Developments in the Management of Advanced Non Small Cell Lung Cancer

Alexandra Kopitopoulou, Ioannis Ntanos, Muhammad W. Saif, Kostas Syrigos

Department of Pulmonology, “Sotiria” General Hospital, Athens, Greece.
Experimental Therapeutics, Tufts University School of Medicine, Boston, USA.
Oncology Unit GPP, “Sotiria” General Hospital, Athens School of Medicine, Athens, Greece.

DOI: 10.4236/jct.2013.41027                

Abstract

Background: Overall survival (OS) and quality of life in patients with advanced non small cell lung cancer (NSCLC) remains to the day highly unsatisfactory. Better understanding of the mechanisms of oncogenesis resulted in the development of new drugs, which target a specific stage in tumor development. Additionally, optimal timing of chemotherapy administration has been readdressed with the introduction of maintenance treatment in clinical practice. The aim of this review is to briefly summarize the developments in first line treatment of NSCLC with small molecule tyrosine kinase inhibitors, the role of crizotinib and the current options in maintenance treatment. Methodology A search was performed in the PubMed database and in Clinical Trials.gov using the keywords erlotinib, gefitinib, crizotinib and maintenance treatment. Findings were reported in form of a narrative review. Conclusions: First line treatment with small molecule TKIs for NSCLC is both effective and feasible. EGFR mutation status remains the main prognostic factor of response. Pemetrexed and Erlotinib, currently approved for Maintenance Treatment in NSCLC, seem to benefit patients with advanced disease. Identification of suitable candidates for Maintenance Treatment, optimal timing and agent selection are issues that still remain largely unanswered. Early study results promise that addition of crizotinib to the treatment regimen of ALK positive NSLCL is likely to be beneficiary for a substantial number of patients.

