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Clinical Cancer Drugs

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ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

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Review Article

Complexity in Clinical Trials: Blind Spots, Misleading Criteria, Winners and Losers

Author(s): Gang Yuan, Lishi Wang, Jing Li, Helin Feng, Jiafu Ji, Weikuan Gu* and Baoen Shan*

Volume 7, Issue 1, 2020

Page: [3 - 15] Pages: 13

DOI: 10.2174/2212697X06666191021125423

Abstract

More than 90% of new potential therapeutic drugs have failed in clinical trials. In this study, the characteristics of failed new drugs for the treatment of seven types of cancer were first examined, followed by a review of the hazard ratios of survival in typical phase III clinical drug trials of these cancers from the last five years. The data suggested that population sizes in most clinical trials were limited to a certain level of detection. Evidently, each drug has its effect only in certain individuals with defined characteristics, and the success and failure of a new drug depend on these characteristics, such as ethnic group, sex, environmental conditions, pathological features, and genotype. Due to the complexity of the influence of multiple factors and the current limitation in understanding them, a large number of subgroups among patients may not have been recognized. Therefore, any decision only based on a few statistical comparisons, may not always provide correct judgement for a new drug. The drugs that are successful in clinical trials are “winners” regardless of how the differences in genotypes or other characteristics' influence on patients as compared to new drugs and placebos, or new and existing drugs. Drugs that are effective on certain characterizations or a specific group of patients are often categorized as a failure in clinical trials based on the current statistical criteria. Thus, previously failed drugs can be reevaluated and reutilized by analyzing whether these drugs have different effects on various genomic populations, or on patients who may emerge as subgroups based on other variables.

Keywords: Cancer, clinical trials, drugs, ethnic diversity, hazard ratio, sub-groups.

