan drug designation for lung, pancreatic cancer. http://www.cancernetwork.com/news/tarextumab-fda-orphan-drug-lung-pancreatic-cancer. Accessed December 28, 2015.Google ScholarDemcizumab (OMP-21M18)DLL4Preclinical, I, II (NSCLC)79Smith D.C. Eisenberg P.D. Manikhas G. et al.A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors.Clin Cancer Res. 2014; 20: 6295-6303Crossref PubMed Scopus (4) Google ScholarPonatinib (AP24534)FGFR1, PDGFRa, VEGFR2Preclinical, I, II80Schultheis A.M. Bos M. Schmitz K. et al.Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer.Mod Pathol. 2014; 27: 214-221Crossref PubMed Scopus (17) Google Scholar, 81Wynes M.W. Hinz T.K. Gao D. et al.FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies.Clin Cancer Res. 2014; 20: 3299-3309Crossref PubMed Scopus (25) Google ScholarLucitanib (E-3810)FGFR1-3, PDGFRα/β, VEGFR1–3Preclinical, I, II82Soria J.C. DeBraud F. Bahleda R. et al.Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.Ann Oncol. 2014; 25: 2244-2251Crossref PubMed Scopus (23) Google ScholarVS-5584mTOR/PI3KPreclinical, I84Kolev VN, Xu Q, Pachter JA, et al. FAK and PI3K/mTOR inhibitors target cancer stem cells: implications for SCLC treatment strategies [abstract]. In Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, April 18-22, 2015. Philadelphia, PA: AACR; 1525.Google ScholarAZD8055mTORPreclinical, IaClinical development halted at the time.67Faber A.C. Farago A.F. Costa C. et al.Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.Proc Natl Acad Sci U S A. 2015; 112: E1288-E1296Crossref PubMed Scopus (0) Google ScholarPonatinib, vandetinib, alectinib, cabozaninibRETPreclinical, I, II85Dabir S. Babakoohi S. Kluge A. et al.RET mutation and expression in small-cell lung cancer.J Thorac Oncol. 2014; 9: 1316-1323Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarTHZ1CDK7Preclinical86Loven J. Hoke H.A. Lin C.Y. et al.Selective inhibition of tumor oncogenes by disruption of super-enhancers.Cell. 2013; 153: 320-334Abstract Full Text Full Text PDF PubMed Scopus (307) Google ScholarRuxolitinib (INCB1824)JAK1/2Preclinical, I, II (NSCLC)90Looyenga B.D. Hutchings D. Cherni I. et al.STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma.PLoS One. 2012; 7: e30820Crossref PubMed Scopus (38) Google ScholarTofacitinib (CP-690550)JAK3Preclinical89Curtis JR, Lee EB, Kaplan IV, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme [e-pub ahead of print]. Ann Rheum Dis. http://dx.doi.org/10.1136/annrheumdis-2014-205847. Accessed December 22, 2015.Google ScholarAZD1480JAK2Preclinical, IaClinical development halted at the time.91Lee J.H. Park K.S. Alberobello A.T. et al.The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.Clin Cancer Res. 2013; 19: 6777-6786Crossref PubMed Scopus (5) Google ScholarAmrubicinTopoisomerase IIPreclinical, I, II, III, Marketed92Ettinger D.S. Jotte R. Lorigan P. et al.Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer.J Clin Oncol. 2010; 28: 2598-2603Crossref PubMed Scopus (69) Google Scholar, 93Onoda S. Masuda N. Seto T. et al.Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301.J Clin Oncol. 2006; 24: 5448-5453Crossref PubMed Scopus (149) Google Scholar, 94von Pawel J. Jotte R. Spigel D.R. 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: 4012-4019Crossref PubMed Scopus (22) Google ScholarPalifosfamideAlkylationPreclinical, I, II, IIIAldoxorubicinAnthracyclinePreclinical, I, II95Mita M.M. Natale R.B. Wolin E.M. et al.Pharmacokinetic study of aldoxorubicin in patients with solid tumors.Invest New Drugs. 2015; 33: 341-348Crossref PubMed Scopus (3) Google ScholarDefactinib (VS 6063)FAKPreclinical, I, II (NSCLC, Meso)97Luo M. Fan H. Nagy T. et al.Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells.Cancer Res. 2009; 69: 466-474Crossref PubMed Scopus (97) Google Scholar, 98Sullivan B. Verastem stops enrollment due to futility in the COMMAND Study of VS-6063 for the Treatment of Malignant Pleural Mesothelioma—no difference in VS-6063 versus placebo in either the intent to treat population or patients with Merlin-low tumors. http://www.businesswire.com/news/home/20150928005465/en/Verastem-Stops-Enrollment-Due-Futility-COMMAND-Study. Accessed December 23, 2015.Google ScholarLY2510924CXCR4Preclinical, I, II103Spigel D.R. Weaver R.W. McCleod M. et al.Phase II study of carboplatin/etoposide plus LY2510924, a CXCR4 peptide antagonist, versus carboplatin/etoposide in patients with extensive-stage small cell lung cancer (SCLC).Ann Oncol. 2014; 25: iv514Google ScholarOlaparib (AZD2281)PARP1/2Preclinical, I, II41Byers L.A. Wang J. Nilsson M.B. et al.Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1.Cancer Discov. 2012; 2: 798-811Crossref PubMed Scopus (66) Google Scholar, 106ISRCTNRegistry. STOMP: Small cell lung cancer Trial of Olaparib (AZD2281) as Maintenance Programme. http://www.isrctn.com/ISRCTN73164486. Accessed December 28, 2015.Google ScholarRucaparib (AG-014699,PF-01367338)PARP1Preclinical, I, II41Byers L.A. Wang J. Nilsson M.B. et al.Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1.Cancer Discov. 2012; 2: 798-811Crossref PubMed Scopus (66) Google ScholarTalazoparib (BMN-673)PARP1/2Preclinical, I, II42Wainberg Z.A. Rafii S. Ramanathan R.K. et al.Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.ASCO Meeting Abstracts. 2014; 32 ([abstract]): 7522Google Scholar, 43Cardnell R.J. Feng Y. Diao L. et al.Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer.Clin Cancer Res. 2013; 19: 6322-6328Crossref PubMed Scopus (29) Google ScholarVeliparib (ABT-888)PARP1/2Preclinical, I, II105Owonikoko T.K. Zhang G. Deng X. et al.Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer.Cancer Med. 2014; 3: 1579-1594Crossref PubMed Google Scholar, 107Owonikoko T.K. Dahlberg S.E. Khan S.A. et al.A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E2511).Lung Cancer. 2015; 89: 66-70Abstract Full Text Full Text PDF PubMed Google ScholarLorvotuzumab mertansineCD56Preclinical, I, IIaClinical development halted at the time.110Whiteman K.R. Johnson H.A. Mayo M.F. et al.Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models.MAbs. 2014; 6: 556-566Crossref PubMed Scopus (1) Google Scholar, 111Spigel D.R. Bendell J. Mita A.C. et al.Phase I/II study to assess the safety, pharmacokinetics (PK) and efficacy of lorvotuzumab mertansine (LM, IMGN901) in combination with carboplatin/etoposide in patients with solid tumors including small-cell lung cancer (SCLC).Ann Oncol. 2012; 23: ix498Google ScholarRovalpituzumab tesirine (SC16LD6.5)DLL3Preclinical, I, II112Saunders L.R. Bankovich A.J. Anderson W.C. et al.A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.Sci Transl Med. 2015; 7 (302ra136)Crossref Scopus (6) Google Scholar, 113Rudin C.M. Pietanza M.C. Spigel D.R. et al.A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC.J Thorac Oncol. 2015; 10: S192-S193Google ScholarGSK126EZH2Preclinical115Romero O.A. Torres-Diz M. Pros E. et al.MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.Cancer Discov. 2014; 4: 292-303Crossref PubMed Scopus (16) Google Scholar, 116Fillmore C.M. Xu C. Desai P.T. et al.EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.Nature. 2015; 520: 239-242Crossref PubMed Scopus (22) Google ScholarSorafenibRAF1, BRAF, PDGFRβ, VEGFR2Preclinical, I, IIaClinical development halted at the time.117Gitlitz B.J. Moon J. Glisson B.S. 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: 1835-1840Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarBevacizumabVEGFPreclinical, I, II, IIIaClinical development halted at the time.118Horn L. Dahlberg S.E. Sandler A.B. 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: 6006-6011Crossref PubMed Scopus (83) Google Scholar, 121Ready N.E. Dudek A.Z. Pang H.H. 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: 4436-4441Crossref PubMed Scopus (38) Google ScholarThalidomideAngiogenesisPreclinical, I, II, III119Lee S.M. Woll P.J. 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: 1049-1057Crossref PubMed Scopus (68) Google Scholar, 120Pujol J.L. Breton J.L. 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: 3945-3951Crossref PubMed Scopus (99) Google ScholarCediranib (AZD2171)VEGFR1-3, FLT1/4, cKit, PDGFRβ, FGFR1Preclinical, I, IIaClinical development halted at the time.122Ramalingam S.S. Belani C.P. Mack P.C. 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: 1279-1284Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarVandetanibVEGFR2Preclinical, I, II123Arnold A.M. 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: 4278-4284Crossref PubMed Scopus (125) Google ScholarAfliberceptVEGF trapPreclinical, I, II124Allen J.W. 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: 2463-2470Crossref PubMed Google ScholarSunitinibVEGFR1-3, PDGFRβ, c-KIT, FLT3, RETPreclinical, I, II125Abdelraouf F. Smit E. Hasan B. et al.Sunitinib (SU11248) in patients with chemo naive extensive small cell lung cancer or who have a 'chemosensitive' relapse: a single-arm phase II study (EORTC-08061).Eur J Cancer. 