Chemotherapy for Non-Small-Cell Lung Carcinoma: From a Blanket Approach to Individual Therapy

ABSTRACT

Only one third of patients with non-small-cell lung carcinoma (NSCLC) present with early-stage disease that is amenable to potentially curative resection and adjuvant therapy. Unfortunately, even in stage I NSCLC, 5-year survival rates are in the range of 55 to 72%. For unresectable disease in stages IIIB and IV, 5-year survival rates are < 5%. Postoperative chemotherapy (adjuvant chemotherapy) using cisplatin-based regimens has become the standard of care for resected stage II to IIIA NSCLC. However, adjuvant chemotherapy may be harmful in stage IA NSCLC, and its role for stage 1B is controversial. There are no conclusive data showing superiority of neoadjuvant chemotherapy (given prior to surgery) over adjuvant chemotherapy (given after surgery) or vice versa in early-stage NSCLC. Several emerging targeted therapy agents [e.g., inhibitors of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), or tyrosine kinase], and combination chemotherapy regimens are currently being evaluated in NSCLC. Specific patient subpopulation characteristics (including EGFR mutations) may be prognostically important to identify potential responders (or nonresponders) to therapy. This review will focus on chemotherapeutic approaches to treat both early stage (adjuvant and neoadjuvant chemotherapy) and metastatic disease including the use of maintenance therapy and novel agents.

KEYWORDS

Non-small-cell lung cancer (NSCLC) - adjuvant chemotherapy - tyrosine kinase inhibitors - epidermal growth factor receptor (EGFR) - angiogenesis - platinum-based chemotherapy

REFERENCES

• 1 Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006.  Ann Oncol. 2007;  18 (3) 581-592
• 2 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M J. Cancer statistics, 2009.  CA Cancer J Clin. 2009;  59 (4) 225-249
• 3 Parkin D M. Global cancer statistics in the year 2000.  Lancet Oncol. 2001;  2 (9) 533-543
• 4 Yang L, Parkin D M, Ferlay J, Li L, Chen Y. Estimates of cancer incidence in China for 2000 and projections for 2005.  Cancer Epidemiol Biomarkers Prev. 2005;  14 (1) 243-250
• 5 Hoffman P C, Mauer A M, Vokes E E. Lung cancer.  Lancet. 2000;  355 (9202) 479-485
• 6 Edward H L. The Cancer-Matrix Manual. 5th ed. Madison, WI: Advanced Medical Publishing; 2010: 208
• 7 Non-small Cell Lung Cancer Collaborative Group . Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials.  BMJ. 1995;  311 (7010) 899-909
• 8 Mountain C F. Revisions in the International System for Staging Lung Cancer.  Chest. 1997;  111 (6) 1710-1717
• 9 Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon J P, Vansteenkiste J. International Adjuvant Lung Cancer Trial Collaborative Group . Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.  N Engl J Med. 2004;  350 (4) 351-360
• 10 Douillard J Y, Rosell R, De Lena M et al.. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.  Lancet Oncol. 2006;  7 (9) 719-727
• 11 Pepe C, Hasan B, Winton T L National Cancer Institute of Canada and Intergroup Study JBR.10 et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10.  J Clin Oncol. 2007;  25 (12) 1553-1561
• 12 Burdett S, Stewart L A, Rydzewska L. A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer.  J Thorac Oncol. 2006;  1 (7) 611-621
• 13 Pignon J P, Tribodet H, Scagliotti G V LACE Collaborative Group et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.  J Clin Oncol. 2008;  26 (21) 3552-3559
• 14 Holmes E, Bleehen N, Le Chevalier T et al.. Postoperative adjuvant treatments for non-small cell lung cancer: a consensus report.  Lung Cancer. 1991;  7 11-13
• 15 Keller S M, Adak S, Wagner H Eastern Cooperative Oncology Group et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer.  N Engl J Med. 2000;  343 (17) 1217-1222