Graphical Abstract

[1]
US Centers for Medicare & Medicaid Services. National health expenditure fact sheet Available: https://www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/nationalhealthexpenddata/nhe-fact-sheet.html (accessed January 11, 2018).
[2]
Schumock GT, Li EC, Wiest MD, et al. National trends in prescription drug expenditures and projections for 2017. Am J Health Syst Pharm 2017; 74(15): 1158-73.
[http://dx.doi.org/10.2146/ajhp170164] [PMID: 28533252]
[3]
Jaffee EM, Dang CV, Agus DB, et al. Future cancer research priorities in the USA: A Lancet Oncology Commission. Lancet Oncol 2017; 18(11): e653-706.
[http://dx.doi.org/10.1016/S1470-2045(17)30698-8] [PMID: 29208398]
[4]
Vogler S, Vitry A, Babar Z-U-D. Cancer drugs in 16 European countries, Australia, and New Zealand: A cross-country price comparison study. Lancet Oncol 2016; 17(1): 39-47.
[http://dx.doi.org/10.1016/S1470-2045(15)00449-0] [PMID: 26670089]
[5]
Fojo T, Lo AW. Price, value, and the cost of cancer drugs. Lancet Oncol 2016; 17(1): 3-5.
[http://dx.doi.org/10.1016/S1470-2045(15)00564-1] [PMID: 26758749]
[6]
Morgan SG, Leopold C, Wagner AK. Drivers of expenditure on primary care prescription drugs in 10 high-income countries with universal health coverage. CMAJ 2017; 189(23): E794-9.
[http://dx.doi.org/10.1503/cmaj.161481] [PMID: 28606975]
[7]
Joseph A. DiMasi, Henry G. Grabowski, Ronald W. Hansen. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 2016; 47: 20-33.
[http://dx.doi.org/10.1016/j.jhealeco.2016.01.012]
[8]
Williams CT. Food and drug administration drug approval process: a history and overview. Nurs Clin North Am 2016; 51(1): 1-11.
[http://dx.doi.org/10.1016/j.cnur.2015.10.007] [PMID: 26897420]
[9]
Vivot A, Jacot J, Zeitoun J-D, Ravaud P, Crequit P, Porcher R. Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000-2015. Ann Oncol 2017; 28(5): 1111-6.
[http://dx.doi.org/10.1093/annonc/mdx053] [PMID: 28453694]
[10]
Parsons HM, Schmidt S, Karnad AB, Liang Y, Pugh MJ, Fox ER. Association between the number of suppliers for critical antineoplastics and drug shortages: Implications for future drug shortages and treatment. J Oncol Pract 2016; 12(3): e289-e298: 249-50.
[http://dx.doi.org/10.1200/JOP.2015.007237] [PMID: 26837565]
[11]
Caulder CR, Mehta B, Bookstaver PB, Sims LD, Stevenson B. Impact of drug shortages on health system pharmacies in the southeastern United States. Hosp Pharm 2015; 50(4): 279-86.
[http://dx.doi.org/10.1310/hpj5004-279] [PMID: 26448658]
[12]
Beck JC, Chen B, Gordon BG. Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists. World J Clin Oncol 2017; 8(4): 336-42.
[http://dx.doi.org/10.5306/wjco.v8.i4.336] [PMID: 28848700]
[13]
Hertz DL, Rae J. Pharmacogenetics of cancer drugs. Annu Rev Med 2015; 66: 65-81.
[http://dx.doi.org/10.1146/annurev-med-053013-053944] [PMID: 25386932]
[14]
Chang DK, Grimmond SM, Evans TRJ, Biankin AV. Mining the genomes of exceptional responders. Nat Rev Cancer 2014; 14(5): 291-2.
[http://dx.doi.org/10.1038/nrc3723] [PMID: 25688402]
[15]
Francis S. Collins, Harold Varmus. A new initiative on precision medicine. N Engl J Med 2015; 372: 793-5.
[http://dx.doi.org/10.1056/NEJMp1500523]
[16]
Barbolosi D, Ciccolini J, Lacarelle B, Barlési F, André N. Computational oncology-mathematical modelling of drug regimens for precision medicine. Nat Rev Clin Oncol 2016; 13(4): 242-54.
[http://dx.doi.org/10.1038/nrclinonc.2015.204] [PMID: 26598946]
[17]
Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date. Pharm Res 2016; 33(10): 2373-87.
[http://dx.doi.org/10.1007/s11095-016-1958-5] [PMID: 27299311]
[18]
Julianne D. Twomey, Nina N. Brahme, Baolin Zhang. Drug-biomarker co-development in oncology-20 years and counting. Drug Resist Updat 2017; 30: 48-62.
[http://dx.doi.org/10.1016/j.drup.2017.02.002]
[19]
Mullard A. Learning from exceptional drug responders. Nat Rev Drug Discov 2014; 13(6): 401-2.
[http://dx.doi.org/10.1038/nrd4338] [PMID: 24875081]
[20]
