Semin Respir Crit Care Med 2005; 26(3): 323-332
DOI: 10.1055/s-2005-871991
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

New Biological Agents in the Treatment of Advanced Non-Small Cell Lung Cancer

Phuong Khanh H. Morrow1 , Edward S. Kim2
  • 1Departments of Cancer Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • 2Thoracic-Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
Further Information

Publication History

Publication Date:
29 June 2005 (online)

ABSTRACT

Molecularly targeted therapies that are more tumor specific in their efficacy, with associated fewer toxicities, are currently being developed. Specific biomarkers that may predict response or resistance to a particular agent are being sought. Several classes of compounds now target specific steps in cellular proliferation and apoptosis. These include epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial cell targeting agents, matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, retinoids, proteosome inhibitors, and raf/MAPkinase (mitogen-activated protein kinase) inhibitors. Many of these agents, such as bortezomib, have demonstrated promise in the fields of non-small cell lung cancer (NSCLC). However, a cautionary perspective must be maintained because agents such as bexarotene, which showed promise in early studies, have proved disappointing in randomized trials. As the number of therapeutic agents increases in NSCLC, there will be greater emphasis on the selection of an appropriate patient population in which to give specific, targeted therapies.

REFERENCES

  • 1 Jemal A, Murray T, Ward E et al.. Cancer statistics, 2005.  CA Cancer J Clin. 2005;  55 10-30
  • 2 Reck M, Gatzemeier U. Chemotherapy in stage-IV NSCLC.  Lung Cancer. 2004;  45(Suppl 2) S217-S222
  • 3 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 2129-2139
  • 4 Kobayashi S, Boggon T J, Dayaram T et al.. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.  N Engl J Med. 2005;  352 786-792
  • 5 Carpenter G, King Jr L, Cohen S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro.  Nature. 1978;  276 409-410
  • 6 Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.  Cell. 2002;  110 669-672
  • 7 Rusch V, Klimstra D, Venkatraman E, Pisters P W, Langenfeld J, Dmitrovsky E. Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression.  Clin Cancer Res. 1997;  3 515-522
  • 8 Nicholson R I, Gee J M, Harper M E. EGFR and cancer prognosis.  Eur J Cancer. 2001;  37(Suppl 4) S9-15
  • 9 Tateishi M, Ishida T, Mitsudomi T, Kaneko S, Sugimachi K. Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung.  Cancer Res. 1990;  50 7077-7080
  • 10 Perez-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 3238-3247
  • 11 Shepherd F, Pereira J, Ciuleanu T E et al.. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of first-line or second-line chemotherapy: a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial [abstract 7022].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)
  • 12 Gatzemeier U PA, Szczesna A et al.. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract 7010].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)
  • 13 Herbst R, Prager D, Hermann R et al.. TRIBUTE: a phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract 7011].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)
  • 14 Miller V, Patel J, Shah N et al.. The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) shows promising activity in patients with bronchioloalveolar cell carcinoma (BAC): preliminary results of a phase II trial [abstract 2491].  Proc Am Soc Clin Oncol. 2003;  22 619
  • 15 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 2237-2246
  • 16 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 2149-2158
  • 17 Herbst R S, Giaccone G, Schiller J H 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;  22 785-794
  • 18 AstraZeneca .Gefitinib (IressaTM) Lung Cancer ISEL Trial Shows No Overall Survival Advantage in a Highly Refractory Population. 2004
  • 19 Li S, Schmitz K R, Jeffrey P D, Wiltzius J J, Kussie P, Ferguson K M. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.  Cancer Cell. 2005;  7 301-311
  • 20 Baselga J, Pfister D, Cooper M R et al.. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin.  J Clin Oncol. 2000;  18 904-914
  • 21 Robert F BG, Dicke J et al.. Phase Ib/IIa study of anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, in combination with gemcitabine/carboplatin in patients with advanced non-small cell lung cancer (NSCLC) [abstract 2587].  Proc Am Soc Clin Oncol. 2003;  22
