The Role of Tyrosine Kinase Inhibitors in Reduction of Mortality from
Non-small Cell Lung Cancer: A Meta-analysis

Tingting      Lian; Xinyu      Zhang

doi:10.2174/1386207325666220701122755

Abstract

Background: Tyrosine kinase inhibitors are widely used in the treatment of non-small cell lung cancer. However, the exact role of these inhibitors, particularly in the reduction of mortality of non-small cell lung cancer, is unclear so far. As a result, we used RevMan 5 to conduct a meta- analysis of accessible data from randomised clinical trials.

Methods: The studies were categorised based on the inclusion and exclusion criteria after being collected from PubMed using appropriate MeSH terms. The fixed or random effect model was used based on heterogeneity among studies. The overall estimate was estimated as an odd ratio with a confidence interval of 95%. The heterogeneity among studies was calculated by I² and Cochrane Q test. The qualitative analysis of publication bias was done using a funnel plot.

Results: The overall estimate measures [OR 1.02 (0.83, 1.25)] have shown non-significant role of tyrosine kinase inhibitors in reduction of deaths of non-small cell lung cancer patients as compared to non-tyrosine kinase inhibitors group. The subgroup analysis of individual tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, osimertinib and vandetanib) has also shown similar findings.

Conclusion: Based on available data, there is no significant role played by tyrosine kinase inhibitors in the reduction of deaths of non-small cell lung cancer patients.

Keywords: Tyrosine kinase inhibitors, Gefitinib, Erlotinib, Afatinib, Osimertinib, Vandetanib, Tivantinib, Sorafeni, Non-small cell lung cancer, Mortality

« Previous Next »

Graphical Abstract

[1]
 Lung cancer in the world: the incidence, mortality rate and risk factors. WCRJ. https://www.wcrj.net/article/911Google

[2]
 What Is Lung Cancer? Available from: https://www.cancer.org/cancer/lung-cancer/about/what-is.html

[3]
Cornfield, J.; Haenszel, W.; Hammond, E.C.; Lilienfeld, A.M.; Shimkin, M.B.; Wynder, E.L. Smoking and lung cancer: Recent evidence and a discussion of some questions. Int. J. Epidemiol.,  2009, 38(5), 1175-1191.
 [http://dx.doi.org/10.1093/ije/dyp289] [PMID: 19773415]

[4]
Lemjabbar-Alaoui, H.; Hassan, O.U.; Yang, Y.W.; Buchanan, P. Lung cancer: Biology and treatment options. Biochim. Biophys. Acta,  2015, 1856(2), 189-210.
 [http://dx.doi.org/10.1016/j.bbcan.2015.08.002] [PMID: 26297204]

[5]
Sundaresan, T.K.; Sequist, L.V.; Heymach, J.V.; Riely, G.J.; Jänne, P.A.; Koch, W.H.; Sullivan, J.P.; Fox, D.B.; Maher, R.; Muzikansky, A.; Webb, A.; Tran, H.T.; Giri, U.; Fleisher, M.; Yu, H.A.; Wei, W.; Johnson, B.E.; Barber, T.A.; Walsh, J.R.; Engelman, J.A.; Stott, S.L.; Kapur, R.; Maheswaran, S.; Toner, M.; Haber, D.A. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin. Cancer Res.,  2016, 22(5), 1103-1110.
 [http://dx.doi.org/10.1158/1078-0432.CCR-15-1031] [PMID: 26446944]

[6]
Johnson, J.R.; Cohen, M.; Sridhara, R.; Chen, Y.F.; Williams, G.M.; Duan, J.; Gobburu, J.; Booth, B.; Benson, K.; Leighton, J.; Hsieh, L.S.; Chidambaram, N.; Zimmerman, P.; Pazdur, R. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin. Cancer Res.,  2005, 11(18), 6414-6421.
 [http://dx.doi.org/10.1158/1078-0432.CCR-05-0790] [PMID: 16166415]

[7]
Dhillon, S. Gefitinib: A review of its use in adults with advanced non-small cell lung cancer. Target. Oncol.,  2015, 10(1), 153-170.
 [http://dx.doi.org/10.1007/s11523-015-0358-9] [PMID: 25637458]

[8]
Harvey, R.D.; Adams, V.R.; Beardslee, T.; Medina, P. Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings. J. Oncol. Pharm. Pract.,  2020, 26(6), 1461-1474.
 [http://dx.doi.org/10.1177/1078155220931926] [PMID: 32567494]

[9]
Piper-Vallillo, A.J.; Sequist, L.V.; Piotrowska, Z. Emerging treatment paradigms for EGFR-mutant lung cancers progressing on osimertinib: A review. J. Clin. Oncol.,  2020, JCO1903123(25), JCO1903123. Epub ahead of print
 [http://dx.doi.org/10.1200/JCO.19.03123] [PMID: 32552277]