Ma BB, Hui EP, Mok TS. Population-based differences in treatment outcome following anticancer drug therapies. Lancet Oncol 2010; 11(1): 75-84.
[http://dx.doi.org/10.1016/S1470-2045(09)70160-3] [PMID: 20129130]
[21]
https://www.clinicaltrials.gov/ct2/help/glossary/recruitment-status
[22]
Hwang TJ, Carpenter D, Lauffenburger JC, Wang B, Franklin JM, Kesselheim AS. Failure of investigational drugs in late-stage clinical development and publication of trial results. JAMA Intern Med 2016; 176(12): 1826-33.
[http://dx.doi.org/10.1001/jamainternmed.2016.6008] [PMID: 27723879]
[23]
Corneli A, Pierre C, Hinkley T, et al. One and done: Reasons principal investigators conduct only one FDA-regulated drug trial. Contemp Clin Trials Commun 2017; 6: 31-8.
[http://dx.doi.org/10.1016/j.conctc.2017.02.009] [PMID: 29740635]
[24]
Thaul S. How FDA approves drugs and regulates their safety and effectiveness. Congressional Research Service 2013.
[25]
Ciociola AA, Cohen LB, Kulkarni P. FDA-Related Matters Committee of the American College of Gastroenterology. How drugs are developed and approved by the FDA: Current process and future directions. Am J Gastroenterol 2014; 109(5): 620-3.
[http://dx.doi.org/10.1038/ajg.2013.407] [PMID: 24796999]
[26]
Tatiana M. Prowell, Marc R. Theoret, Richard Pazdur. Seamless oncology-drug development. N Engl J Med 2016; 374: 2001-3.
[http://dx.doi.org/10.1056/NEJMp1603747]
[27]
Sachs JR, Mayawala K, Gadamsetty S, Kang SP, de Alwis DP. Optimal dosing for targeted therapies in oncology: Drug development cases leading by example. Clin Cancer Res 2016; 22(6): 1318-24.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1295] [PMID: 26597302]
[28]
Iorio F, Knijnenburg TA, Vis DJ, et al. A landscape of pharmacogenomic interactions in cancer. Cell 2016; 166(3): 740-54.
[http://dx.doi.org/10.1016/j.cell.2016.06.017] [PMID: 27397505]
[29]
Abrams J, Conley B, Mooney M, et al. National cancer institute’s precision medicine initiatives for the new national clinical trials network. Am Soc Clin Oncol Educ Book 2014; 71-6.
[http://dx.doi.org/10.14694/EdBook_AM.2014.34.71] [PMID: 24857062]
[30]
Patel JN. Cancer pharmacogenomics: Implications on ethnic diversity and drug response. Pharmacogenet Genomics 2015; 25(5): 223-30.
[http://dx.doi.org/10.1097/FPC.0000000000000134] [PMID: 25751395]
[31]
Bose K, Franck C, Müller MN, Canbay A, Link A, Venerito M. Perioperative therapy of oesophagogastric adenocarcinoma: Mainstay and future directions. Gastroenterol Res Pract 2017., 20175651903
[http://dx.doi.org/10.1155/2017/5651903] [PMID: 28785280]
[32]
Rebecca L. Siegel, Kimberly D. Miller, Ahmedin Jemal. Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7-30.
[33]
Tan DSW, Mok TSK, Rebbeck TR. Cancer genomics: Diversity and disparity across ethnicity and geography. J Clin Oncol 2016; 34(1): 91-101.
[http://dx.doi.org/10.1200/JCO.2015.62.0096] [PMID: 26578615]
[34]
Jia F, Teer JK, Knepper TC, et al. Discordance of somatic mutations between Asian and Caucasian patient populations with gastric cancer. Mol Diagn Ther 2017; 21(2): 179-85.
[http://dx.doi.org/10.1007/s40291-016-0250-z] [PMID: 28039579]
[35]
Huo D, Hu H, Rhie SK, et al. Comparison of breast cancer molecular features and survival by African and European ancestry in the Cancer Genome Atlas. JAMA Oncol 2017; 3(12): 1654-62.
[http://dx.doi.org/10.1001/jamaoncol.2017.0595] [PMID: 28472234]
[36]
Ramamoorthy A, Pacanowski MA, Bull J, Zhang L. Racial/ethnic differences in drug disposition and response: review of recently approved drugs. Clin Pharmacol Ther 2015; 97(3): 263-73.
[http://dx.doi.org/10.1002/cpt.61] [PMID: 25669658]
[37]
Schmoll HJ, Stein A. Colorectal cancer in 2013: Towards improved drugs, combinations and patient selection. Nat Rev Clin Oncol 2014; 11(2): 79-80.
[http://dx.doi.org/10.1038/nrclinonc.2013.254] [PMID: 24445520]
[38]
Mirnezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med 2012; 366(6): 489-91.
[http://dx.doi.org/10.1056/NEJMp1114866] [PMID: 22256780]
[39]
Paul Kiet Tang. The future of medicine: A 30-year perspective. Lancet Respir Med 2017; 5: 855-6.
[http://dx.doi.org/10.1016/S2213-2600(17)30388-0]
[40]
Shah RR, Gaedigk A. Precision medicine: Does ethnicity information complement genotype-based prescribing decisions? Ther Adv Drug Saf 2018; 9(1): 45-62.
[http://dx.doi.org/10.1177/2042098617743393] [PMID: 29318005]
[41]
Phipps AI, Shi Q, Limburg PJ, et al. Alliance for clinical trials in oncology. Alcohol consumption and colon cancer prognosis among participants in north central cancer treatment group phase III trial N0147. Int J Cancer 2016; 139(5): 986-95.
[http://dx.doi.org/10.1002/ijc.30135] [PMID: 27060850]
[42]
Huang J, Nair SG, Mahoney MR, et al. Alliance for clinical trials in oncology. Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147. Clin Colorectal Cancer 2014; 13(2): 100-9.
[http://dx.doi.org/10.1016/j.clcc.2013.12.002] [PMID: 24512953]
[43]
Cheung WY, Shi Q, O’Connell M, et al. ACCENT Collaborative Group. The predictive and prognostic value of sex in early-stage colon cancer: A pooled analysis of 33,345 patients from the ACCENT database. Clin Colorectal Cancer 2013; 12(3): 179-87.
[http://dx.doi.org/10.1016/j.clcc.2013.04.004] [PMID: 23810482]
[44]
Lee AM, Shi Q, Pavey E, et al. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst 2014; 106(12): 1-12.
[http://dx.doi.org/10.1093/jnci/dju298] [PMID: 25381393]
[45]
Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 2017; 318(23): 2306-16.
[http://dx.doi.org/10.1001/jama.2017.18718] [PMID: 29260225]
[46]
Chu MP, Hecht JR, Slamon D, et al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: Secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol 2017; 3(6): 767-73.
[http://dx.doi.org/10.1001/jamaoncol.2016.3358] [PMID: 27737436]
[47]
Hecht JR, Bang Y-J, Qin SK, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC-a randomized phase III trial. J Clin Oncol 2016; 34(5): 443-51.
[http://dx.doi.org/10.1200/JCO.2015.62.6598] [PMID: 26628478]
[48]
Fuchs CS, Tomasek J, Yong CJ, et al. REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383(9911): 31-9.
[http://dx.doi.org/10.1016/S0140-6736(13)61719-5] [PMID: 24094768]
[49]
Wilke H, Muro K, Van Cutsem E, et al. RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15(11): 1224-35.
[http://dx.doi.org/10.1016/S1470-2045(14)70420-6] [PMID: 25240821]
[50]
Catenacci DVT, Tebbutt NC, Davidenko I, et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18(11): 1467-82.
[http://dx.doi.org/10.1016/S1470-2045(17)30566-1] [PMID: 28958504]
[51]
Noh SH, Park SR, Yang H-K, et al. CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15(12): 1389-96.
[http://dx.doi.org/10.1016/S1470-2045(14)70473-5] [PMID: 25439693]
[52]
Lordick F, Kang Y-K, Chung H-C, et al. Arbeitsgemeinschaft Internistische Onkologie and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol 2013; 14(6): 490-9.
[http://dx.doi.org/10.1016/S1470-2045(13)70102-5] [PMID: 23594786]
[53]
Shah MA, Bang Y-J, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: The METGastric randomized clinical trial. JAMA Oncol 2017; 3(5): 620-7.
[http://dx.doi.org/10.1001/jamaoncol.2016.5580] [PMID: 27918764]
[54]
Ohtsu A, Ajani JA, Bai Y-X, et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013; 31(31): 3935-43.
[http://dx.doi.org/10.1200/JCO.2012.48.3552] [PMID: 24043745]
[55]
Shah MA, Xu RH, Bang Y-J, et al. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2–positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2017; 35(22): 2558-67.
[http://dx.doi.org/10.1200/JCO.2016.71.6852] [PMID: 28574779]
[56]
Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol 2017; 18(5): 640-53.
[http://dx.doi.org/10.1016/S1470-2045(17)30111-0] [PMID: 28343975]
[57]
Bruix J, Takayama T, Mazzaferro V, et al. STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): A phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015; 16(13): 1344-54.
[http://dx.doi.org/10.1016/S1470-2045(15)00198-9] [PMID: 26361969]
[58]
Kudo M, Han G, Finn RS, et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology 2014; 60(5): 1697-707.
[http://dx.doi.org/10.1002/hep.27290] [PMID: 24996197]
[59]
Llovet JM, Decaens T, Raoul J-L, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: Results from the randomized phase III BRISK-PS study. J Clin Oncol 2013; 31(28): 3509-16.
[http://dx.doi.org/10.1200/JCO.2012.47.3009] [PMID: 23980090]
[60]
Johnson PJ, Qin S, Park J-W, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study. J Clin Oncol 2013; 31(28): 3517-24.
[http://dx.doi.org/10.1200/JCO.2012.48.4410] [PMID: 23980084]
[61]
Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014; 312(1): 57-67.
[http://dx.doi.org/10.1001/jama.2014.7189] [PMID: 25058218]
[62]
Cainap C, Qin S, Huang W-T, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015; 33(2): 172-9.
[http://dx.doi.org/10.1200/JCO.2013.54.3298] [PMID: 25488963]
[63]
Zhu AX, Park JO, Ryoo BY, et al. REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015; 16(7): 859-70.
[http://dx.doi.org/10.1016/S1470-2045(15)00050-9] [PMID: 26095784]
[64]
Bruix J, Qin S, Merle P, et al. RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389(10064): 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[65]
Zhu AX, Rosmorduc O, Evans TRJ, et al. SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015; 33(6): 559-66.
[http://dx.doi.org/10.1200/JCO.2013.53.7746] [PMID: 25547503]
[66]
Cheng A-L, Kang Y-K, Lin D-Y, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: Results of a randomized phase III trial. J Clin Oncol 2013; 31(32): 4067-75.
[http://dx.doi.org/10.1200/JCO.2012.45.8372] [PMID: 24081937]
[67]
Rodriguez PC, Popa X, Martínez O, et al. A phase III clinical trial of the epidermal growth factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res 2016; 22(15): 3782-90.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0855] [PMID: 26927662]
[68]
Smit EF, Wu Y-L, Gervais R, et al. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer 2016; 99: 94-101.
[http://dx.doi.org/10.1016/j.lungcan.2016.06.019] [PMID: 27565921]
[69]
Wakelee HA, Dahlberg SE, Keller SM, et al. ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): An open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2017; 18(12): 1610-23.
[http://dx.doi.org/10.1016/S1470-2045(17)30691-5] [PMID: 29129443]
[70]
Wu Y-L, Zhou C, Hu C-P, et al. 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): 213-22.
[http://dx.doi.org/10.1016/S1470-2045(13)70604-1] [PMID: 24439929]
[71]
Yang JC-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16(2): 141-51.
[http://dx.doi.org/10.1016/S1470-2045(14)71173-8] [PMID: 25589191]
[72]
Soria J-C, Felip E, Cobo M, et al. LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16(8): 897-907.
[http://dx.doi.org/10.1016/S1470-2045(15)00006-6] [PMID: 26156651]
[73]
Peters S, Camidge DR, Shaw AT, et al. ALEX Trial investigators. alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med 2017; 377(9): 829-38.
[http://dx.doi.org/10.1056/NEJMoa1704795] [PMID: 28586279]
[74]
Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol 2016; 17(4): 519-31.
[http://dx.doi.org/10.1016/S1470-2045(15)00558-6] [PMID: 26906526]
[75]
Rittmeyer A, Barlesi F, Waterkamp D, et al. OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389(10066): 255-65.
[http://dx.doi.org/10.1016/S0140-6736(16)32517-X] [PMID: 27979383]
[76]
Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: Randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2013; 31(31): 3926-34.
[http://dx.doi.org/10.1200/JCO.2012.47.3983] [PMID: 24101054]
[77]
Shaw AT, Kim TM, Crinò L, et al. 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): 874-86.
[http://dx.doi.org/10.1016/S1470-2045(17)30339-X] [PMID: 28602779]
[78]
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(8): 1573-9.
[http://dx.doi.org/10.1093/annonc/mdw214] [PMID: 27207107]
[79]
Ramalingam SS, Jänne PA, Mok T, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): A randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15(12): 1369-78.
[http://dx.doi.org/10.1016/S1470-2045(14)70452-8] [PMID: 25439691]