2016; 54: 35-39Abstract Full Text Full Text PDF PubMed Google Scholar, 126Ready N.E. Pang H.H. 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: 1660-1665Crossref PubMed Scopus (12) Google ScholarImatinibPDGFR, c-KitPreclinical, I, IIaClinical development halted at the time.127Schneider B.J. Kalemkerian G.P. 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: 223-227Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 128Spigel D.R. Hainsworth J.D. Simons L. et al.Irinotecan, carboplatin, and imatinib in untreated extensive-stage small-cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network.J Thorac Oncol. 2007; 2: 854-861Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarRilotumumab (AMG 102)HGFPreclinical, I, IIaClinical development halted at the time.129Maulik G. Kijima T. Ma P.C. et al.Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer.Clin Cancer Res. 2002; 8: 620-627PubMed Google ScholarGanitumab (AMG 479)IGF-1RPreclinical, I, II130Martinez P. Sales Fidalgo P.A. Felip E. Ganitumab for the treatment of small-cell lung cancer.Expert Opin Investig Drugs. 2014; 23: 1423-1432Crossref PubMed Scopus (1) Google ScholarEverolimusmTORPreclinical, I, II131Owonikoko T.K. Stoller R.G. Petro D. et al.Phase II study of RAD001 (Everolimus) in previously treated small cell lung cancer (SCLC).ASCO Meeting Abstracts. 2008; 26 ([abstract]): 19017Google Scholar, 132Tarhini A. Kotsakis A. Gooding W. et al.Phase II study of everolimus (RAD001) in previously treated small cell lung cancer.Clin Cancer Res. 2010; 16: 5900-5907Crossref PubMed Scopus (58) Google ScholarTemsirolimusmTORPreclinical, I, II133Pandya K.J. 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: 1036-1041Abstract Full Text Full Text PDF PubMed Scopus (96) Google ScholarAZD1775 (MK-1775)WEE1Preclinical, I, II134Do K. Wilsker D. Ji J. et al.Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors.J Clin Oncol. 2015; 33: 3409-3415Crossref PubMed Scopus (0) Google ScholarIpilimumabCTLA-4Preclinical, I, II, III151Reck M. Bondarenko I. Luft A. et al.Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.Ann Oncol. 2013; 24: 75-83Crossref PubMed Scopus (129) Google Scholar, 152Antonia S.J. Bendell J.C. Taylor M.H. 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; 33 ([abstract]): 7503Google ScholarNivolumabPD-1Preclinical, I, II, III152Antonia S.J. Bendell J.C. Taylor M.H. 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; 33 ([abstract]): 7503Google ScholarPembrolizumabPD-1Preclinical, I, II153Ott P.A. Fernandez M.E.E. Hiret S. 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; 33 ([abstract]): 7502Google ScholarBMS-986012Fucosyl-GM1Preclinical, I, II158Giaccone 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: 6854-6864Crossref PubMed Scopus (130) Google ScholarCAR T cellsCD56Preclinical159Levine B.L. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells.Cancer Gene Ther. 2015; 22: 79-84Crossref PubMed Scopus (3) Google Scholar, 160Rosenberg S.A. Restifo N.P. Adoptive cell transfer as personalized immunotherapy for human cancer.Science. 2015; 348: 62-68Crossref PubMed Scopus (76) Google ScholarAnti CD47 antibodiesCD47Preclinical, I165Liu X. Pu Y. Cron K. et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.Nat Med. 2015; 21: 1209-1215Crossref PubMed Scopus (5) Google ScholarBcl, B-cell lymphoma; EIF4E, eukaryotic translation initiation factor 4E; DLL4, delta-like 4 (Drosophila); FGFR, fibroblast growth factor receptor; PDGFR, platelet derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; mTOR, mammalian target of rapamycin; RET, ret proto-oncogene; CDK7, cyclin-dependent kinase 7; JAK, Janus kinase; FAK, focal adhesion kinase; CXCR4, chemokine receptor 4; PARP, poly-ADP ribose polymerase; CD56, neural cell adhesion molecule; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; RAF1, Raf-1 proto-oncogene, serine/threonine kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; VEGF, vascular endothelial growth factor; FLT, fms-related tyrosine kinase; HGF, hepatocyte growth factor (hepapoietin A; scatter factor); IGF-1R, insulin-like growth factor 1 receptor; WEE1, WEE1 G2 checkpoint kinase; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; PD-1, programmed death-1; GM1, monosialotetrahexosylganglioside; CD47, integrin-associated protein.a Clinical development halted at the time. 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