  • 22 Kim E S, Mauer A M, Tran H T et al.. A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer: final report [abstract 2581].  Proc Am Soc Clin Oncol. 2003;  22 642
  • 23 Gatzemeier U, Rosell R, Ramlau G et al.. Cetuximab (C225) in combination with cisplatin/vinorelbine vs. cisplatin/vinorelbine alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR) positive advanced non-small-cell lung cancer (NSCLC) [abstract 2582].  Proc Am Soc Clin Oncol. 2003;  22
  • 24 Bonner J A, Giralt J, Harari P M et al.. Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: a phase III study of high dose radiation therapy with or without cetuximab [abstract 5507].  Proc Am Soc Clin Oncol. 2004;  22
  • 25 Yang X D, Jia X C, Corvalan J R, Wang P, Davis C G. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy.  Crit Rev Oncol Hematol. 2001;  38 17-23
  • 26 Foon K A, Yang X D, Weiner L M et al.. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody.  Int J Radiat Oncol Biol Phys. 2004;  58 984-990
  • 27 Crawford J, Sandler A, Hammond J et al.. ABX-EGF in combination with paclitaxel and carboplatin for advanced non-small cell lung cancer (NSCLC) [abstract 7083].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)
  • 28 Gatzemeier U, Groth G, Hirsh V et al.. Gemcitabine/cisplatin alone and with trastuzumab (Herceptin) in patients with non-small cell lung cancer overexpressing HER2: results of a randomised phase II study [abstract 1185].  Proc Am Soc Clin Oncol. 2002;  21
  • 29 Denekamp J, Hobson B. Endothelial-cell proliferation in experimental tumours.  Br J Cancer. 1982;  46 711-720
  • 30 Kerbel R S. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents.  Bioessays. 1991;  13 31-36
  • 31 Herbst R S, Hidalgo M, Pierson A S, Holden S N, Bergen M, Eckhardt S G. Angiogenesis inhibitors in clinical development for lung cancer.  Semin Oncol. 2002;  29(1 Suppl 4) 66-77
  • 32 Gordon M S, Margolin K, Talpaz M et al.. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.  J Clin Oncol. 2001;  19 843-850
  • 33 Devore R, Fehrenbacher L, Herbst R et al.. A randomized phase II trial comparing RhuMab VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIB/IV NSCLC.  Proc Am Soc Clin Oncol. 2000; 
  • 34 Johnson D H, Devore R, Kabbinavar F et al.. Carboplatin (C) + paclitaxel (T) + RhuMab-VEGF (AVF) may prolong survival in advanced non-squamous lung cancer [abstract 1256].  Proc Am Soc Clin Oncol. 2001;  20
  • 35 Sandler A, Gray R, Brahmer J et al.. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599.  Proc Am Soc Clin Oncol. 2005;  23
  • 36 Herbst R S, Johnson D H, Mininberg E et al.. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.  J Clin Oncol. 2005;  23 2544-2555
  • 37 Fong T A, Shawver L K, Sun L et al.. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.  Cancer Res. 1999;  59 99-106
  • 38 Rosen L, Mulay N, Mayers A et al.. Phase I dose-escalating trial of SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies[abstract 843].  Proc Am Soc Clin Oncol. 1999;  18
  • 39 Kuenen B C, Rosen L, Smit E F et al.. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.  J Clin Oncol. 2002;  20 1657-1667
  • 40 Wedge S R, Ogilvie D J, Dukes M et al.. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration.  Cancer Res. 2002;  62 4645-4655
  • 41 Carlomagno F, Vitagliano D, Guida T et al.. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases.  Cancer Res. 2002;  62 7284-7290
  • 42 Hurwitz H, Halden S N, Eckhardt S et al.. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF signaling in patients with solid tumors [abstract 325].  Proc Am Soc Clin Oncol. 2002;  21
  • 43 Heymach J, Dong R P, Dimery C et al.. ZD6474, a novel antiangiogenic agent, in combination with docetaxel in patients with NSCLC: results of the run-in phase of a two-part, randomized phase II study [abstract 3051].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)
  • 44 Merchant J J, Kim K, Mehta M P et al.. Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer.  Clin Lung Cancer. 2000;  2 48-52 , discussion 53-54
  • 45 Sills Jr A K, Williams J I, Tyler B M et al.. Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.  Cancer Res. 1998;  58 2784-2792
  • 46 Patnaik A, Rowinsky E, Hammond L et al.. A phase I and pharmacokinetic study of the unique angiogenesis inhibitor squalamine lactate [abstract 623].  Proc Am Soc Clin Oncol. 1999;  18
