Skip to main content

Advertisement

SpringerLink
Log in

Investigational agents in the management of non-small cell lung cancer

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Novel therapeutic agents are playing an increasingly prominent role in the treatment of non-small cell lung cancer (NSCLC). Drugs that target important oncogenic proteins or pathways, whether used as monotherapy or in combination with established regimens, have largely supplanted traditional cytotoxic agents in modern clinical trials. In particular, inhibitors of the epidermal growth factor receptor (EGFR) and/or vascular endothelial growth factor (VEGF) pathways have shown significant clinical activity and in some cases have changed the standard of care for advanced NSCLC. In the past year, an unprecedented number of trials have been reported using agents targeting the EGFR (erlotinib, gefitinib, cetuximab), VEGF (bevacizumab) or the VEGF receptor (sorafenib, sunitinib, cediranib), and inhibitors of both pathways (vandetanib, erlotinib, or cetuximab plus bevacizumab). This review focuses on recently reported trials of targeted agents that have the potential to affect the treatment of patients with NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. American Cancer Society: Statistics. Cancer facts & figures 2008. Available at http://www.cancer.org/docroot/stt/content/stt_1x_cancer_facts_and_figures_2008.asp. Accessed March 2009.

  2. Greenlee RT, Hill-Harmon MB, Murray T, et al.: Cancer statistics, 2001. CA Cancer J Clin 2001, 51:15–36.

    Article  PubMed  CAS  Google Scholar 

  3. Hynes NE, Lane HA: ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005, 5:341–354.

    Article  PubMed  CAS  Google Scholar 

  4. Sordella R, Bell DW, Haber DA, et al.: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004, 305:1163–1167.

    Article  PubMed  CAS  Google Scholar 

  5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005, 353:123–132.

    Article  PubMed  CAS  Google Scholar 

  6. Herbst 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, 23:5892–5899.

    Article  PubMed  CAS  Google Scholar 

  7. Gatzemeier U, Pluzanska A, 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]. J Clin Oncol 2004, 22(Suppl 14):7010.

    Google Scholar 

  8. Davies AM, Ho C, Lara PN Jr, et al.: Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer 2006, 7:385–388.

    Article  PubMed  CAS  Google Scholar 

  9. Liao ML, Wu Y, Srimuninnimit V, et al.: Sequential scheduling of erlotinib with chemotherapy as 1stline therapy for advanced NSCLC: subgroup analyses of a randomized double-blind placebo-controlled phase II trial (FASTACT). J Thorac Oncol 2008, 3:S265.

    Article  Google Scholar 

  10. Fidias PM, Dakhil SR, Lyss AP, et al.: Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009, 27:591–598.

    Article  PubMed  CAS  Google Scholar 

  11. Ciuleanu TE, Brodowicz T, Belani CP, et al.: Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study [abstract]. J Clin Oncol 2008, 26(May 20 Suppl):8011.

    Google Scholar 

  12. Phase III study (SATURN) showed Tarceva improved progression-free survival as a first-line maintenance therapy for advanced non-small cell lung cancer [press release]. South San Francisco, CA: Genentech; November 6, 2008. Available at http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11647. Accessed March 2009.

  13. Kris MG, Natale RB, Herbst RS, 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.

    Article  PubMed  CAS  Google Scholar 

  14. 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. J Clin Oncol 2003, 21:2237–2246.

    Article  PubMed  CAS  Google Scholar 

  15. 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 2004, 366:1527–1537.

    Article  Google Scholar 

  16. Sequist LV, Martins RG, Spigel D, et al.: First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008, 26:2442–2449.

    Article  PubMed  CAS  Google Scholar 

  17. Takano T, Fukui T, Ohe Y, et al.: EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol 2008, 26:5589–5595.

    Article  PubMed  CAS  Google Scholar 

  18. Mok T: Phase III, randomised, open-label, first-line study of gefitinib vs carboplatin/paclitaxel (C/P) in clinically selected patients with advanced non-small-cell lung cancer (NSCLC) [abstract]. Ann Oncol 2008, 19(Suppl 8):LBA2.

    Google Scholar 

  19. Kim ES, 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, 372:1809–1818.

    Article  PubMed  CAS  Google Scholar 

  20. Kelly K, Chansky K, Gaspar LE, 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, 26:2450–2456.

    Article  PubMed  CAS  Google Scholar 

  21. Maheswaran S, Sequist LV, Nagrath S, et al.: Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008, 359:366–377.

    Article  PubMed  CAS  Google Scholar 

  22. Kimura H, Kasahara K, Kawaishi M, et al.: Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer. Clin Cancer Res 2006, 12:3915–3921.

    Article  PubMed  CAS  Google Scholar 

  23. Butts CA, Bodkin D, Middleman EL, et al.: Randomized phase II study of gemcitabine plus cisplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol 2007, 25:5777–5784.

    Article  PubMed  CAS  Google Scholar 

  24. Lynch T, Patel T, Dreisbach L, et al.: A randomized multicenter phase III study of cetuximab (Erbitux[R]) in combination with taxane/carboplatin versus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer (NSCLC): B3-03. J Thorac Oncol 2007, 2:S340–S341.

    Article  Google Scholar 

  25. Lynch TJ, Patel T, Dreisbach L, et al.: Overall survival (os) results from the phase III trial BMS 099: cetuximab+taxane/carboplatin as 1st-line treatment for advanced NSCLC [abstract]. Presented at the 2008 International Association for the Study of Lung Cancer (IASLC)/American Society for Therapeutic Radiology and Oncology (ASTRO) Multidisciplinary Symposium on Thoracic Malignancies. Chicago, IL; November 13–15, 2008.

  26. Pirker R, Szczesna A, von Pawel J, et al.: FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2008, 26(May 20 Suppl):3.

    Article  Google Scholar 

  27. Gatzemeier U: FLEX: cetuximab in combination with platinum-based chemotherapy (CT) improves survival versus CT alone in the first-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC) [abstract]. Presented at ASTRO/IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology. Chicago, IL; November 13–15, 2008.

  28. Khambata-Ford S, Harbison CT, Hart LL, et al.: K-Ras mutations (mt) and EGFR-related markers as potential predictors of cetuximab benefit in 1st line advanced NSCLC: results from the BMS099 study [abstract]. Presented at ASTRO/IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology. Chicago, IL; November 13–15, 2008.

  29. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003, 9:669–676.

    Article  PubMed  CAS  Google Scholar 

  30. Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355:2542–2550.

    Article  PubMed  CAS  Google Scholar 

  31. Manegold C, von Pawel J, Zatloukal P, et al.: Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapynaïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704 [abstract]. J Clin Oncol 2007, 25(June 20 Suppl):LBA7514.

    Google Scholar 

  32. 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, 27:1227–1234.

    Article  PubMed  CAS  Google Scholar 

  33. Hanna NH, von Pawel J, Reck M, et al.: Carboplatin/paclitaxel with/without sorafenib in chemonaive patients with stage IIIB-IV non-small cell lung cancer (NSCLC): interim analysis (IA) results from a randomized phase III trial (ESCAPE). J Thorac Oncol 2008, 3:S268.

    Google Scholar 

  34. Socinski MA, Novello S, Brahmer JR, et al.: Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 2008, 26:650–656.

    Article  PubMed  CAS  Google Scholar 

  35. Socinski MA, Samant M, Strickland D, et al.: Sabre-l: a randomized phase II trial evaluating the safety and efficacy of combining sunitinib (S) with bevacizumab (BV) paclitaxel/carboplatin (PC) as first-line treatment for metastatic nonsquamous non-small cell lung cancer (NSCLC). J Thorac Oncol 2008, 3:S281.

    Google Scholar 

  36. Genentech: Important drug warning. Subject: microangiopathic hemolytic anemia (MAHA) in patients treated with Avastin. Available at http://www.fda.gov/medwatch/safety/2008/MAHA_DHCP.pdf. Accessed March 2009.

  37. AstraZeneca provides update on cediranib (RECENTIN®, AZD2171) clinical development programme [news release]. Wilmington, DE: AstraZeneca; February 27, 2008. Available at http://www.astrazeneca-us.com/search/?itemId=2289031. Accessed March 2009.

  38. Herbst RS, Johnson DH, 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.

    Article  PubMed  CAS  Google Scholar 

  39. Herbst RS, O’Neill VJ, 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(June 20 Suppl):4743–4750.

    Article  PubMed  CAS  Google Scholar 

  40. Hainsworth J, Herbst R: A phase III, multicenter, placebocontrolled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (Beta). Presented at ASTRO/IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology. Chicago, IL; November 13–15, 2008.

  41. Phase III study showed Tarceva in combination with avastin as first-line maintenance therapy improved progression-free survival in advanced lung cancer [press release]. South San Francisco, CA: Genentech; February 2, 2009. Available at http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11827. Accessed March 2009.

  42. Kim ES, Herbst RS, Moon J, et al.: S0536: SWOG phase II trial of carboplatin (C), paclitaxel (P), cetuximab (CX) and bevacizumab (B) followed by cetuximab and bevacizumab. J Thorac Oncol 2008, 3:S266.

    Google Scholar 

  43. Wedge SR, Ogilvie DJ, Dukes M, et al.: ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002, 62:4645–4655.

    PubMed  CAS  Google Scholar 

  44. Heymach JV, Johnson BE, 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, 25:4270–4277.

    Article  PubMed  CAS  Google Scholar 

  45. Heymach JV, Paz-Ares L, De Braud F, et al.: Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2008, 26:5407–5415.

    Article  PubMed  CAS  Google Scholar 

  46. Phase III studies show that vandetanib (ZACTIMA) brings clinical benefits to patients with lung cancer [press release]. Wilmington, DE: AstraZeneca; November 19, 2008. Available at http://astrazeneca.com/media/latest-press-releases/2008/4215815?itemId=4215815. Accessed March 2009.

  47. Karp DD, Paz-Ares LG, Blakely LJ, et al.: Efficacy of the anti-insulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2007, 25:7506.

    Google Scholar 

  48. Townsend DM, He L, Hutchens S, et al.: NOV-002, a glutathione disulfide mimetic, as a modulator of cellular redox balance. Cancer Res 2008, 68:2870–2877.

    Article  PubMed  CAS  Google Scholar 

  49. Pazoles CJ, Gerstein H: NOV-002, a chemoprotectant/immunomodulator, added to first-line carboplatin/paclitaxel in advanced non-small cell lung cancer (NSCLC): a randomized phase 1/2, open-label, controlled study. J Clin Oncol 2006, 24(June 20 Suppl):17021.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, R-35, Cleveland, OH, 44195, USA

    Nathan A. Pennell

Authors
  1. Nathan A. Pennell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tarek Mekhail
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nathan A. Pennell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pennell, N.A., Mekhail, T. Investigational agents in the management of non-small cell lung cancer. Curr Oncol Rep 11, 275–284 (2009). https://doi.org/10.1007/s11912-009-0039-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-009-0039-x

Keywords

Search

Navigation