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Targeted Therapies in Non–Small-Cell Lung Cancer: A Paradigm in Evolution
i ntroduction Targeted Therapies in Non–Small-Cell Lung Cancer: A Paradigm in Evolution Randeep Sangha, MD; Primo N. Lara, Jr, MD; Philip Mack, PhD; David R. Gandara, MD Advanced-stage non–small-cell lung cancer (NSCLC), once generally considered untreatable, is now a disease for which patients and oncologists sense new hope and new expectations from therapeutic intervention. Platinum-based chemotherapy has become universally accepted as the standard of care for fit patients, with demonstrated improvement in overall survival as well as quality of life and symptom control.1-2 Nevertheless, recent studies suggest the relative equivalency of several different chemotherapy regimens, leaving the practicing oncologist with an empiric decision-making process in terms of what regimen to use in which patient.3 Furthermore, recent attempts to develop so-called targeted therapies in NSCLC have resulted in many more failures than successes, the notable exceptions being the antiangiogenic agent bevacizumab and erlotinib, a tyrosine kinase inhibitor (TKI) directed against the epidermal growth factor receptor (EGFR).4-5 Even here, 4 large randomized trials have failed to demonstrate increased efficacy of EGFR TKIs (erlotinib or gefitinib) plus concurrent chemotherapy, a major disappointment in drug development for NSCLC.6-9 In this supplement to Clinical Lung Cancer, we revisit the paradigm of targeted therapies, taking into account recent failures as well as recent successes in their clinical application to NSCLC. Moving forward, there is a growing consensus that the therapeutic ratio of targeted therapies will be highest in patient populations in which the targeted pathway is a driving force in tumor cell proliferation and survival. Thus, the appropriate selection of patients, based on predictive biomarkers, will increase the likelihood of efficacy in a defined subgroup and reduce toxicities and costs for patients unlikely to benefit. The article by Bar et al emphasizes the promise of multitargeted therapies as well as the possible pitfalls in this therapeutic approach. It is worthwhile to point out that the use of trastuzumab in breast cancer is largely restricted to patients defined as having
University of California, Davis Cancer Center, 4501 X Street, Sacramento, CA 95817
HER2-positive disease, thereby maximizing the potential for benefit. In contrast, the addition of bevacizumab to chemotherapy currently represents the “untargeted use of a targeted agent” because there are no currently accepted biomarkers predictive for efficacy. Here, the article by Manegold updates clinical trial–derived data in support of the efficacy of antiangiogenic therapy and highlights new toxicities associated with this drug class (also detailed by Bar et al). Pirker and colleagues discuss the perplexing data regarding EGFR inhibitors in NSCLC and the emerging differences between EGFR TKIs and monoclonal antibodies such as cetuximab: clear activity of TKIs as single agents in clinically selected patient populations but lack of efficacy in combination with concurrent chemotherapy versus the apparent lesser activity of cetuximab as a single agent and no “hypersensitivity” in patients with EGFR mutant tumors but additive activity with concurrent chemotherapy in the FLEX trial. Clearly, these EGFR inhibitors are different drugs in NSCLC. Furthermore, this supplement explores novel chemotherapeutic strategies in the articles by Spigel and Greco, Scagliotti and Salvaggi, and Gautschi et al. In particular, the potential to transform chemotherapy into “targeted therapy” by the use of biomarkers or pathologic features predictive of improved patient outcomes represents an evolution of the targeted therapy paradigm. After all, chemotherapeutic agents are designed to inhibit molecular targets largely associated with DNA synthesis, DNA replication, or microtubule function, as discussed by Gautschi et al. Pharmacogenomic approaches offer the potential to tailor a chemotherapy regimen for patient populations expressing the appropriate tumor targets and, similarly, to avoid patient populations with host factors predicting excessive toxicity. In this regard, it is increasingly apparent that quantitating tumor expression levels of DNA repair genes, such as ERCC1, can guide clinical decision-making. Most intriguing is the hypothesis put forth by Scagliotti and Salvaggi that the chemotherapeutic agent pemetrexed is more active in the NSCLC histologic subtype of adenocarcinoma and that this enhanced activity can accounted for by differential expression of genes
This summary includes discussion of investigational and/or unlabeled uses of drugs, including the use of gemcitabine/carboplatin or docetaxel with gemcitabine, vinorelbine, or carboplatin in advanced non–small-cell lung cancer. Dr Sangha has no relevant relationships to disclose. Dr Mack has no relevant relationships to disclose. Dr Lara has no relevant relationships to disclose. Dr Gandara has received research support from Bristol-Myers Squibb and Eli Lilly and has served as a paid consultant for or been on the Advisory Board of Genentech BioOncology, AstraZeneca, sanofi-aventis, Pfizer, and Bayer.