  • 47 Bhargava P TN, Marshall J et al.. A phase I safety, tolerance, and pharmacokinetic study of rising dose, rising duration continuous infusion MSI-1256F (squalamine lactate) in patients with advanced malignancies) [abstract 623].  Proc Am Soc Clin Oncol. 1999;  18
  • 48 Kalidas M, Hammond L, Patnaik A et al.. A phase I and pharmacokinetic study of the angiogenesis inhibitor, squalamine lactate (MSI 1256-F) [abstract 698].  Proc Am Soc Clin Oncol. 2000;  19(180a)
  • 49 Nelson A R, Fingleton B, Rothenberg M L, Matrisian L M. Matrix metalloproteinases: biologic activity and clinical implications.  J Clin Oncol. 2000;  18 1135-1149
  • 50 Michael M, Babic B, Khokha R et al.. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer.  J Clin Oncol. 1999;  17 1802-1808
  • 51 Garbisa S, Scagliotti G, Masiero L et al.. Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy.  Cancer Res. 1992;  52 4548-4549
  • 52 Thomas P, Khokha R, Shepherd F A, Feld R, Tsao M S. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer.  J Pathol. 2000;  190 150-156
  • 53 Rizvi N A, Humphrey J S, Ness E A et al.. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer.  Clin Cancer Res. 2004;  10 1963-1970
  • 54 Leighl N B, Paz-Ares L, Douillard J Y 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 2831-2839
  • 55 Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.  Semin Oncol. 2001;  28 620-625
  • 56 Latreille J, Batist G, Laberge F et al.. Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer.  Clin Lung Cancer. 2003;  4 231-236
  • 57 Lowy D R, Willumsen B M. Function and regulation of ras.  Annu Rev Biochem. 1993;  62 851-891
  • 58 Bos J L. ras oncogenes in human cancer: a review.  Cancer Res. 1989;  49 4682-4689
  • 59 Xiong H Q. Molecular targeting therapy for pancreatic cancer.  Cancer Chemother Pharmacol. 2004;  54(Suppl 1) S69-S77
  • 60 Khuri F R, Glisson B S, Kim E S et al.. Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.  Clin Cancer Res. 2004;  10 2968-2976
  • 61 Kim E S, Kies M, Fosella F V et al.. A phase I/II study of the farnesyl transferase inhibitor (FTI) SCH66336 with paclitaxel in taxane-refractory/resistant patients with non-small cell lung cancer (NSCLC): final report.  Proc Annu Meet Am Assoc Cancer Res. 2003;  43
  • 62 Adjei A, Mauer A, Marks R A. Phase II study of the farnesyltransferase inhibitor R115777 in patients with advanced non-small cell lung cancer [abstract 1156].  Proc Am Soc Clin Oncol. 2002;  21
  • 63 Rose W C, Lee F Y, Fairchild C R et al.. Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor.  Cancer Res. 2001;  61 7507-7517
  • 64 Ryan D P, Eder Jr J P, Puchlaski T et al.. Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors.  Clin Cancer Res. 2004;  10 2222-2230
  • 65 Mackay H J, Hoekstra R, Eskens F A et al.. A phase I pharmacokinetic and pharmacodynamic study of the farnesyl transferase inhibitor BMS-214662 in combination with cisplatin in patients with advanced solid tumors.  Clin Cancer Res. 2004;  10 2636-2644
  • 66 Dy G K, Bruzek L M, Croghan G A et al.. A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.  Clin Cancer Res. 2005;  11 1877-1883
  • 67 Khuri F R, Rigas J R, Figlin R A et al.. Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.  J Clin Oncol. 2001;  19 2626-2637
  • 68 Ligand . Targretin fails to meet primary or secondary endpoints in pivotal trials for front-line non-small cell lung cancer. 2005
  • 69 Estephan F, Hasham-Jiwa N, Klementich F et al.. Phase II trial of gemcitabine, carboplatin, and bexarotene in patients with newly diagnosed, locally advanced or metastatic non-small cell carcinoma of the lung [abstract 7308].  Proc Am Soc of Clin Oncol. 2005;  23
  • 70 Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson K C. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.  Oncogene. 2001;  20 4519-4527
  • 71 Mitsiades N, Mitsiades C S, Poulaki V et al.. Molecular sequelae of proteasome inhibition in human multiple myeloma cells.  Proc Natl Acad Sci U S A. 2002;  99 14374-14379
  • 72 Hideshima T, Richardson P, Chauhan D et al.. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.  Cancer Res. 2001;  61 3071-3076
  • 73 Fanucchi M P, Belt R J, Fosella F V et al.. Phase (ph) 2 study of bortezomib ± docetaxel in previously treated patients (pts) with advanced non-small cell lung cancer (NSCLC): preliminary results [abstract 7107].  Proc Am Soc Clin Oncol. 2004;  22(Suppl 14)

Edward S KimM.D. 

Department of Thoracic-Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center

1515 Holcombe Blvd., Box 432

Houston, TX 77030-4095

Email: ekim@mdanderson.org

    >