Keywords

Erlotinib; Gefitinib; Crizotinib; Maintenance Treatment; NSCLC

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	E. A. Kotteas, A. G. Charpidou and K. N. Syrigos, “Targeted Therapy for Nonsmall Cell Lung Cancer: Focusing on Angiogenesis, the Epidermal Growth Factor Receptor and Multikinase Inhibitors,” Anticancer Drugs, Vol. 21, No. 2, 2010, pp. 151-168. doi:10.1097/CAD.0b013e328334da02
[2]	A. Charpidou, D. Blatza, V. Anagnostou, K. N. Syrigos, “EGFR Mutations in Non-Small-Cell Lung Cancer— Clinical Implications,” In Vivo, Vol. 22, No. 4, 2008, pp. 529-536.
[3]	G. Giaccone, M. Gallegos Ruiz, T. Le Chevalier, et al., “Erlotinib for Frontline Treatment of Advanced Non-Small-Cell Lung Cancer: A Phase II Study,” Clinical Cancer Research, Vol. 12, No. 20, 2006, pp. 6049-6055. doi:10.1158/1078-0432.CCR-06-0260
[4]	M. Reck, E. Buchholz, K. S. Romer, et al., “Gefitinib Monotherapy in Chemotherapy-Naive Patients with Inoperable Stage III/IV Non-Smallcell Lung Cancer,” Clin Lung Cancer, Vol. 7, No. 6, 2006, pp. 406-411. doi:10.3816/CLC.2006.n.025
[5]	W. Akerley, K. M. Boucher, J. S. Bentz, et al., “A Phase II Study of Erlotinib as Initial Treatment for Patients with Stage IIIB-IV Non-Small-Cell Lung Cancer,” Journal of Thoracic Oncology, Vol. 4, No. 2, 2009, pp. 214-219. doi:10.1097/JTO.0b013e3181943bb9
[6]	D. M. Jackman, B. Y. Yeap, N. I. Lindeman, et al., “Phase II Clinical Trial of Chemotherapy-Naive Patients > or = 70 Years of Age Treated with Erlotinib for Advanced Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 25, No. 7, 2007, pp. 760-766. doi:10.1200/JCO.2006.07.5754
[7]	P. J. Hesketh, K. Chansky, A. J. Wozniak, et al., “Southwest Oncology Group Phase II Trial (S0341) of Erlotinib (OSI-774) in Patients with Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2,” Journal of Thoracic Oncology, Vol. 3, No. 9, 2008, pp. 1026-1031. doi:10.1097/JTO.0b013e318183aa1f
[8]	L. Crino, F. Cappuzzo, P. Zatloukal, et al., “Gefitinib versus Vinorelbine in Chemotherapy-Naive Elderly Patients with Advanced Non-Small-Cell Lung Cancer (INVITE): A Randomized, Phase II Study,” Journal of Clinical Oncology, Vol. 26, No. 26, 2008, pp. 4253-4260. doi:10.1200/JCO.2007.15.0672
[9]	R. Lilenbaum, R. Axelrod, S. Thomas, et al., “Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2,” Journal of Clinical Oncology, Vol. 26, No. 6, 2008, pp. 863-869. doi:10.1200/JCO.2007.13.2720
[10]	S. Niho, K. Kubota, K. Goto, et al., “First-Line Single Agent Treatment with Gefitinib in Patients with Advanced Non-Small-Cell Lung Cancer: A Phase II Study,” Journal of Clinical Oncology, Vol. 24, No. 1, 2006, pp. 64-69. doi:10.1200/JCO.2005.02.5825
[11]	C. H. Yang, C. J. Yu, J. Y. Shih, et al., “Specific EGFR Mutations Predict Treatment Outcome of Stage IIIB/IV Patients with Chemotherapy-Naive Non-Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy,” Journal of Clinical Oncology, Vol. 26, No. 16, 2008, pp. 2745-2753. doi:10.1200/JCO.2007.15.6695
[12]	N. Ebi, H. Semba, S. J. Tokunaga, et al., “A Phase II Trial of Gefitinib Monotherapy in Chemotherapy-Naive Patients of 75 Years or Older with Advanced Non-Small-Cell Lung Cancer,” Journal of Thoracic Oncology, Vol. 3, No. 10, 2008, pp. 1166-1171. doi:10.1097/JTO.0b013e318186a88d
[13]	D. H. Lee, J. Y. Han, S. Y. Yu, et al., “The Role of Gefitinib Treatment for Korean Never-Smokers with Advanced or Metastatic Adenocarcinoma of the Lung: A Prospective Study,” Journal of Thoracic Oncology, Vol. 1, No. 9, 2006, pp. 965-971. doi:10.1097/01243894-200611000-00008
[14]	D. M. Jackman, L. Cioffredi, N. I. Lindeman, et al., “Phase II Trial of Erlotinib in Chemotherapy-Naive Women with Advanced Pulmonary Adenocarcinoma (Abstract 8065),” Journal of Clinical Oncology, Vol. 27, No. 15S, 2009, p. 423s.
[15]	V. A. Miller, G. J. Riely, M. F. Zakowski, et al., “Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib,” Journal of Clinical Oncology, Vol. 26, No. 9, 2008, pp. 1472-1478. doi:10.1200/JCO.2007.13.0062