• 16 Scagliotti G V, Fossati R, Torri V Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer.  J Natl Cancer Inst. 2003;  95 (19) 1453-1461
• 17 Waller D, Peake M D, Stephens R J et al.. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial.  Eur J Cardiothorac Surg. 2004;  26 (1) 173-182
• 18 Arriagada R, Dunant A, Pignon J P et al.. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer.  J Clin Oncol. 2010;  28 (1) 35-42
• 19 Winton T, Livingston R, Johnson D National Cancer Institute of Canada Clinical Trials Group et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer.  N Engl J Med. 2005;  352 (25) 2589-2597
• 20 Butts C A, Ding K, Seymour L et al.. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10.  J Clin Oncol. 2010;  28 (1) 29-34
• 21 Strauss G M, Herndon II J E, Maddaus M A et al.. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.  J Clin Oncol. 2008;  26 (31) 5043-5051
• 22 Hamada C, Tanaka F, Ohta M et al.. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer.  J Clin Oncol. 2005;  23 (22) 4999-5006
• 23 Ardizzoni A, Boni L, Tiseo M CISCA (CISplatin versus CArboplatin) Meta-analysis Group et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.  J Natl Cancer Inst. 2007;  99 (11) 847-857
• 24 Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer.  J Clin Oncol. 2004;  22 (19) 3852-3859
• 25 Depierre A, Milleron B, Moro-Sibilot D French Thoracic Cooperative Group et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer.  J Clin Oncol. 2002;  20 (1) 247-253
• 26 Gilligan D, Nicolson M, Smith I et al.. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review.  Lancet. 2007;  369 (9577) 1929-1937
• 27 Pisters K M, Vallières E, Crowley J J et al.. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.  J Clin Oncol. 2010;  28 (11) 1843-1849
• 28 Scagliotti G V, Parikh P, von Pawel J et al.. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.  J Clin Oncol. 2008;  26 (21) 3543-3551
• 29 Lim E, Harris G, Patel A, Adachi I, Edmonds L, Song F. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials.  J Thorac Oncol. 2009;  4 (11) 1380-1388
• 30 Felip E, Rosell R, Maestre J A Spanish Lung Cancer Group et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer.  J Clin Oncol. 2010;  28 (19) 3138-3145
• 31 Reck 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 (8) 1227-1234
• 32 Sandler A, Gray R, Perry M C et al.. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.  N Engl J Med. 2006;  355 (24) 2542-2550
• 33 Kelly K, Chansky K, Gaspar L E et al.. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023.  J Clin Oncol. 2008;  26 (15) 2450-2456
• 34 Thatcher N, Chang A, Parikh P et al.. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).  Lancet. 2005;  366 (9496) 1527-1537
• 35 Olaussen K A, Dunant A, Fouret P IALT Bio Investigators et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.  N Engl J Med. 2006;  355 (10) 983-991
• 36 Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer.  N Engl J Med. 2007;  356 (8) 800-808
• 37 Potti A, Mukherjee S, Petersen R et al.. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer.  N Engl J Med. 2006;  355 (6) 570-580
• 38 Pisters K M, Evans W K, Azzoli C G Cancer Care Ontario et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline.  J Clin Oncol. 2007;  25 (34) 5506-5518
• 39 Robinson L A, Ruckdeschel J C, Wagner Jr H, Stevens C W. American College of Chest Physicians . Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition).  Chest. 2007;  132 (3, Suppl) 243S-265S
• 40 Scott W J, Howington J, Feigenberg S, Movsas B, Pisters K. American College of Chest Physicians . Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition).  Chest. 2007;  132 (3, Suppl) 234S-242S
• 41 NCCN clinical practice guidelines in oncology: non-small cell lung cancer version 1. 2011. http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf Accessed November 3, 2010
