Targeted Therapy in Lung Cancer; Lessons Learned from Past Experiences

Abstract

Exactly a 100 years ago, the discovery of a cancer-causing virus by Rous1Rous P A sarcoma of the fowl transmissible by an agent seperable from the tumor cells.J Exp Med. 1911; 13: 397-411Crossref PubMed Scopus (565) Google Scholar laid the foundations for research on the molecular basis of cancer. Initially, this finding was met with considerable skepticism; however, subsequent work on Rous sarcoma virus led to the discovery of the first known cancer-associated molecular alteration, the proto-oncogene c-src.2Martin GS The hunting of the Src.Nat Rev Mol Cell Biol. 2001; 2: 467-475Crossref PubMed Scopus (481) Google Scholar, 3Stehelin D Varmus HE Bishop JM et al.DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA.Nature. 1976; 260: 170-173Crossref PubMed Scopus (792) Google Scholar Since then, we have come a long way in our understanding of the molecular alterations that drive cancer. Identifying and targeting the key driver molecular alterations has led to the development of some remarkably effective therapies against cancer. The development of imatinib for the treatment of chronic myelogenous leukemia and trastuzumab for breast cancer opened a new era in the treatment of cancer. In the past decade, a number of clinical trials with molecularly targeted drugs in the treatment of lung cancer and particularly in non-small cell lung cancer (NSCLC). However, only a few of the targeted therapies have shown promise in the treatment of lung cancer. In the 11th annual meeting of molecularly targeted therapy in NSCLC, a number of molecularly targeted drugs were discussed. Given the large number of targeted therapies under evaluation, it is important to reflect on our past experience with targeted therapies and identify lessons that are relevant for effective drug development in future. On the basis of our review of the past successes and failures with targeted therapy in cancer, we have identified the following key points that would be of relevance to future drug development in lung cancer. The identification of high expression levels of c-kit and its ligand stem cell factor (SCF) in small cell lung cancer (SCLC) and subsequent clinical trials with imatinib for the treatment of patients with SCLC is a relevant example for this dictum.4Sekido Y Obata Y Ueda R et al.Preferential expression of c-kit protooncogene transcripts in small cell lung cancer.Cancer Res. 1991; 51: 2416-2419PubMed Google Scholar Coexpression of SCF and c-kit suggested an autocrine loop that promotes cell proliferation.5Hibi K Takahashi T Sekido Y et al.Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer.Oncogene. 1991; 6: 2291-2296PubMed Google Scholar These findings led to the evaluation of imatinib a c-kit inhibitor in the treatment of patients with SCLC either as a single agent or in combination with cytotoxic chemotherapy; however, these trials failed to show meaningful therapeutic benefit from imatinib treatment.6Dy 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 (134) Google Scholar, 7Krug 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 (138) Google Scholar, 8Spigel DR Hainsworth JD 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 (48) Google Scholar Subsequent studies identified that SCF stimulation of c-kit played only a minor role in cell proliferation, and there were several other signaling pathways that maintained tumor cell proliferation, in the absence of the SCF/c-kit activation.9Papadimitriou CA Topp MS Serve H et al.Recombinant human stem cell factor does exert minor stimulation of growth in small cell lung cancer and melanoma cell lines.Eur J Cancer. 1995; 31A: 2371-2378Abstract Full Text PDF PubMed Scopus (27) Google Scholar Inactivation of the retinoblastoma (Rb) gene makes the SCF/C-kit/mitogen-activated protein kinase pathway for proliferation redundant in SCLC.10Bondzi C Litz J Dent P et al.Src family kinase activity is required for Kit-mediated mitogen-activated protein (MAP) kinase activation, however loss of functional retinoblastoma protein makes MAP kinase activation unnecessary for growth of small cell lung cancer cells.Cell Growth Differ. 