[10]
Chu, C.T.; Sada, Y.H.; Kim, E.S. Vandetanib for the treatment of lung cancer. Expert Opin. Investig. Drugs,  2012, 21(8), 1211-1221.
 [http://dx.doi.org/10.1517/13543784.2012.694866] [PMID: 22667325]

[11]
Paz-Ares, L.; Hirsh, V.; Zhang, L.; de Marinis, F.; Yang, J.C.H.; Wakelee, H.A.; Seto, T.; Wu, Y.L.; Novello, S.; Juhász, E.; Arén, O.; Sun, Y.; Schmelter, T.; Ong, T.J.; Peña, C.; Smit, E.F.; Mok, T.S. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of Sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J. Thorac. Oncol.,  2015, 10(12), 1745-1753.
 [http://dx.doi.org/10.1097/JTO.0000000000000693] [PMID: 26743856]

[12]
Mok, T.S.; Wu, Y.L.; Ahn, M.J.; Garassino, M.C.; Kim, H.R.; Ramalingam, S.S.; Shepherd, F.A.; He, Y.; Akamatsu, H.; Theelen, W.S.; Lee, C.K.; Sebastian, M.; Templeton, A.; Mann, H.; Marotti, M.; Ghiorghiu, S.; Papadimitrakopoulou, V.A. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med.,  2017, 376(7), 629-640.
 [http://dx.doi.org/10.1056/NEJMoa1612674] [PMID: 27959700]

[13]
Ciuleanu, T.; Stelmakh, L.; Cicenas, S.; Miliauskas, S.; Grigorescu, A.C.; Hillenbach, C.; Johannsdottir, H.K.; Klughammer, B.; Gonzalez, E.E. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): A randomised multicentre, open-label, phase 3 study. Lancet Oncol.,  2012, 13(3), 300-308.
 [http://dx.doi.org/10.1016/S1470-2045(11)70385-0] [PMID: 22277837]

[14]
Cufer, T.; Vrdoljak, E.; Gaafar, R.; Erensoy, I.; Pemberton, K. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. Anticancer Drugs,  2006, 17(4), 401-409.
 [http://dx.doi.org/10.1097/01.cad.0000203381.99490.ab] [PMID: 16549997]

[15]
Gatzemeier, U.; Pluzanska, A.; Szczesna, A.; Kaukel, E.; Roubec, J.; De Rosa, F.; Milanowski, J.; Karnicka-Mlodkowski, H.; Pesek, M.; Serwatowski, P.; Ramlau, R.; Janaskova, T.; Vansteenkiste, J.; Strausz, J.; Manikhas, G.M.; Von Pawel, J. 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(12), 1545-1552.
 [http://dx.doi.org/10.1200/JCO.2005.05.1474] [PMID: 17442998]

[16]
Hosomi, Y.; Morita, S.; Sugawara, S.; Kato, T.; Fukuhara, T.; Gemma, A.; Takahashi, K.; Fujita, Y.; Harada, T.; Minato, K.; Takamura, K.; Hagiwara, K.; Kobayashi, K.; Nukiwa, T.; Inoue, A. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J. Clin. Oncol.,  2020, 38(2), 115-123.
 [http://dx.doi.org/10.1200/JCO.19.01488] [PMID: 31682542]

[17]
Kelly, K.; Altorki, N.K.; Eberhardt, W.E.; O’Brien, M.E.; Spigel, D.R.; Crinò, L.; Tsai, C.M.; Kim, J.H.; Cho, E.K.; Hoffman, P.C.; Orlov, S.V.; Serwatowski, P.; Wang, J.; Foley, M.A.; Horan, J.D.; Shepherd, F.A. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J. Clin. Oncol.,  2015, 33(34), 4007-4014.
 [http://dx.doi.org/10.1200/JCO.2015.61.8918] [PMID: 26324372]

[18]
Lee, J.S.; Hirsh, V.; Park, K.; Qin, S.; Blajman, C.R.; Perng, R.P.; Chen, Y.M.; Emerson, L.; Langmuir, P.; Manegold, C. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: A randomized, double-blind phase III trial (ZEPHYR). J. Clin. Oncol.,  2012, 30(10), 1114-1121.
 [http://dx.doi.org/10.1200/JCO.2011.36.1709] [PMID: 22370318]

[19]
Li, N.; Ou, W.; Yang, H.; Liu, Q.W.; Zhang, S.L.; Wang, B.X.; Wang, S.Y. A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Cancer,  2014, 120(9), 1379-1386.
 [http://dx.doi.org/10.1002/cncr.28591] [PMID: 24481719]