• 42 Mountain C F. The international system for staging lung cancer.  Semin Surg Oncol. 2000;  18 (2) 106-115
• 43 Schiller J H. Small cell lung cancer: defining a role for emerging platinum drugs.  Oncology. 2002;  63 (2) 105-114
• 44 NSCLC Meta-Analyses Collaborative Group . Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials.  J Clin Oncol. 2008;  26 (28) 4617-4625
• 45 Souquet P J, Chauvin F, Boissel J P et al.. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis.  Lancet. 1993;  342 (8862) 19-21
• 46 Baggstrom M Q, Stinchcombe T E, Fried D B, Poole C, Hensing T A, Socinski M A. Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis.  J Thorac Oncol. 2007;  2 (9) 845-853
• 47 Kelly K, Crowley J, Bunn Jr P A et al.. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non—small-cell lung cancer: a Southwest Oncology Group trial.  J Clin Oncol. 2001;  19 (13) 3210-3218
• 48 Schiller J H, Harrington D, Belani C P Eastern Cooperative Oncology Group et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.  N Engl J Med. 2002;  346 (2) 92-98
• 48a LeChevalier T, Scagliotti G, Natale R et al.. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimen in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.  Lung Cancer. 2005;  47 (1) 69-80
• 49 Ohe Y, Ohashi Y, Kubota K et al.. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan.  Ann Oncol. 2007;  18 (2) 317-323
• 50 Fossella F, Pereira J R, von Pawel J et al.. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.  J Clin Oncol. 2003;  21 (16) 3016-3024
• 51 Smit E F, van Meerbeeck J P, Lianes P European Organization for Research and Treatment of Cancer Lung Cancer Group et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975.  J Clin Oncol. 2003;  21 (21) 3909-3917
• 52 Booton R, Lorigan P, Anderson H et al.. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).  Ann Oncol. 2006;  17 (7) 1111-1119
• 53 Danson S, Middleton M R, O'Byrne K J et al.. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma.  Cancer. 2003;  98 (3) 542-553
• 54 Pujol J L, Breton J L, Gervais R et al.. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin.  Ann Oncol. 2005;  16 (4) 602-610
• 55 Azzoli C G, Baker Jr S, Temin S American Society of Clinical Oncology et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer.  J Clin Oncol. 2009;  27 (36) 6251-6266
• 56 Bergers G, Benjamin L E. Tumorigenesis and the angiogenic switch.  Nat Rev Cancer. 2003;  3 (6) 401-410
• 57 Ellis L M, Hicklin D J. VEGF-targeted therapy: mechanisms of anti-tumour activity.  Nat Rev Cancer. 2008;  8 (8) 579-591
• 58 Jain R K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.  Science. 2005;  307 (5706) 58-62
• 59 Augustin H G. Antiangiogenic tumour therapy: will it work?.  Trends Pharmacol Sci. 1998;  19 (6) 216-222
• 60 Dvorak H F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.  J Clin Oncol. 2002;  20 (21) 4368-4380
• 61 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 (21) 1182-1186
• 62 Johnson D H, Fehrenbacher L, Novotny W F et al.. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.  J Clin Oncol. 2004;  22 (11) 2184-2191
• 63 Besse B, Lasserre S F, Compton P, Huang J, Augustus S, Rohr U P. Bevacizumab safety in patients with central nervous system metastases.  Clin Cancer Res. 2010;  16 (1) 269-278
• 64 Scagliotti G, Von Pawel J, Reck M et al.. Sorafenib plus carboplatin/paclitaxel in chemonaive patients with stage IIIB-IV non small cell lung cancer (NSCLC): interim analysis (IA) results from the phase III, randomized, double-blind, placebo-controlled, ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC) trial.  J Thorac Oncol. 2008;  3 (Suppl 1) S97-S98
• 65 Salomon D S, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies.  Crit Rev Oncol Hematol. 1995;  19 (3) 183-232
• 66 Ohsaki Y, Tanno S, Fujita Y et al.. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression.  Oncol Rep. 2000;  7 (3) 603-607
• 67 Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas.  Br J Cancer. 1998;  77 (4) 663-669
• 68 Laack E, Sauter G, Bokemeyer C. Lessons learnt from gefitinib and erlotinib: Key insights into small-molecule EGFR-targeted kinase inhibitors in non-small cell lung cancer.  Lung Cancer. 2010;  69 (3) 259-264
• 69 Wieduwilt M J, Moasser M M. The epidermal growth factor receptor family: biology driving targeted therapeutics.  Cell Mol Life Sci. 2008;  65 (10) 1566-1584
• 70 Pirker R, Pereira J R, Szczesna A FLEX Study Team 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 (9674) 1525-1531
• 71 O' Byrne K, Bondarenko I, Barrios C et al.. Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study.  [abstract 8007] J Clin Oncol. 2009;  27 (15S)
• 72 Hirsch F R, Herbst R S, Olsen C et al.. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy.  J Clin Oncol. 2008;  26 (20) 3351-3357
• 73 Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer?.  Lancet Oncol. 2006;  7 (6) 499-507
• 74 Kim E S, Hirsh V, Mok T et al.. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.  Lancet. 2008;  372 (9652) 1809-1818
• 75 Shepherd F A, Rodrigues Pereira J, Ciuleanu T National Cancer Institute of Canada Clinical Trials Group et al. Erlotinib in previously treated non-small-cell lung cancer.  N Engl J Med. 2005;  353 (2) 123-132
• 76 Lynch T J, Bell D W, Sordella R et al.. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.  N Engl J Med. 2004;  350 (21) 2129-2139
• 77 Paez J G, Jänne P A, Lee J C et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.  Science. 2004;  304 (5676) 1497-1500
• 78 Pao W, Miller V, Zakowski M et al.. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.  Proc Natl Acad Sci U S A. 2004;  101 (36) 13306-13311
• 79 Sequist L V, Lynch T J. EGFR tyrosine kinase inhibitors in lung cancer: an evolving story.  Annu Rev Med. 2008;  59 429-442
• 80 Kimura H, Kasahara K, Shibata K et al.. EGFR mutation of tumor and serum in gefitinib-treated patients with chemotherapy-naive non-small cell lung cancer.  J Thorac Oncol. 2006;  1 (3) 260-267
• 81 Lin W C, Chiu C H, Liou J L, Chen Y M, Perng R P, Tsai C M. Gefitinib as front-line treatment in Chinese patients with advanced non-small-cell lung cancer.  Lung Cancer. 2006;  54 (2) 193-199
• 82 Niho S, Kubota K, Goto K et al.. First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer: a phase II study.  J Clin Oncol. 2006;  24 (1) 64-69
• 83 Suzuki R, Hasegawa Y, Baba K et al.. A phase II study of single-agent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer.  Br J Cancer. 2006;  94 (11) 1599-1603
• 84 Mok T S, Wu Y L, Thongprasert S et al.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.  N Engl J Med. 2009;  361 (10) 947-957
• 85 Gatzemeier 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 (12) 1545-1552
• 86 Herbst R S, Prager D, Hermann R TRIBUTE Investigator Group 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 (25) 5892-5899
• 87 Fukuoka M, Yano S, Giaccone G et al.. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].  J Clin Oncol. 2003;  21 (12) 2237-2246
• 88 Kris M G, Natale R B, Herbst R S et al.. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.  JAMA. 2003;  290 (16) 2149-2158
• 89 Pérez-Soler R, Chachoua A, Hammond L A et al.. Determinants of tumor response and survival with erlotinib in patients with non—small-cell lung cancer.  J Clin Oncol. 2004;  22 (16) 3238-3247
• 90 Ceppi P, Volante M, Saviozzi S et al.. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase.  Cancer. 2006;  107 (7) 1589-1596
• 91 Hanauske A R, Eismann U, Oberschmidt O et al.. In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression.  Invest New Drugs. 2007;  25 (5) 417-423