2000; 11: 305-314PubMed Google Scholar Hence, it is important to identify if a potentially targetable molecular alteration has a dominant role in the maintenance and progression of the malignant phenotype. This requires well-designed, hypothesis-driven functional studies to establish the role of a specific molecular target in cancer. Promising preclinical findings with novel targeted agents do not always translate into improved outcomes in the clinic. Biomarker identification and patient selection are crucial for optimal drug development. Patients with treatment refractory NSCLC who were positive for the EML4-ALK fusion gene had a response rate of 57% after treatment with crizotinib.11Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3603) Google Scholar Similarly, treatment with vemurafenib, a BRAF inhibitor, resulted in an 81% response rate in 38 patients with malignant melanoma whose tumor cells harboring BRAF mutations.12Flaherty KT Puzanov I Kim KB et al.Inhibition of mutated, activated BRAF in metastatic melanoma.N Engl J Med. 2010; 363: 809-819Crossref PubMed Scopus (2813) Google Scholar Every attempt should be made to identify predictive biomarkers using innovative approaches and emerging technologies. As always, studies should be thoughtfully designed and tissue collection should be made mandatory.13Ellis M Buzdar A Unzeitig G et al.ACOSOG Z1031: a randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer.J Clin Oncol. 2010; 28: 7sCrossref Scopus (26) Google Scholar Empiric combinations of chemotherapeutic agents and targeted drugs have proven to be unsuccessful in unselected patients with NSCLC. Attempts have been made to build on the efficacy of standard front-line platinum doublet therapy with the addition of a molecularly targeted agent. In this context, the epidermal growth factor tyrosine kinase inhibitors have been the most extensively studied in combination with chemotherapy in patients with previously untreated NSCLC. Two randomized phase III trials evaluating the combination of erlotinib- and platinum-based front-line chemotherapy failed to demonstrate a survival benefit.14Herbst RS Prager D Hermann R et al.TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.J Clin Oncol. 2005; 23: 5892-5899Crossref PubMed Scopus (1359) Google Scholar, 15Gatzemeier U Pluzanska A Szczesna A et al.Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.J Clin Oncol. 2007; 25: 1545-1552Crossref PubMed Scopus (836) Google Scholar Similarly, the combination of gefitinib and front-line platinum-doublet therapy did not show any improvement in survival compared with chemotherapy alone.16Giaccone G Herbst RS Manegold C et al.Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1.J Clin Oncol. 2004; 22: 777-784Crossref PubMed Scopus (1643) Google Scholar, 17Herbst RS Giaccone G Schiller JH et al.Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2.J Clin Oncol. 2004; 22: 785-794Crossref PubMed Scopus (1620) Google Scholar, 18Eberhard DA Johnson BE Amler LC et al.Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.J Clin Oncol. 2005; 23: 5900-5909Crossref PubMed Scopus (1296) Google Scholar, 19Janne PA Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406.J Clin Oncol. 2010; 28 (abstract 7503)Google Scholar It has become increasingly clear that such trials are likely to fail, whereas mechanistically sound combinations, targeting specific population subsets, are more likely to succeed. In fact only 3 of 15 (20%) published phase III trials evaluating empiric combination of targeted drugs and platinum doublet chemotherapy in the front-line treatment of NSCLC met their primary end points (Table 1). In fact, one of the phase III studies amended their original primary end point from overall survival to progression-free survival22Reck M von Pawel J Zatloukal P et al.Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.J Clin Oncol. 2009; 27: 1227-1234Crossref PubMed Scopus (1323) Google Scholar and in another the drug combination failed to meet its primary end point in a separate phase III trial20Lynch TJ Patel T Dreisbach L et al.Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.J Clin Oncol. 2010; 28: 911-917Crossref PubMed Scopus (374) Google Scholar, 21Pirker R Pereira JR Szczesna A et al.Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet. 2009; 373: 1525-1531Abstract Full Text Full Text PDF PubMed Scopus (1216) Google Scholar; if those two phase III studies are excluded, then the success rate is even lower (6.7%).TABLE 1Selected Phase III Trials Using Empiric Combinations of Targeted Agents and First-Line Platinum-Based Doublet Therapy in Patients with Advanced NSCLCAuthorFirst-Line Platinum DoubletTargeted AgentPrimary End PointPrimary End Point Met?Gatzemeier et al.15Gatzemeier U Pluzanska A Szczesna A et al.Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.J Clin Oncol. 2007; 25: 1545-1552Crossref PubMed Scopus (836) Google ScholarCisplatin gemcitabineErlotinibOSNoHerbst et al.14Herbst RS Prager D Hermann R et al.TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.J Clin Oncol. 2005; 23: 5892-5899Crossref PubMed Scopus (1359) Google ScholarCarboplatin paclitaxelErlotinibOSNoGiaccone et al.16Giaccone G Herbst RS Manegold C et al.Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1.J Clin Oncol. 2004; 22: 777-784Crossref PubMed Scopus (1643) Google ScholarCisplatin gemcitabineGefitinibOSNoHerbst et al.17Herbst RS Giaccone G Schiller JH et al.Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2.J Clin Oncol. 2004; 22: 785-794Crossref PubMed Scopus (1620) Google ScholarCarboplatin paclitaxelGefitinibOSNoLynch et al.20Lynch TJ Patel T Dreisbach L et al.Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.J Clin Oncol. 2010; 28: 911-917Crossref PubMed Scopus (374) Google ScholarCarboplatin paclitaxel or docetaxelCetuximabPFSNoPirker et al.21Pirker R Pereira JR Szczesna A et al.Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet. 2009; 373: 1525-1531Abstract Full Text Full Text PDF PubMed Scopus (1216) Google ScholarCisplatin vinorelbineCetuximabOSYesReck et al.22Reck M von Pawel J Zatloukal P et al.Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.J Clin Oncol. 2009; 27: 1227-1234Crossref PubMed Scopus (1323) Google ScholarCisplatin gemcitabineBevacizumabOS (amended to PFS)YesSandler et al.23Sandler A Gray R Perry MC et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006; 355: 2542-2550Crossref PubMed Scopus (4947) Google ScholarCarboplatin paclitaxelBevacizumabOSYesLeighl et al.24Leighl NB Paz-Ares L Douillard JY et al.Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR. 18.J Clin Oncol. 2005; 23: 2831-2839Crossref PubMed Scopus (153) Google ScholarCarboplatin paclitaxelBMS-275291OSNoBissett et al.25Bissett D O'Byrne KJ von Pawel J et al.Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer.J Clin Oncol. 2005; 23: 842-849Crossref PubMed Scopus (164) Google ScholarCisplatin gemcitabinePrinomastatOSNoRamlau et al.26Ramlau R Zatloukal P Jassem J et al.Randomized phase III trial comparing bexarotene (L1069–49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I.J Clin Oncol. 2008; 26: 1886-1892Crossref PubMed Scopus (74) Google ScholarCisplatin vinorelbineBexaroteneOSNoBlumenschein et al.27Blumenschein Jr, GR Khuri FR von Pawel J et al.Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II.J Clin Oncol. 2008; 26: 1879-1885Crossref PubMed Scopus (78) Google ScholarCarboplatin paclitaxelBexaroteneOSNoLee et al.28Lee SM Rudd R Woll PJ et al.Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer.J Clin Oncol. 2009; 27: 5248-5254Crossref PubMed Scopus (55) Google ScholarCarboplatin gemcitabineThalidomideOSNoPaz-Ares et al.29Paz-Ares L Douillard JY Koralewski P et al.Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.J Clin Oncol. 2006; 24: 1428-1434Crossref PubMed Scopus (110) Google ScholarCisplatin gemcitabineAprinocarsenOSNoWilliamson et al.30Williamson SK Crowley JJ Lara Jr, PN et al.Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003.J Clin Oncol. 2005; 23: 9097-9104Crossref PubMed Scopus (94) Google ScholarCarboplatin paclitaxelTirapazamineOSNoOS, overall survival; PFS, progression-free survival; NSCLC, non-small cell lung cancer. Open table in a new tab OS, overall survival; PFS, progression-free survival; NSCLC, non-small cell lung cancer. The combination of bevacizumab and chemoradiation for limited stage SCLC and locally advanced NSCLC has resulted in the development of trachea-esophageal fistula.31Spigel DR Hainsworth JD Yardley DA et al.Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab.J Clin Oncol. 2010; 28: 43-48Crossref PubMed Scopus (232) Google Scholar Another case in point is cediranib, an inhibitor of all three VEGF receptors, which showed encouraging tumor control in the phase I setting, when used at the doses of 30 mg and 45 mg, in combination with platinum-based chemotherapy in patients with advanced NSCLC. In this study, partial responses were seen in 9 of the 20 enrolled patients, whereas 11 patients had stable disease.32Laurie SA Gauthier I Arnold A et al.Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group.J Clin Oncol. 2008; 26: 1871-1878Crossref PubMed Scopus (112) Google Scholar Nevertheless, in the phase II/III double-blinded trial of carboplatin and paclitaxel with either cediranib or placebo at these doses resulted in excessive treatment-related toxicities and mortality in the cediranib arm.33Goss GD Arnold A Shepherd FA et al.Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study.J Clin Oncol. 2010; 28: 49-55Crossref PubMed Scopus (209) Google Scholar Patients treated with cediranib experienced a higher rate of serious adverse events, fatal events, hospitalizations, and death within 30 days of last dose of study drug. Hypertension, hypothyroidism, hand-foot syndrome, and gastrointestinal toxicity were more commonly seen in the patients treated with cediranib. Consequently, a trial using a lower dose of cediranib (20 mg) or placebo along with carboplatin and paclitaxel is underway. Targeted therapies hold considerable promise in the treatment of patients with lung cancer. Nevertheless, success lies in our ability to learn from our previous experience and implement those lessons in our future plans for targeted drug development against lung cancer.