[80]
Wu Y-L, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18(11): 1454-66.
[http://dx.doi.org/10.1016/S1470-2045(17)30608-3] [PMID: 28958502]
[81]
Reck M, Kaiser R, Mellemgaard A, et al. LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15(2): 143-55.
[http://dx.doi.org/10.1016/S1470-2045(13)70586-2] [PMID: 24411639]
[82]
Antonia SJ, Villegas A, Daniel D, et al. PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017; 377(20): 1919-29.
[http://dx.doi.org/10.1056/NEJMoa1709937] [PMID: 28885881]
[83]
Vansteenkiste JF, Cho BC, Vanakesa T, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17(6): 822-35.
[http://dx.doi.org/10.1016/S1470-2045(16)00099-1] [PMID: 27132212]
[84]
Yao JC, Fazio N, Singh S, et al. RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387(10022): 968-77.
[http://dx.doi.org/10.1016/S0140-6736(15)00817-X] [PMID: 26703889]
[85]
Reynolds CH, Patel JD, Garon EB, et al. Exploratory subset analysis of African Americans from the PointBreak study: pemetrexed-carboplatin-bevacizumab followed by maintenance pemetrexed-bevacizumab versus paclitaxel-carboplatin-bevacizumab followed by maintenance bevacizumab in patients with stage IIIB/IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2015; 16(3): 200-8.
[http://dx.doi.org/10.1016/j.cllc.2014.11.004] [PMID: 25516338]
[86]
Solomon BJ, Mok T, Kim D-W, et al. PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371(23): 2167-77.
[http://dx.doi.org/10.1056/NEJMoa1408440] [PMID: 25470694]
[87]
Yang JC-H, Kang JH, Mok T, et al. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer 2014; 50(13): 2219-30.
[http://dx.doi.org/10.1016/j.ejca.2014.05.011] [PMID: 24953333]
[88]
Soria J-C, Wu Y-L, Nakagawa K, et al. 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): 990-8.
[http://dx.doi.org/10.1016/S1470-2045(15)00121-7] [PMID: 26159065]
[89]
Obasaju C, Bowman L, Wang P, et al. Identifying the target NSCLC patient for maintenance therapy: an analysis from a placebo-controlled, phase III trial of maintenance pemetrexed (H3E-MC-JMEN). Ann Oncol 2013; 24(6): 1534-42.
[http://dx.doi.org/10.1093/annonc/mdt123] [PMID: 23559150]
[90]
Baggstrom MQ, Socinski MA, Wang XF, et al. Maintenance Sunitinib following Initial Platinum-Based Combination Chemotherapy in Advanced-Stage IIIB/IV Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study-CALGB 30607 (Alliance). J Thorac Oncol 2017; 12(5): 843-9.
[http://dx.doi.org/10.1016/j.jtho.2017.01.022] [PMID: 28161554]
[91]
Ahn JS, Ahn YC, Kim J-H, et al. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol 2015; 33(24): 2660-6.
[http://dx.doi.org/10.1200/JCO.2014.60.0130] [PMID: 26150444]
[92]
Thatcher N, Hirsch FR, Luft AV, et al. SQUIRE Investigators. 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(7): 763-74.
[http://dx.doi.org/10.1016/S1470-2045(15)00021-2] [PMID: 26045340]
[93]
Hanna NH, Kaiser R, Sullivan RN, et al. LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer 2016; 102: 65-73.
[http://dx.doi.org/10.1016/j.lungcan.2016.10.011] [PMID: 27987591]
[94]
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. N Engl J Med 2015; 373(17): 1627-39.
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[95]
Soria JC, Ohe Y, Vansteenkiste J, et al. FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 2018; 378(2): 113-25.
[http://dx.doi.org/10.1056/NEJMoa1713137] [PMID: 29151359]
[96]
Mok TS, Wu Y-L, Ahn M-J, et al. AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2017; 376(7): 629-40.
[http://dx.doi.org/10.1056/NEJMoa1612674] [PMID: 27959700]
[97]
Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013; 31(23): 2895-902.
[http://dx.doi.org/10.1200/JCO.2012.47.1102] [PMID: 23835707]
[98]
Reck M, Rodríguez-Abreu D, Robinson AG, et al. KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016; 375(19): 1823-33.
[http://dx.doi.org/10.1056/NEJMoa1606774] [PMID: 27718847]
[99]
Scagliotti G, von Pawel J, Novello S, et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol 2015; 33(24): 2667-74.
[http://dx.doi.org/10.1200/JCO.2014.60.7317] [PMID: 26169611]
[100]
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(31): 3740-8.
[http://dx.doi.org/10.1200/JCO.2016.67.6601] [PMID: 27458307]
[101]
Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31(27): 3327-34.
[http://dx.doi.org/10.1200/JCO.2012.44.2806] [PMID: 23816960]
[102]
Govindan R, Szczesna A, Ahn M-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(30): 3449-57.
[http://dx.doi.org/10.1200/JCO.2016.71.7629] [PMID: 28854067]
[103]
Kubota K, Yoshioka H, Oshita F, et al. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2017; 35(32): 3662-70.
[http://dx.doi.org/10.1200/JCO.2017.72.7297] [PMID: 28902534]
[104]
Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013; 31(34): 4349-57.
[http://dx.doi.org/10.1200/JCO.2012.47.9626] [PMID: 24145346]
[105]
Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2016; 34(9): 953-62.
[http://dx.doi.org/10.1200/JCO.2015.64.8824] [PMID: 26811519]
[106]
Langer CJ, Novello S, Park K, et al. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol 2014; 32(19): 2059-66.
[http://dx.doi.org/10.1200/JCO.2013.54.4932] [PMID: 24888810]
[107]
Spigel DR, Edelman MJ, O’Byrne K, et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 2017; 35(4): 412-20.
[http://dx.doi.org/10.1200/JCO.2016.69.2160] [PMID: 27937096]
[108]
Butts C, Socinski MA, Mitchell PL, et al. START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15(1): 59-68.
[http://dx.doi.org/10.1016/S1470-2045(13)70510-2] [PMID: 24331154]
[109]
Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9(2): 154-62.
[http://dx.doi.org/10.1097/JTO.0000000000000033] [PMID: 24419411]
[110]
Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis. Oncotarget 2016; 7(48): 78985-93.
[http://dx.doi.org/10.18632/oncotarget.12587] [PMID: 27738317]
[111]
Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009; 27(10): 1667-74.
[http://dx.doi.org/10.1200/JCO.2008.19.1635] [PMID: 19255323]
[112]
Zhao H, Zhu H, Huang J, et al. The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk Res 2018; 66: 1-7.
[http://dx.doi.org/10.1016/j.leukres.2017.12.009] [PMID: 29331774]
[113]
Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 2017; 170(6): 1079-1095.e20.
[http://dx.doi.org/10.1016/j.cell.2017.07.032] [PMID: 28823558]
[114]
Susa T, Iizuka M, Okinaga H, Tamamori-Adachi M, Okazaki T. Without 1α-hydroxylation, the gene expression profile of 25(OH)D3 treatment overlaps deeply with that of 1,25(OH)2D3 in prostate cancer cells. Sci Rep 2018; 8(1): 9024.
[http://dx.doi.org/10.1038/s41598-018-27441-x] [PMID: 29899561]
[115]
Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277(18): 1445-51.
[http://dx.doi.org/10.1001/jama.1997.03540420041027] [PMID: 9145716]
[116]
Retnakumari AP, Hanumanthu PL, Malarvizhi GL, et al. Rationally designed aberrant kinase-targeted endogenous protein nanomedicine against oncogene mutated/amplified refractory chronic myeloid leukemia. Mol Pharm 2012; 9(11): 3062-78.
[http://dx.doi.org/10.1021/mp300172e] [PMID: 22971013]
[117]
Joseph L. Fleiss, Table A3 Sample sizes per group for a two-tailed test on proportions Statistical Methods for Rates and Proportions. John Wiley & Sons 1981; pp. 260-1.
[118]
Gibson AJW, D’Silva A, Elegbede AA, et al. Impact of Asian ethnicity on outcome in metastatic EGFR-mutant non-small cell lung cancer. Asia Pac J Clin Oncol 2019.
[http://dx.doi.org/10.1111/ajco.13234] [PMID: 31486229]
[119]
Healy DG, Falchi M, O’Sullivan SS, et al. International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: A case-control study. Lancet Neurol 2008; 7(7): 583-90.
[http://dx.doi.org/10.1016/S1474-4422(08)70117-0] [PMID: 18539534]
[120]
Okubadejo NU, Rizig M, Ojo OO, et al. Leucine rich repeat kinase 2 (LRRK2) GLY2019SER mutation is absent in a second cohort of Nigerian Africans with Parkinson disease. PLoS One 2018; 13(12)e0207984
[http://dx.doi.org/10.1371/journal.pone.0207984] [PMID: 30507963]

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