[16]	H. L. West, W. A. Franklin, J. McCoy, et al., “Gefitinib Therapy in Advanced Bronchioloalveolar Carcinoma: Southwest Oncology Group Study S0126,” Journal of Clinical Oncology, Vol. 24, No. 12, 2006, pp. 1807-1813. doi:10.1200/JCO.2005.04.9890
[17]	J. Cadranel, E. Quoix, L. Baudrin, et al., “IFCT-0401 trial: A Phase II Study of Gefitinib Administered as First-Line Treatment in Advanced Adenocarcinoma with Bronchioloalveolar Carcinoma Subtype,” Journal of Thoracic Oncology, Vol. 4, No. 9, 2009, pp. 1126-1135. doi:10.1097/JTO.0b013e3181abeb5d
[18]	F. Cappuzzo, C. Ligorio, P. A. Janne, et al., “Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence in Situ Hybridization-Positive/Phospho-Akt-Positive or Never Smoker Patients with Advanced Non-Small-Cell Lung Cancer: The ONCOBELL Trial,” Journal of Clinical Oncology, Vol. 25, No. 16, 2007, pp. 2248-2255. doi:10.1200/JCO.2006.09.4300
[19]	H. Asahina, K. Yamazaki, I. Kinoshita, et al., “A Phase II Trial of Gefitinib as First-Line Therapy for Advanced Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations,” British Journal of Cancer, Vol. 95, No. 8, 2006, pp. 998-1004. doi:10.1038/sj.bjc.6603393
[20]	A. Inoue, T. Suzuki, T. Fukuhara, et al., “Prospective Phase II Study of Gefitinib for Chemotherapy-Naive Patients with Advanced Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Gene Mutations,” Journal of Clinical Oncology, Vol. 24, No. 21, 2006, pp. 3340-3346. doi:10.1200/JCO.2005.05.4692
[21]	L. V. Sequist, R. G. Martins, D. Spigel, et al., “First-Line Gefitinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations,” Journal of Clinical Oncology, Vol. 26, No. 15, 2008, pp. 2442-2449. doi:10.1200/JCO.2007.14.8494
[22]	R. Rosell, T. Moran, C. Queralt, et al., “Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer,” The New England Journal of Medicine, Vol. 361, No. 10, 2009, pp. 958-967. doi:10.1056/NEJMoa0904554
[23]	A. Inoue, K. Kobayashi, K. Usui, et al., “First-Line Gefitinib for Patients with Advanced Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations without Indication for Chemotherapy,” Journal of Clinical Oncology, Vol. 27, No. 9, 2009, pp. 1394-1400. doi:10.1200/JCO.2008.18.7658
[24]	T. S. Mok, Y.-L. Wu, S. Thongprasert, et al., “Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma,” The New England Journal of Medicine, Vol. 361, No. 10, 2009, pp. 947-957. doi:10.1056/NEJMoa0810699
[25]	I. Gkiozos, A. Charpidou and K. Syrigos, “Developments in the Treatment of Non-Small-Cell Lung Cancer,” Anticancer Research, Vol. 27, No. 4C, 2007, pp. 2823-7.
[26]	G. S. Papaetis, C. Roussos and K. N. Syrigos, “Targeted Therapies for Non-Small-Cell Lung Cancer,” Current Pharmaceutical Design, Vol. 13, No. 27, 2007, pp. 2810-2831. doi:10.2174/138161207781757079
[27]	A. G. Pallis and K. Syrigos, “Targeted (and Chemotherapeutic) Agents as Maintenance Treatment in Patients with Metastatic Non-Small-Cell Lung Cancer: Current Status and Future Challenges,” Cancer Treatment Reviews, Vol. 38, No. 7, 2012, pp. 861-867. doi:10.1016/j.ctrv.2011.12.006
[28]	G. Mountzios, D. Sanoudou and K. N. Syrigos, “Clinical Pharmacogenetics in Oncology: The Paradigm of Molecular Targeted Therapies,” Current Pharmaceutical Design, Vol. 16, No. 20, 2010, pp. 2184-93. doi:10.2174/138161210791792859
[29]	E. L. Kwak, D. R. Camidge, J. Clark, et al., “Clinical Activity Observed in a Phase I Dose Escalation Trial of An Oral C-MET and ALK Inhibitor, PF-02341066,” Journal of Clinical Oncology, Vol. 27, No. 15S 2009, p. 148s.
[30]	E. Kwak, Y. Bang, D. Camidge, et al., “Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer,” The New England Journal of Medicine, Vol. 363, No. 18, 2010, pp. 1693-703.
[31]	A. Shaw, B. Yeap, B. Solomon, et al., “Effect of Crizotinib on Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer Harboring ALK Gene Rearrangement: A Retrospective Analysis,” The Lancet Oncology, 2011, Vol. 12, No. 11, pp. 1004-12. doi:10.1016/S1470-2045(11)70232-7
[32]	L. Crinò, D. Kim, G. J. Riely, et al., “Initial Phase II Results with Crizotinib in Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC): PROFILE 1005,” Journal of Clinical Oncology, Vol. 29, No. 15, 2011, p. 7514.