[20]
Ma, W.; Xu, M.; Liu, Y.; Liu, H.; Huang, J.; Zhu, Y.; Ji, L.J.; Qi, X. Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small-cell lung cancer: A meta-analysis of 15 phase II/III randomized trials. Int. J. Cancer,  2015, 137(2), 409-419.
 [http://dx.doi.org/10.1002/ijc.29377] [PMID: 25471638]

[21]
Miller, V.A.; Hirsh, V.; Cadranel, J.; Chen, Y.M.; Park, K.; Kim, S.W.; Zhou, C.; Su, W.C.; Wang, M.; Sun, Y.; Heo, D.S.; Crino, L.; Tan, E.H.; Chao, T.Y.; Shahidi, M.; Cong, X.J.; Lorence, R.M.; Yang, J.C. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol.,  2012, 13(5), 528-538.
 [http://dx.doi.org/10.1016/S1470-2045(12)70087-6] [PMID: 22452896]

[22]
Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; Asami, K.; Katakami, N.; Takada, M.; Yoshioka, H.; Shibata, K.; Kudoh, S.; Shimizu, E.; Saito, H.; Toyooka, S.; Nakagawa, K.; Fukuoka, M. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol.,  2010, 11(2), 121-128.
 [http://dx.doi.org/10.1016/S1470-2045(09)70364-X] [PMID: 20022809]

[23]
Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; Nishiwaki, Y.; Ohe, Y.; Yang, J.J.; Chewaskulyong, B.; Jiang, H.; Duffield, E.L.; Watkins, C.L.; Armour, A.A.; Fukuoka, M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med.,  2009, 361(10), 947-957.
 [http://dx.doi.org/10.1056/NEJMoa0810699] [PMID: 19692680]

[24]
Shaw, A.T.; Kim, T.M.; Crinò, L.; Gridelli, C.; Kiura, K.; Liu, G.; Novello, S.; Bearz, A.; Gautschi, O.; Mok, T.; Nishio, M.; Scagliotti, G.; Spigel, D.R.; Deudon, S.; Zheng, C.; Pantano, S.; Urban, P.; Massacesi, C.; Viraswami-Appanna, K.; Felip, E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol.,  2017, 18(7), 874-886.
 [http://dx.doi.org/10.1016/S1470-2045(17)30339-X] [PMID: 28602779]

[25]
Soria, J.C.; Wu, Y.L.; Nakagawa, K.; Kim, S.W.; Yang, J.J.; Ahn, M.J.; Wang, J.; Yang, J.C.; Lu, Y.; Atagi, S.; Ponce, S.; Lee, D.H.; Liu, Y.; Yoh, K.; Zhou, J.Y.; Shi, X.; Webster, A.; Jiang, H.; Mok, T.S. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): A phase 3 randomised trial. Lancet Oncol.,  2015, 16(8), 990-998.
 [http://dx.doi.org/10.1016/S1470-2045(15)00121-7] [PMID: 26159065]

[26]
Stephenson, J.J.; Nemunaitis, J.; Joy, A.A.; Martin, J.C.; Jou, Y.M.; Zhang, D.; Statkevich, P.; Yao, S.L.; Zhu, Y.; Zhou, H.; Small, K.; Bannerji, R.; Edelman, M.J. Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer,  2014, 83(2), 219-223.
 [http://dx.doi.org/10.1016/j.lungcan.2013.11.020] [PMID: 24388167]

[27]
Wu, Y.L.; Chu, D.T.; Han, B.; Liu, X.; Zhang, L.; Zhou, C.; Liao, M.; Mok, T.; Jiang, H.; Duffield, E.; Fukuoka, M. Phase III, randomized, open-label, first-line study in Asia of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: Evaluation of patients recruited from mainland China. Asia Pac. J. Clin. Oncol.,  2012, 8(3), 232-243.
 [http://dx.doi.org/10.1111/j.1743-7563.2012.01518.x] [PMID: 22897752]

[28]
Wu, Y.L.; Tsuboi, M.; He, J.; John, T.; Grohe, C.; Majem, M.; Goldman, J.W.; Laktionov, K.; Kim, S.W.; Kato, T.; Vu, H.V.; Lu, S.; Lee, K.Y.; Akewanlop, C.; Yu, C.J.; de Marinis, F.; Bonanno, L.; Domine, M.; Shepherd, F.A.; Zeng, L.; Hodge, R.; Atasoy, A.; Rukazenkov, Y.; Herbst, R.S. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med.,  2020, 383(18), 1711-1723.
 [http://dx.doi.org/10.1056/NEJMoa2027071] [PMID: 32955177]

[29]
Wu, Y.L.; Zhou, C.; Hu, C.P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J.H.; Lee, K.Y.; Xu, C.R.; Massey, D.; Kim, M.; Shi, Y.; Geater, S.L. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol.,  2014, 15(2), 213-222.
 [http://dx.doi.org/10.1016/S1470-2045(13)70604-1] [PMID: 24439929]

