DOI QR코드

DOI QR Code

전이성 위암의 새로운 치료 요법

Novel Therapeutics for Recurrent or Metastatic Gastric Cancer

  • 이희연 (가톨릭대학교 의과대학 인천성모병원 종양내과) ;
  • 고윤호 (가톨릭대학교 의과대학 의정부성모병원 종양내과)
  • Lee, Hee Yeon (Division of Oncology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Ko, Yoon Ho (Division of Oncology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
  • 발행 : 2018.02.01

초록

Despite advances in cancer therapy, gastric cancer has a poor prognosis and high cancer-related mortality. Based on the molecular characteristics of cancer, specific targeted therapies have shown clinical benefits for various tumors. In addition, immunotherapy using immune checkpoint inhibitors has led to a paradigm shift in cancer treatment and shown remarkable results in some solid tumors. Although immunotherapy has been actively applied to gastric cancer, the efficacy is unsatisfactory compared with other solid tumors, such as melanoma and lung cancers. This is because of the complex mechanism of gastric cancer, tumor heterogeneity, heterogeneity among patients, and the absence of appropriate biomarkers to predict response. An effective new cancer treatment strategy that combines targeted therapies and various immunotherapies based on biological markers such as tumor mutation burden and microsatellite instability is urgently needed. Furthermore, customized treatment is necessary to overcome tumor heterogeneity.