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within targeted pathways. Thus, the paradigm of “targeted therapies” comes full circle: chemotherapy is actually targeted therapy and has been all along.
References 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311:899-909. 2. Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17:3188-94. 3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92-8.
4. 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; 355:2542-50. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123-32. 6. Giaccone 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; 22:777-84. 7. Herbst 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; 22:785-94. 8. 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; 25:1545-52. 9. 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; 23:5892-9.
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University of California, Davis Cancer Center, 4501 X Street, Sacramento, CA 95817
HER2-positive disease, thereby maximizing the potential for benefit. In contrast, the addition of bevacizumab to chemotherapy currently represents the “untargeted use of a targeted agent” because there are no currently accepted biomarkers predictive for efficacy. Here, the article by Manegold updates clinical trial–derived data in support of the efficacy of antiangiogenic therapy and highlights new toxicities associated with this drug class (also detailed by Bar et al). Pirker and colleagues discuss the perplexing data regarding EGFR inhibitors in NSCLC and the emerging differences between EGFR TKIs and monoclonal antibodies such as cetuximab: clear activity of TKIs as single agents in clinically selected patient populations but lack of efficacy in combination with concurrent chemotherapy versus the apparent lesser activity of cetuximab as a single agent and no “hypersensitivity” in patients with EGFR mutant tumors but additive activity with concurrent chemotherapy in the FLEX trial. Clearly, these EGFR inhibitors are different drugs in NSCLC. Furthermore, this supplement explores novel chemotherapeutic strategies in the articles by Spigel and Greco, Scagliotti and Salvaggi, and Gautschi et al. In particular, the potential to transform chemotherapy into “targeted therapy” by the use of biomarkers or pathologic features predictive of improved patient outcomes represents an evolution of the targeted therapy paradigm. After all, chemotherapeutic agents are designed to inhibit molecular targets largely associated with DNA synthesis, DNA replication, or microtubule function, as discussed by Gautschi et al. Pharmacogenomic approaches offer the potential to tailor a chemotherapy regimen for patient populations expressing the appropriate tumor targets and, similarly, to avoid patient populations with host factors predicting excessive toxicity. In this regard, it is increasingly apparent that quantitating tumor expression levels of DNA repair genes, such as ERCC1, can guide clinical decision-making. Most intriguing is the hypothesis put forth by Scagliotti and Salvaggi that the chemotherapeutic agent pemetrexed is more active in the NSCLC histologic subtype of adenocarcinoma and that this enhanced activity can accounted for by differential expression of genes
This summary includes discussion of investigational and/or unlabeled uses of drugs, including the use of gemcitabine/carboplatin or docetaxel with gemcitabine, vinorelbine, or carboplatin in advanced non–small-cell lung cancer. Dr Sangha has no relevant relationships to disclose. Dr Mack has no relevant relationships to disclose. Dr Lara has no relevant relationships to disclose. Dr Gandara has received research support from Bristol-Myers Squibb and Eli Lilly and has served as a paid consultant for or been on the Advisory Board of Genentech BioOncology, AstraZeneca, sanofi-aventis, Pfizer, and Bayer.
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Clinical Lung Cancer Vol 9 • Suppl 3 March 2008
within targeted pathways. Thus, the paradigm of “targeted therapies” comes full circle: chemotherapy is actually targeted therapy and has been all along.
References 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311:899-909. 2. Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17:3188-94. 3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92-8.
4. 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; 355:2542-50. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123-32. 6. Giaccone 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; 22:777-84. 7. Herbst 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; 22:785-94. 8. 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; 25:1545-52. 9. 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; 23:5892-9.
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