CURRENT THERAPEUTIC STRATEGIES AND CHALLENGES IN NSCLC TREATMENT: A COMPREHENSIVE REVIEW
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-44-no-1.17411Keywords:
chemoresistance, NSCLC, targeted therapies, therapeutic mAbs, treatmentAbstract
Non-small cell lung cancer (NSCLC) is one of the most lethal malignancies accountings for nearly 80% of all lung cancer cases diagnosed and causing over one million deaths annually worldwide. The discovery of molecular alterations including driver mutations and gene fusions has led to innovation of numerous targeted therapies, which certainly provided an edge over the classical chemotherapeutic treatment regimens and improved survival of the patients. Despite all the breakthrough innovations, the five-year survival statistics has not improved the way it was expected, pointing the challenges and limitations of currently approved diagnostic methods and therapies. This review summarizes various innovative therapies, treatment regimens developed over the last two decades for NSCLC treatment and the current challenges and limitations in the NSCLC treatment landscape.
References
Kadara H, Scheet P, Wistuba II, et al. Early events in the molecular pathogenesis of lung cancer. Cancer Prev Res 2016; 9: 518–27. https://doi.org/10.1158/1940-6207.CAPR-15-0400
Müller FH. Tobacco abuse and lung cancer. J Cancer Res 1940; 49: 57–85.
Doll R, Hill AB. The mortality of doctors in relation to their smoking habits. Brit Med J 1954; 1: 1451. https://doi.org/10.1136/bmj.1.4877.1451
Hilding AC. Ciliary streaming in the bronchial tree and the time element in carcinogenesis. N Engl J Med 1957; 256: 634–40. https://doi.org/10.1056/NEJM195704042561403
Janssen-Heijnen ML, Coebergh JW, et al. Is there a common etiology for the rising incidence of and decreasing survival with adenocarcinoma of the lung? Epidemiology 2001; 12: 256–8.
Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003; 123: 21S–49S. https://doi.org/10.1378/chest.123.1_suppl.21S
Lorigan P, Radford J, Howell A, et al. Lung cancer after treatment for Hodgkin’s lymphoma: a systematic review. Lancet Oncol 2005; 6: 773–9. https://doi.org/10.1016/S1470-2045(05)70387-9
Huang YJ, Huang TW, Lin FH, et al. Radiation therapy for invasive breast cancer increases the risk of second primary lung cancer: a nationwide population-based cohort analysis. J Thorac Oncol 2017; 12: 782–90. https://doi.org/10.1016/j.jtho.2017.01.021
Hubbard R, Venn A, Lewis S, et al. Lung cancer and cryptogenic fibrosing alveolitis: a population-based cohort study. Am J Resp Crit Care Med 2000; 161: 5–8. https://doi.org/10.1164/ajrccm.161.1.9906062
Kirk GD, Merlo C, O’Driscoll P, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis 2007; 45: 103–10. https://doi.org/10.1086/518606
Ihde DC. Chemotherapy of lung cancer. N Engl J Med 1992; 327: 1434–41. https://doi.org/10.1056/NEJM199211123272006
Gebbia V, Gridelli C, Verusio C, et al. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: The DISTAL-2 randomized trial. Lung Cancer 2009; 63: 251–8. https://doi.org/10.1016/j.lungcan.2008.05.027
Hanna N, Shepherd FA, Fossella FV, 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: 1589–97. https://doi.org/10.1200/JCO.2004.08.163
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. https://doi.org/10.1056/NEJMoa011954
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57. https://doi.org/10.1056/NEJMoa0810699
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–6. doi: doi.org/10.1038/nature05945
Azim Jr HA, Ganti AK. Targeted therapy in advanced non-small cell lung cancer (NSCLC): where do we stand? Cancer Treat Rev 2006; 32: 630–6. doi: doi.org/10.1016/j.ctrv.2006.07.014
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–8. https://doi.org/10.1056/NEJMoa0909530
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735–42. https://doi.org/10.1016/S1470-2045(11)70184-X
Lee JK, Hahn S, Kim DW, et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non–small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014; 311: 1430–7. https://doi.org/10.1001/jama.2014.3314
Gatzemeier U, Blumenschein G, Fosella F, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol 2006; 24: 7002. https://doi.org/10.1200/jco.2006.24.18_suppl.7002
Blumenschein Jr GR, Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non–small-cell lung cancer. J Clin Oncol 2009; 27: 4274–80. https://doi.org/10.1200/JCO.2009.22.0541
Blumenschein GR, Saintigny P, Liu S, et al. Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. Clin Cancer Res 2013; 19: 6967–75. https://doi.org/10.1158/1078-0432.CCR-12-1818
Boyer MJ, Blackhall FH, Park K, et al. Efficacy and safety of PF299804 versus erlotinib (E): A global, randomized phase II trial in patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT). J Clin Oncol 2010; 28: LBA7523. https://doi.org/10.1200/jco.2010.28.18_suppl.lba7523
Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016; 17: 984–93. https://doi.org/10.1016/S1470-2045(16)30146-2
Planchard D, Smit EF, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017; 18: 1307–16. https://doi.org/10.1016/S1470-2045(17)30679-4
Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011; 12: 1004–12. https://doi.org/10.1016/S1470-2045(11)70232-7
Poon CC, Kelly JJ. Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer. Int J Cancer 2017; 140: 1945–54. https://doi.org/10.1002/ijc.30533
Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC)(PROFILE 1007). Ann Oncol 2012; 23: ixe21. https://doi.org/10.1016/S0923-7534(20)34338-6
Sahu A, Prabhash K, Noronha V, et al. Crizotinib: A comprehensive review. South Asian J Cancer 2013; 2: 91. https://doi.org/10.4103/2278-330X.110506
Watanabe M, Wallace PK, Keler T, et al. Antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC) of breast cancer cells mediated by bispecific antibody, MDX-210. Breast Cancer Res Treat 1999; 53: 199–207. https://doi.org/10.1023/A:1006145507567
Gelderman KA, Tomlinson S, Ross GD, et al. Complement function in mAb-mediated cancer immunotherapy. Trends Immunol 2004; 25: 158–64. https://doi.org/10.1016/j.it.2004.01.008
Janjigian YY, Azzoli CG, Krug LM, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res 2011; 17: 2521–7. https://doi.org/10.1158/1078-0432.CCR-10-2662
Bonomi PD, Mace J, Mandanas RA, et al. Randomized phase II study of cetuximab and bevacizumab in combination with two regimens of paclitaxel and carboplatin in chemonaive patients with stage IIIB/IV non–small-cell lung cancer. J Thorac Oncol 2013; 8: 338–45. https://doi.org/10.1097/JTO.0b013e318282ded5
Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. The Lancet 2009; 373: 1525–31. https://doi.org/10.1016/S0140-6736(09)60569-9
Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–74. https://doi.org/10.1016/S1470-2045(15)00021-2
Paz-Ares L, Socinski MA, Shahidi J, et al. Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer. Ann Oncol 2016; 27: 1573–9. https://doi.org/10.1093/annonc/mdw214
Aonuma M, Saeki Y, Akimoto T, et al. Vascular endothelial growth factor overproduced by tumour cells acts predominantly as a potent angiogenic factor contributing to malignant progression. Int J Exp Pathol 1999; 80: 271. https://doi.org/10.1046/j.1365-2613.1999.00122.x
Zhan P, Wang J, Lv XJ, et al. Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thor Oncol 2009; 4: 1094–103. https://doi.org/10.1097/JTO/0b013e3181a97e31
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. https://doi.org/10.1056/NEJMoa061884
Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non–small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013; 31: 3004–11. https://doi.org/10.1200/JCO.2012.42.3749
Li Y, Yi Y, Lin A, et al. A comparison of the efficacy of antiangiogenic agents combined with chemotherapy for the treatment of non-small cell lung cancer: a network meta-analysis. Cancer Cell Int 2020; 20: 1–8. https://doi.org/10.1186/s12935-020-01639-4
Garon EB, Scagliotti GV, Gautschi O, et al. Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy. ESMO Open 2020; 5: e000567. https://doi.org/10.1136/esmoopen-2019-000567
Yoh K, Hosomi Y, Kasahara K, et al. A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Lung Cancer 2016; 99: 186–93. https://doi.org/10.1016/j.lungcan.2016.07.019
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–74. doi 10.1016/j.cell.2011.02.013
Neurath MF, Finotto S. The emerging role of T cell cytokines in non-small cell lung cancer. Cytokine Growth Factor Rev 2012; 23: 315–22. https://doi.org/10.1016/j.cytogfr.2012.08.009
Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies. J Exp Med 2009; 206: 1717–25. https://doi.org/10.1084/jem.20082492
Blank CU, Enk A. Therapeutic use of anti-CTLA-4 antibodies. Int Immunol 2015; 27: 3–10. https://doi.org/10.1093/intimm/dxu076
Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012; 30: 2046–54. https://doi.org/10.1200/JCO.2011.38.4032
Govindan R, Szczesna A, Jassem J, et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 2017; 35: 3449–59. https://doi.org/10.1200/JCO.2016.71.7629
Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016; 34: 3740–8. https://doi.org/10.1200/JCO.2016.67.660
Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22: 198–211. https://doi.org/10.1016/S1470-2045(20)30641-0
D’incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer 2015; 112: 95–102. https://doi.org/10.1038/bjc.2014.555
Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: 257–65. https://doi.org/10.1016/S1470-2045(15)70054-9
Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab (anti–programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol 2015; 33: 2004. https://doi.org/10.1200/JCO.2014.58.3708
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 2015; 373: 123–35. https://doi.org/10.1056/NEJMoa1504627
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet 2016; 387: 1540–50. https://doi.org/10.1016/S0140-6736(15)01281-7
Yang H, Shen K, Zhu C, et al. Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Drug Des Devel Ther 2018; 12: 2085–96. https://doi.org/10.2147/DDDT.S162214
Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. J Thorac Oncol 2021; 16: 860–7. https://doi.org/10.1016/j.jtho.2020.12.015
Owonikoko TK, Dahlberg SE, Sica GL, et al. Randomized phase II trial of cisplatin and etoposide in combination with veliparib or placebo for extensive-stage small-cell lung cancer: ECOG-ACRIN 2511 study. J Clin Oncol 2019; 37: 222. https://doi.org/10.1200/JCO.18.00264
Kozono DE, Stinchcombe T, Salama JK, et al. Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 2021; 159: 56–65. https://doi.org/10.1016/j.lungcan.2021.06.028
Fennell DA, Lester JF, Danson S, et al. A randomized phase II trial of olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer. J Clin Oncol 2020; 38: e21649. https://doi.org/10.1200/JCO.2020.38.15_suppl.e21649
Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol 2020; 38: 1164. https://doi.org/10.1200/JCO.19.02745
Ramalingam SS, Parise RA, Ramananthan RK, et al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007; 13: 3605–10. https://doi.org/10.1158/1078-0432.CCR-07-0162
Gray JE, Saltos A, Tanvetyanon T, et al. Phase I/Ib study of pembrolizumab plus vorinostat in advanced/metastatic non–small cell lung cancer. Clin Cancer Res 2019; 25: 6623–32. https://doi.org/10.1158/1078-0432.CCR-19-1305
Mottamal M, Zheng S, Huang TL, et al. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 2015; 20: 3898–941. https://doi.org/10.3390/molecules20033898
El-Baz A, Beache GM, Gimel’farb G, et al. Computer-aided diagnosis systems for lung cancer: challenges and methodologies. Int J Biomed Imaging 2013; 2013: 942353. https://doi.org/10.1155/2013/942353
Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 2012; 76: 1–8. https://doi.org/10.1016/j.lungcan.2011.10.017
Loo PS, Thomas SC, Nicolson MC, et al. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 2010; 5: 442–7. https://doi.org/10.1097/JTO.0b013e3181d40fac
Mukhopadhyay S, Katzenstein AL. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Sur Pathol 2011; 35: 15–25. https://doi.org/10.1097/PAS.0b013e3182036d05
Puderecki M, Szumiło J, Marzec‑Kotarska B. Novel prognostic molecular markers in lung cancer. Oncol Lett 2020; 20: 9–18. https://doi.org/10.3892/ol.2020.11541
Cubero MA, Lorente JA, Robles-Fernandez I, et al. Circulating tumor cells: markers and methodologies for enrichment and detection. In: Circulating Tumor Cells 2017 (pp. 283–303). Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7144-2_24
Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer 2011; 71: 3–10. https://doi.org/10.1016/j.lungcan.2010.08.022
Sève P, Dumontet C. Chemoresistance in non-small cell lung cancer. Curr Med Chem Anti-Cancer Agents 2005; 5: 73–88. https://doi.org/10.2174/1568011053352604
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Trans Med 2011; 3: 75ra26. https://doi.org/10.1126/scitranslmed.3002003
Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007; 104: 20932–7. https://doi.org/10.1073/pnas.0710370104
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 786–92. https://doi.org/10.1056/NEJMoa044238
Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. New Engl J Med 2015; 372: 1689–99. https://doi.org/10.1056/NEJMoa1411817
Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer. Clin Cancer Res 2007; 13: 2890–6. https://doi.org/10.1158/1078-0432.CCR-06-3043
Macerelli M, Caramella C, Faivre L, et al. Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer (NSCLC)? Lung Cancer 2014; 83: 383–8. https://doi.org/10.1016/j.lungcan.2013.12.013
Riely GJ, Johnson ML, Medina C, et al. A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol 2011; 6: 1435–7. https://doi.org/10.1097/JTO.0b013e318223c099
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