• 92 Karp D D, Paz-Ares L G, Novello S et al.. Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer.  J Clin Oncol. 2009;  27 (15) 2516-2522
• 93 Jassem J, Langer C, Karp D et al.. Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC).  [abstract 7500] J Clin Oncol. 2010;  28 (Suppl) 539s
• 94 Ciuleanu T, Brodowicz T, Zielinski C et al.. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.  Lancet. 2009;  374 (9699) 1432-1440
• 95 Soon Y Y, Stockler M R, Askie L M, Boyer M J. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials.  J Clin Oncol. 2009;  27 (20) 3277-3283
• 96 Belani C P, Waterhouse D M, Ghazal H et al.. Phase III study of maintenance gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC).  [abstract 7506] J Clin Oncol. 2010;  28 (15 Suppl) 540s
• 97 Cappuzzo F, Ciuleanu T, Stelmakh L SATURN investigators et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.  Lancet Oncol. 2010;  11 (6) 521-529
• 98 Herbst R S, O'Neill V J, Fehrenbacher L et al.. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer.  J Clin Oncol. 2007;  25 (30) 4743-4750
• 99 Miller V, O'Connor P, Soh C, Kabbinavar F. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC).  [abstract 8002] J Clin Oncol. 2009;  27 (15 Suppl)
• 100 Hanna N, Shepherd F A, Fossella F V et al.. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.  J Clin Oncol. 2004;  22 (9) 1589-1597
• 101 Novello S, Le Chevalier T. Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease.  Oncology (Williston Park). 2003;  17 (4) 457-464, 469–471, discussion 471, 478–480, 483–484
• 102 Shepherd F A, Dancey J, Ramlau R et al.. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.  J Clin Oncol. 2000;  18 (10) 2095-2103
• 103 Bezjak A, Tu D, Seymour L National Cancer Institute of Canada Clinical Trials Group Study BR. 21 et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR. 21.  J Clin Oncol. 2006;  24 (24) 3831-3837
• 104 Soda M, Choi Y L, Enomoto M et al.. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.  Nature. 2007;  448 (7153) 561-566
• 105 Inamura K, Takeuchi K, Togashi Y et al.. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.  Mod Pathol. 2009;  22 (4) 508-515
• 106 Wong D W, Leung E L, So K K University of Hong Kong Lung Cancer Study Group et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.  Cancer. 2009;  115 (8) 1723-1733
• 107 Kwak E, Camidge D, Clark J et al.. Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066.  [abstract 3509] J Clin Oncol. 2009;  27 (Suppl) 148s
• 108 Shaw A, Costa D, Iafrate A. Clinical activity of the oral ALK and MET inhibitor PF-02341066 in non-small cell lung cancer (NSCLC) with EML4-ALK translocations.  J Thorac Oncol. 2009;  4 (Suppl 1) S305
• 109 Kwak E L, Bang Y J, Camidge D R et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.  N Engl J Med. 2010;  363 (18) 1693-1703
• 110 Heymach J V, Johnson B E, Prager D et al.. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer.  J Clin Oncol. 2007;  25 (27) 4270-4277
• 111 Herbst R S, Sun Y, Korfee S et al.. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZODIAC).  [abstract CRA 8003] J Clin Oncol. 2009;  27 (Suppl) 807s
• 112 De Boer R, Arrieta O, Gottfried M et al.. Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZEAL).  [abstract 8010] J Clin Oncol. 2009;  27 (Suppl) 15s
• 113 Natale R B, Thongprasert S, Greco F A et al.. Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST).  [abstract 8009] J Clin Oncol. 2009;  27 (15 Suppl)
• 114 Li D, Ambrogio L, Shimamura T et al.. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.  Oncogene. 2008;  27 (34) 4702-4711
• 115 Shih J, Yang C, Su W et al.. A phase II study of BIBW 2922, a novel irreversible dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in patients with adenocarcinoma of the lung and activation EGFR mutations after failure of one line of chemotherapy (LUX-Lung2).  [abstract 8013] J Clin Oncol. 2009;  27 (Suppl) 410s