키워드

참고문헌

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108. https://doi.org/10.3322/canjclin.55.2.74
  2. National Cancer Information Center. Cancer incidence [Internet]. Goyang (KR): National Cancer Information Center, c2017 [cited 2017 Dec 21]. Available from: https://www.cancer.go.kr/docview/preview.do?attach_seq=8039.
  3. Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24:2903-2909. https://doi.org/10.1200/JCO.2005.05.0245
  4. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697. https://doi.org/10.1016/S0140-6736(10)61121-X
  5. Wilke H, Muro K, Van Cutsem E, et al. 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;15:1224-1235. https://doi.org/10.1016/S1470-2045(14)70420-6
  6. Lordick F, Kang YK, Chung HC, et al. 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;14:490-499. https://doi.org/10.1016/S1470-2045(13)70102-5
  7. Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14:481-489. https://doi.org/10.1016/S1470-2045(13)70096-2
  8. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011;29:3968-3976. https://doi.org/10.1200/JCO.2011.36.2236
  9. Van Cutsem E, Bang YJ, Mansoor W, et al. A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann Oncol 2017;28:1316-1324. https://doi.org/10.1093/annonc/mdx107
  10. 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;373:123-135. https://doi.org/10.1056/NEJMoa1504627
  11. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-133. https://doi.org/10.1056/NEJMoa1302369
  12. Takehana T, Kunitomo K, Suzuki S, et al. Expression of epidermal growth factor receptor in gastric carcinomas. Clin Gastroenterol Hepatol 2003;1:438-445. https://doi.org/10.1016/S1542-3565(03)00219-2
  13. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-2970.
  14. Tokunaga A, Onda M, Okuda T, et al. Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer. Cancer 1995;75(6 Suppl):1418-1425. https://doi.org/10.1002/1097-0142(19950315)75:6+<1418::AID-CNCR2820751505>3.0.CO;2-Y
  15. Enzinger PC, Burtness BA, Niedzwiecki D, et al. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol 2016;34:2736-2742. https://doi.org/10.1200/JCO.2015.65.5092
  16. Kim C, Lee JL, Ryu MH, et al. A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Invest New Drugs 2011;29:366-373. https://doi.org/10.1007/s10637-009-9363-0
  17. Pinto C, Di Fabio F, Barone C, et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer 2009;101:1261-1268. https://doi.org/10.1038/sj.bjc.6605319
  18. Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510-517.
  19. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697-4705. https://doi.org/10.1200/JCO.2009.27.4860
  20. Du F, Zheng Z, Shi S, et al. S-1 and Cisplatin with or without nimotuzumab for patients with untreated unresectable or metastatic gastric cancer: a randomized, open-label phase 2 trial. Medicine (Baltimore) 2015;94:e958. https://doi.org/10.1097/MD.0000000000000958
  21. Rao S, Starling N, Cunningham D, et al. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol 2010;21:2213-2219. https://doi.org/10.1093/annonc/mdq247
  22. Satoh T, Lee KH, Rha SY, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer 2015;18:824-832. https://doi.org/10.1007/s10120-014-0420-9
  23. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 2014;16:209.
  24. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-471. https://doi.org/10.1016/S1470-2045(13)70130-X
  25. Shah MA, Xu RH, Bang YJ, 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;35:2558-2567. https://doi.org/10.1200/JCO.2016.71.6852
  26. Hecht JR, Bang YJ, 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; 34:443-451.
  27. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol 2014;32:2039-2049. https://doi.org/10.1200/JCO.2013.53.6136
  28. Kang YK, Rha SY, Tassone P, et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br J Cancer 2014;111:660-666. https://doi.org/10.1038/bjc.2014.356
  29. Hoff P, Tabernero J, Shen L, et al. P-0111Pertuzumab, trastuzumab and chemotherapy in HER2-positive metastatic gastric or gastro-oesophageal junction cancer: an international phase III study (JACOB). Ann Oncol 2013;24(Suppl 4):iv67-iv67.
  30. 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;18:640-653. https://doi.org/10.1016/S1470-2045(17)30111-0
  31. Grigore D, Simionescu CE, Stepan A, et al. Assessment of CD105, ${\alpha}$-SMA and VEGF expression in gastric carcinomas. Rom J Morphol Embryol 2013;54(3 Suppl):701-707.
  32. Shen L, Li J, Xu J, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer 2015;18:168-176. https://doi.org/10.1007/s10120-014-0351-5
  33. Cunningham D, Stenning SP, Smyth EC, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol 2017;18:357-370. https://doi.org/10.1016/S1470-2045(17)30043-8
  34. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31-39. https://doi.org/10.1016/S0140-6736(13)61719-5
  35. Yoon HH, Bendell JC, Braiteh FS, et al. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol 2016;27:2196-2203. https://doi.org/10.1093/annonc/mdw423
  36. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the atomach or gastroesophageal junction. J Clin Oncol 2016;34:1448-1454. https://doi.org/10.1200/JCO.2015.63.5995
  37. Martin-Richard M, Gallego R, Pericay C, et al. Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study. Invest New Drugs 2013;31:1573-1579. https://doi.org/10.1007/s10637-013-0020-2
  38. Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson AB 3rd. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 2010;28:2947-2951. https://doi.org/10.1200/JCO.2009.27.7988
  39. Bang YJ, Kang YK, Kang WK, et al. Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs 2011;29:1449-1458. https://doi.org/10.1007/s10637-010-9438-y
  40. Kim ST, Lee J, Lee SJ, et al. Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer. Oncotarget 2016;7:24088-24096.
  41. Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the Treatment of Advanced Gastric Cancer (INTEGRATE): a multinational placebo-controlled phase II trial. J Clin Oncol 2016;34:2728-2735. https://doi.org/10.1200/JCO.2015.65.1901
  42. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract (review). Int J Oncol 2006;29:163-168.
  43. Deng N, Goh LK, Wang H, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 2012;61:673-684. https://doi.org/10.1136/gutjnl-2011-301839
  44. Su X, Zhan P, Gavine PR, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 2014;110:967-975. https://doi.org/10.1038/bjc.2013.802
  45. Catenacci DV, Rha SY, Bang YJ, et al. Updated antitumor activity and safety of FPA144, an ADCC-enhanced, FGFR2b isoform-specific monoclonal antibody, in patients with FGFR2b+ gastric cancer. J Clin Oncol 2017;35(15 suppl):4067-4067.
  46. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-209. https://doi.org/10.1038/nature13480
  47. Yao F, Kausalya JP, Sia YY, et al. Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity. Cell Rep 2015;12:272-285. https://doi.org/10.1016/j.celrep.2015.06.020
  48. Schuler MH, Zvirbule Z, Lordick F, et al. Safety, tolerability, and efficacy of the first-in-class antibody IMAB362 targeting claudin 18.2 in patients with metastatic gastroesophageal adenocarcinomas. J Clin Oncol 2013;31(15 suppl):4080-4080.
  49. Al-Batran SE, Schuler MH, Zvirbule Z, et al. FAST: an international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18. 2 antibody, as first-line therapy in patients with advanced CLDN18. 2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol 2016;34(18 suppl):LBA4001-LBA4001. https://doi.org/10.1200/JCO.2016.34.18_suppl.LBA4001
  50. Moehler MH, Cho JY, Kim YH, et al. A randomized, open-label, two-arm phase II trial comparing the efficacy of sequential ipilimumab (ipi) versus best supportive care (BSC) following first-line (1L) chemotherapy in patients with unresectable, locally advanced/metastatic (A/M) gastric or gastro-esophageal junction (G/GEJ) cancer. J Clin Oncol 2016;34(15 suppl):4011-4011.
  51. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17:717-726. https://doi.org/10.1016/S1470-2045(16)00175-3
  52. Fuchs CS, Doi T, Jang RWJ, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 2017;35(15 suppl):4003-4003. https://doi.org/10.1200/JCO.2017.75.8177
  53. Ohtsu A, Tabernero J, Bang YJ, et al. Pembrolizumab versus paclitaxel as second-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: phase 3 KEYNOTE-061 study. J Clin Oncol 2016;34(15 suppl):TPS4137-TPS4137.
  54. National Library of Medicine. Efficacy and safety study of pembrolizumab (MK-3475) versus paclitaxel in Asian participants with advanced gastric or gastroesophageal junction adenocarcinoma who progressed after first-line therapy with platinum and fluoropyrimidine (MK-3475-063/KEYNOTE-063) [Internet]. Bethesda (MD): National Library of Medicine, c2017 [cited 2017 Jan 12]. Available from: https://clinicaltrials. gov/ct2/show/NCT03019588.
  55. Tabernero J, Bang YJ, Fuchs CS, et al. KEYNOTE-062: phase III study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol 2016;34(4 suppl):TPS185-TPS185. https://doi.org/10.1200/jco.2016.34.4_suppl.tps185
  56. Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol 2016;34(15 suppl):4010-4010.
  57. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:2461-2471. https://doi.org/10.1016/S0140-6736(17)31827-5
  58. Chung HC, Arkenau H-T, Wyrwicz L, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN solid tumor phase Ib trial: analysis of safety and clinical activity. J Clin Oncol 2016;34(15 suppl):4009-4009.
  59. National Library of Medicine. Pembrolizumab, trastuzumab, HER2 positive gastric cancer [Internet]. Bethesda (MD): National Library of Medicine, c2016 [cited 2016 Sep 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT02901301.
  60. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol 2011;11:702-711. https://doi.org/10.1038/nri3064
  61. Yasuda S, Sho M, Yamato I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013;172:500-506. https://doi.org/10.1111/cei.12069
  62. Chau I, Bendell JC, Calvo E, et al. Interim safety and clinical activity in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase 1 study of ramucirumab (R) plus pembrolizumab (P). J Clin Oncol 2017;35(4 suppl):102-102.
  63. National Library of Medicine. A phase 1/2 study of ramucirumab plus nivolumab in participants with gastric or GEJ cancer [Internet]. Bethesda (MD): National Library of Medicine, c2016 [cited 2016 Dec 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT02999295.
  64. National Library of Medicine. A study of ramucirumab (LY3009806) plus MEDI4736 in participants with advanced gastrointestinal or thoracic malignancies [Internet]. Bethesda (MD): National Library of Medicine, c2015 [cited 2015 Oct 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02572687.
  65. National Library of Medicine. Biomarker-integrated umbrella, advanced gastric cancer [Internet]. Bethesda (MD): National Library of Medicine, c2016 [cited 2016 Nov 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT02951091.
  66. National Library of Medicine. A study of multiple immunotherapy-based treatment combinations in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer (G/GEJ) (morpheus-gastric cancer) [Internet]. Bethesda (MD): National Library of Medicine, c2017 [cited 2017 Sep 13]. Available from: https://clinicaltrials.gov/ct2/show/NCT03281369.
  67. National Library of Medicine. The screening protocol for the VIKTORY trial [Internet]. Bethesda (MD): National Library of Medicine, c2014 [cited 2014 Nov 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT02299648.