[30]
Wu, Y.L.; Zhou, C.; Liam, C.K.; Wu, G.; Liu, X.; Zhong, Z.; Lu, S.; Cheng, Y.; Han, B.; Chen, L.; Huang, C.; Qin, S.; Zhu, Y.; Pan, H.; Liang, H.; Li, E.; Jiang, G.; How, S.H.; Fernando, M.C.L.; Zhang, Y.; Xia, F.; Zuo, Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann. Oncol.,  2015, 26(9), 1883-1889.
 [http://dx.doi.org/10.1093/annonc/mdv270] [PMID: 26105600]

[31]
Yoshioka, H.; Azuma, K.; Yamamoto, N.; Takahashi, T.; Nishio, M.; Katakami, N.; Ahn, M.J.; Hirashima, T.; Maemondo, M.; Kim, S.W.; Kurosaki, M.; Akinaga, S.; Park, K.; Tsai, C.M.; Tamura, T.; Mitsudomi, T.; Nakagawa, K. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann. Oncol.,  2015, 26(10), 2066-2072.
 [http://dx.doi.org/10.1093/annonc/mdv288] [PMID: 26153496]

[32]
Zhang, L.; Ma, S.; Song, X.; Han, B.; Cheng, Y.; Huang, C.; Yang, S.; Liu, X.; Liu, Y.; Lu, S.; Wang, J.; Zhang, S.; Zhou, C.; Zhang, X.; Hayashi, N.; Wang, M. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): A multicentre, double-blind randomised phase 3 trial. Lancet Oncol.,  2012, 13(5), 466-475.
 [http://dx.doi.org/10.1016/S1470-2045(12)70117-1] [PMID: 22512843]

[33]
Zhou, C.; Wu, Y.L.; Chen, G.; Feng, J.; Liu, X.Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; Lu, S.; Zhang, L.; Hu, C.; Hu, C.; Luo, Y.; Chen, L.; Ye, M.; Huang, J.; Zhi, X.; Zhang, Y.; Xiu, Q.; Ma, J.; Zhang, L.; You, C. 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(8), 735-742.
 [http://dx.doi.org/10.1016/S1470-2045(11)70184-X] [PMID: 21783417]

[34]
Singh, R.K.; Kumar, S.; Prasad, D.N.; Bhardwaj, T.R. Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. Eur. J. Med. Chem.,  2018, 151, 401-433.
 [http://dx.doi.org/10.1016/j.ejmech.2018.04.001] [PMID: 29649739]

[35]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther.,  2005, 315(3), 971-979.
 [http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463]

[36]
Singh, R.K. Protein kinases - Promising targets for anticancer
drug research; IntechOpen: London, 2021.  https://www.intechopen.com/books/8977 Internet
 [http://dx.doi.org/10.5772/intechopen.82939]

[37]
Elliott, J.; Bai, Z.; Hsieh, S.C.; Kelly, S.E.; Chen, L.; Skidmore, B.; Yousef, S.; Zheng, C.; Stewart, D.J.; Wells, G.A. ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis. PLoS One,  2020, 15(2), e0229179.
 [http://dx.doi.org/10.1371/journal.pone.0229179] [PMID: 32074131]

[38]
Yang, Z.; Hackshaw, A.; Feng, Q.; Fu, X.; Zhang, Y.; Mao, C.; Tang, J. Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis. Int. J. Cancer,  2017, 140(12), 2805-2819.
 [http://dx.doi.org/10.1002/ijc.30691] [PMID: 28295308]

[39]
Zhao, Y.; Liu, J.; Cai, X.; Pan, Z.; Liu, J.; Yin, W.; Chen, H.; Xie, Z.; Liang, H.; Wang, W.; Guo, Z.; Zhao, S.; Liang, W.; He, J. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: Systematic review and network meta-analysis. BMJ,  2019, 367, l5460.
 [http://dx.doi.org/10.1136/bmj.l5460] [PMID: 31591158]

[40]
Srivastava, R.; Kumar, A. Use of aspirin in reduction of mortality of COVID-19 patients: A meta-analysis. Int. J. Clin. Pract.,  2021, 75(11), e14515.
 [http://dx.doi.org/10.1111/ijcp.14515] [PMID: 34118111]

[41]
D, V.; Sharma, A.; Kumar, A.; Flora, S.J.S. Neurological manifestations in COVID-19 patients: A meta-analysis. ACS Chem. Neurosci.,  2021, 12(15), 2776-2797.
 [http://dx.doi.org/10.1021/acschemneuro.1c00353] [PMID: 34260855]

Rights & Permissions Print Cite

Article Metrics

5

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207325666220701122755	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

The Role of Tyrosine Kinase Inhibitors in Reduction of Mortality from Non-small Cell Lung Cancer: A Meta-analysis

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract