E11-03: Controversy in small cell lung cancer: targeted therapy

Abstract

For three decades, trials of new chemotherapy regimens for small cell lung cancer (SCLC) have failed to substantially improve clinical outcomes. The promise of targeted therapy has yet to be realised for SCLC but there is cautious optimism that there will soon be a breakthrough for this disease. Angiogenesis Inhibitors: To date the majority of agents evaluated in SCLC have been inhibitors of angiogenesis. Trials of interferons conducted during the early 1990's were halted due to lack of significant benefit and toxicities that limited administration [1Jett JR Maksymiuk AW Su JQ et al.Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer.J Clin Oncol. 1994; 12: 2321-2326PubMed Google Scholar, 2Kelly K Crowley JJ Bunn Jr, PA et al.Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study.J Clin Oncol. 1995; 13: 2924-2930PubMed Google Scholar, 3Lebeau B Salmoniere PDL Ozenne G et al.Alpha Interferon as maintenance therapy for small cell lung cancer (SCLC).Proceedings ASCO. 1999; 18: 475aGoogle Scholar, 4Mattson K Niiranen A Pyrhonen S et al.Natural interferon alfa as maintenance therapy for small cell lung cancer.Eur J Cancer. 1992; 28A: 1387-1391Abstract Full Text PDF PubMed Scopus (79) Google Scholar]. Trials of matrix metalloproteinase inhibitors also failed, and proved toxic due to musculoskeletal toxicity [5Erlichman C Adjei AA Alberts SR et al.Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566.Ann Oncol. 2001; 12: 389-395Crossref PubMed Scopus (73) Google Scholar, 6Shepherd FA Giaccone G Seymour L et al.Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer.J Clin Oncol. 2002; 20: 4434-4439Crossref PubMed Scopus (236) Google Scholar]. The first evidence that inhibition of angiogenesis may be a viable therapeutic strategy comes from the results of a randomised, phase III, placebo-controlled trial of maintenance thalidomide in patients with previously untreated extensive stage SCLC conducted by the French Intergroup [7Pujol JL Breton JL Gervais R et al.A prospective randomized phase III, double-blind, placebo-controlled study of thalidomide in extended-disease (ED) SCLC patients after response to chemotherapy (CT): An intergroup study FNCLCC Cleo04 - IFCT 00–01.Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24 (2006;24.): 17089Google Scholar]. The thalidomide treated group had a median survival of 11.7 months versus 8.7 months for the placebo group (HR: 0.48 [95% CI: 0.24–0.93]; p = 0.03). However toxicity, principally neuropathy and constipation led to withdrawal from the study in just over half the patients who received thalidomide. In a phase III trial conducted by the London Lung Cancer Group a lower dose (100-200mg daily) of thalidomide has been evaluated in combination with etoposide and cisplatin but results are not yet available. Due to the toxicities observed with thalidomide and the success of bevacizumab (Avastin, Genentech, San Francisco, CA, USA), a humanized monoclonal antibody directed against the vascular endothelial cell growth factor (VEGF) in non-small cell lung and colorectal cancer, results from trials of this agent in SCLC are awaited with interest. Bevacizumab is generally well-tolerated although associated with increased risk of fatal haemorrhage, hypertension and thromboembolic events [8Sanborn RE Sandler AB The safety of bevacizumab.Expert Opin Drug Saf. 2006; 5: 289-301Crossref PubMed Scopus (27) Google Scholar]. Vandetanib (Zactima, Astra-Zeneca, Macclesfield, UK), a small molecule oral inhibitor of VEGF receptor-2 tyrosine kinase, and to a lesser extent, epidermal growth factor receptor (EGFR) tyrosine kinase, is also well tolerated. The main side effects of vandetanib are thrombocytopenia, diarrhoea, rash and asymptomatic QTc prolongation [9Kovacs MJ Reece DE Marcellus D et al.A phase II study of ZD6474 (Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma—NCIC CTG IND.145.Invest New Drugs. 2006; 24: 529-535PubMed Google Scholar]. A number of studies in SCLC are ongoing with these agents [10www.ClinicalTrials.govGoogle Scholar], some of which have completed recruitment. The National Cancer Institute of Canada - Clinical Trials Group have recently completed recruitment to a randomized phase II trial of vandetanib as maintenance chemotherapy in patients with SCLC with a response to first line treatment. A Cancer and Leukemia Group B (CALGB) study of cisplatin, irinotecan and bevacizumab in extensive stage SCLC, and a Sarah Cannon Research Institute trial evaluating carboplatin, irinotecan and concurrent radiotherapy followed by bevacizumab in limited stage SCLC have also completed recruitment. Other anti-angiogenic agents that are being evaluated include sorafenib (Nexafar, Bayer Pharmaceuticals, West Haven, CT, USA; Onyx Pharmaceuticals, Richmond, CA, USA), that is a multiple kinase inhibitor of Raf kinase, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor beta and AZD2171 (AstraZeneca, Macclesfield, UK), an inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, c-kit, platelet derived growth factor alpha and beta [10www.ClinicalTrials.govGoogle Scholar]. Growth and proliferation pathway inhibitors: Several studies identify c-kit tyrosine kinase signalling as a dominant pathway for growth that is upregulated in SCLC [11Lloyd KP Krystal GW Role of small-molecule kit receptor tyrosine kinase inhibitors in the treatment of small-cell lung cancer.Clin Lung Cancer. 2002; 3: 213-218Abstract Full Text PDF PubMed Scopus (6) Google Scholar]. However, the clinical trials of imatinib (Gleevec, Glivec, Novartis, Basel, Switzerland; East Hanover, NJ, USA), a small molecule inhibitor of the c-kit tyrosine kinase, proved particularly disappointing. Negative results were first attributed to inclusion of patients with tumours that did not express the c-kit receptor [12Johnson BE Fischer T Fischer B et al.Phase II study of imatinib in patients with small cell lung cancer.Clin Cancer Res. 2003; 9: 5880-5887PubMed Google Scholar], but imatinib subsequently failed in trials that selected for patients with c-kit positive tumours [13Dy GK Miller AA Mandrekar SJ et al.A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study.Ann Oncol. 2005; 16: 1811-1816Crossref PubMed Scopus (142) Google Scholar, 14Krug LM Crapanzano JP Azzoli CG et al.Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial.Cancer. 2005; 103: 2128-2131Crossref PubMed Scopus (145) Google Scholar, 15Schneider B Gadgeel S 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 (ES SCLC).Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24: 17089Google Scholar]. Also, a combination study of imatinib with irinotecan demonstrated higher than anticipated neutropenia, diarrhoea, and thrombosis likely due to decreased clearance of irinotecan in the presence of imatinib [16Johnson FM Krug LM Tran HT et al.Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma.Cancer. 2006; 106: 366-374Crossref PubMed Scopus (45) Google Scholar]. The potent efficacy of imatinib in patients with gastrointestinal stromal tumours is attributed to the presence of activating mutations in the c-kit tyrosine kinase domain. The rare occurrence of c-kit mutation in SCLC may account for the failure of imatinib in this disease. The EGFR inhibitor, gefitinib (Iressa, AstraZeneca, Macclesfield, UK), also failed in SCLC [17Moore 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: 93-97Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar] but this is less surprising because over-expression of EGFR is infrequent in SCLC compared to non-small cell lung cancer. Temsirolimus (Wyeth Pharmaceuticals, Collegeville, PA, USA) inhibits the mammalian target of rapamycin (mTOR), a downstream mediator in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, leading to cell cycle arrest. A randomized phase II trial of temsirolimus maintenance conducted in patients with extensive stage SCLC was not conclusive for further evaluation [18Pandya K Levy D Hidalgo M J Clin Oncol. 2005; 23: 622sGoogle Scholar]. Another strategy to inhibit growth signal transduction cascades in tumours is farnesyl transferase inhibition but this does not appear to be a feasible approach for SCLC [19Heymach JV Johnson DH Khuri FR et al.Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.Ann Oncol. 2004; 15: 1187-1193Crossref PubMed Scopus (92) Google Scholar]. Apoptosis promoters: Defective apoptosis underpins cancer cell survival and treatment resistance. The Bcl-2 family proteins are central regulators of apoptosis and Bcl-2 is overexpressed in 90% of SCLC [20Shivapurkar N Reddy J Chaudhary PM Gazdar AF Apoptosis and lung cancer: a review.J Cell Biochem. 2003; 88: 885-898Crossref PubMed Scopus (178) Google Scholar]. Oblimersen (Genasense, Genta, Berkeley Heights, NJ, USA), an antisense oligonucleotide, is the first bcl-2 inhibitor to be tested in SCLC. In a phase I study, administration of oblimersen with carboplatin and etoposide was well tolerated with a response rate of 86% and time to disease progression of 5.9 months in patients with extensive stage disease [21Rudin 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: 1110-1117Crossref PubMed Scopus (158) Google Scholar]. Results from phase II evaluation are currently awaited. Several small molecule inhibitors of Bcl-2 family proteins are in preclinical development and will soon enter clinical trial. Notably, ABT-737 (Abbott Laboratories San Diego, California, USA) inhibits the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, and has demonstrated unprecedented single agent activity in SCLC xenografts [22Oltersdorf T Elmore SW Shoemaker AR et al.An inhibitor of Bcl-2 family proteins induces regression of solid tumours.Nature. 2005; 435: 677-681Crossref PubMed Scopus (2939) Google Scholar]. Other pro-apoptotic strategies include aplidine (Pharma Mar, Madrid Spain; Cambridge, USA), a novel marine cyclodepsipeptide that also has antiangiogenic properties. Aplidine is noted to cause muscle toxicity [23Faivre S Chieze S Delbaldo C et al.Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies.J Clin Oncol. 2005; 23: 7871-7880Crossref PubMed Scopus (86) Google Scholar] and the results of phase II testing in SCLC are due to be reported soon. The 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin suppresses growth, induces apoptosis and enhances sensitivity to etoposide in preclinical studies of SCLC [24Khanzada UK Pardo OE Meier C et al.Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling.Oncogene. 2006; 25: 877-887Crossref PubMed Scopus (95) Google Scholar]. A phase III trial to evaluate the concept that statins combined with chemotherapy will improve on chemotherapy alone has recently opened in Great Britain and a phase II study is also open in South Korea [10www.ClinicalTrials.govGoogle Scholar]. Apoptosis has also been correlated with proteasome activity. Bortezomib is a proteasome inhibitor that has been approved for use in multiple myeloma. In SCLC cell lines bortezomib reduces Bcl-2 levels and induces apoptosis[25Mortenson MM Schlieman MG Virudachalam S et al.Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer.Lung Cancer. 2005; 49: 163-170Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar] but it is not active as a single agent in patients with extensive stage SCLC[26Lara Jr, PN Chansky K Davies AM et al.Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327).J Thorac Oncol. 2006; 1: 996-1001Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] and results from combination studies are awaited. Perspectives and Future challenges: The development of targeted therapy for SCLC is proving frustrating. Although various targeted therapies have been evaluated, the majority of studies have been conducted in ‘untargeted’ populations[27Blackhall FH Shepherd FA Small cell lung cancer and targeted therapies.Curr Opin Oncol. 2007; 19: 103-108Crossref PubMed Scopus (31) Google Scholar]. Yet, strong preclinical data to pursue c-kit inhibition with imatinib did not translate to the clinic even when patients were selected for tumoural expression of c-kit. One caveat to using SCLC tumour for patient selection is the propensity for this disease to be exquisitively chemo / radiosensitive at presentation but substantially more resistant to treatment at relapse. Targets identified in chemonaive tumours may be irrelevant for previously treated tumours. Thus, greater understanding of mechanisms governing treatment resistance may be required to shape the future development of targeted therapy and aid in selection of the most appropriate agents to prioritise for trials in this disease.