A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer

Xin Liu, Weijian Guo, Wen Zhang, Jiliang Yin, Jun Zhang, Xiaodong Zhu, Tianshu Liu, Zhiyu Chen, Biyun Wang, Jianhua Chang, Fangfang Lv, Xiaonan Hong, Huijie Wang, Jialei Wang, Xinmin Zhao, Xianghua Wu, Jin Li, Xin Liu, Weijian Guo, Wen Zhang, Jiliang Yin, Jun Zhang, Xiaodong Zhu, Tianshu Liu, Zhiyu Chen, Biyun Wang, Jianhua Chang, Fangfang Lv, Xiaonan Hong, Huijie Wang, Jialei Wang, Xinmin Zhao, Xianghua Wu, Jin Li

Abstract

Background: To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes.

Methods: All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP).

Results: The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations.

Conclusions: Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes.

Trial registration: ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered).

Keywords: Biomarker; Cetuximab; FOLFIRI; Gastric cancer.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimates of (a) time-to-progression (TTP) and (b) overall survival (OS) among patients with metastatic gastric cancer treated with cetuximab, irinotecan, folinic acid and 5-fluorouracil (FOLFIRI)
Fig. 2
Fig. 2
Kaplan–Meier curves of time-to-progression (a) and overall survival (b) according to serum protein level of vascular endothelial growth factor (VEGF). P-value by log-rank test

References

    1. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46. doi: 10.1056/NEJMoa073149.
    1. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki 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. doi: 10.1016/S0140-6736(10)61121-X.
    1. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol. 2006;24:4991–4997. doi: 10.1200/JCO.2006.06.8429.
    1. Kang JH, Lee SI, Lim d H, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–1518. doi: 10.1200/JCO.2011.39.4585.
    1. Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013;31:4438–4444. doi: 10.1200/JCO.2012.48.5805.
    1. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, 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. doi: 10.1016/S1470-2045(14)70420-6.
    1. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–2319. doi: 10.1200/JCO.2007.13.1193.
    1. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–2048. doi: 10.1056/NEJMoa071834.
    1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345. doi: 10.1056/NEJMoa033025.
    1. Luber B, Deplazes J, Keller G, Walch A, Rauser S, Eichmann M, et al. Biomarker analysis of cetuximab plus Oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the arbeitsgemeinschaft internistische onkologie (AIO) BMC Cancer. 2011;11:509. doi: 10.1186/1471-2407-11-509.
    1. Pinto C, Di Fabio F, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, 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. doi: 10.1093/annonc/mdl459.
    1. Liu X, Guo WJ, Zhang XW, Cai X, Tian S, Li J. Cetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecan. Cancer Chemother Pharmacol. 2011;68:871–8. doi: 10.1007/s00280-011-1559-2.
    1. Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, 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. doi: 10.1016/S1470-2045(13)70102-5.
    1. Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, 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. doi: 10.1016/S1470-2045(13)70096-2.
    1. Perez M, Lucena-Cacace A, Marin-Gomez LM, Padillo-Ruiz J, Robles-Frias MJ, Saez C, et al. Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src. Oncotarget. 2016;7:33111–24.
    1. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103–2114. doi: 10.1016/S0140-6736(11)60613-2.
    1. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755–1762. doi: 10.1200/JCO.2011.38.0915.
    1. Elez E, Argiles G, Tabernero J. First-line treatment of metastatic colorectal cancer: interpreting FIRE-3, PEAK, and CALGB/SWOG 80405. Curr Treat Options Oncol. 2015;16:52. doi: 10.1007/s11864-015-0369-x.
    1. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–1417. doi: 10.1056/NEJMoa0805019.
    1. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with Oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol. 2007;25:1539–1544. doi: 10.1200/JCO.2006.09.6305.
    1. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–2019. doi: 10.1200/JCO.2007.14.9930.
    1. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, 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. doi: 10.1200/JCO.2011.36.2236.
    1. Liu ZM, Liu LN, Li M, Zhang QP, Cheng SH, Lu S. Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer. Oncol Rep. 2009;22:515–520.
    1. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. doi: 10.1056/NEJMoa0804385.
    1. Moehler M, Mueller A, Trarbach T, Lordick F, Seufferlein T, Kubicka S, et al. Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol. 2011;22:1358–66. doi: 10.1093/annonc/mdq591.
    1. Han SW, Oh DY, Im SA, Park SR, Lee KW, Song HS, et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer. 2009;100:298–304. doi: 10.1038/sj.bjc.6604861.
    1. Duffy A, Rahma O, Greten TF. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer. 2013;132:1718. doi: 10.1002/ijc.27805.
    1. Kim C, Lee JL, Ryu MH, Chang HM, Kim TW, Lim HY, 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. doi: 10.1007/s10637-009-9363-0.
    1. Wei ZW, Xia GK, Wu Y, Chen W, Xiang Z, Schwarz RE, et al. CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer. Cancer Lett. 2015;359:335–343. doi: 10.1016/j.canlet.2015.01.033.
    1. Oh SY, Kwon HC, Kim SH, Lee S, Lee JH, Hwang JA, et al. The relationship of vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer. BMC Cancer. 2013;13:43. doi: 10.1186/1471-2407-13-43.
    1. Juttner S, Wissmann C, Jons T, Vieth M, Hertel J, Gretschel S, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006;24:228–240. doi: 10.1200/JCO.2004.00.3467.
    1. Jung YD, Mansfield PF, Akagi M, Takeda A, Liu W, Bucana CD, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002;38:1133–1140. doi: 10.1016/S0959-8049(02)00013-8.
    1. Vincenzi B, Santini D, Russo A, Gavasci M, Battistoni F, Dicuonzo G, et al. Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan. Pharmacogenomics. 2007;8:319–327. doi: 10.2217/14622416.8.4.319.
    1. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–1174. doi: 10.1056/NEJMra0707704.
    1. Khong TL, Thairu N, Larsen H, Dawson PM, Kiriakidis S, Paleolog EM. Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer. BMC Cancer. 2013;13:518. doi: 10.1186/1471-2407-13-518.
    1. Grimminger PP, Danenberg P, Dellas K, Arnold D, Rodel C, Machiels JP, et al. Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer. Clin Cancer Res. 2011;17:3469–3477. doi: 10.1158/1078-0432.CCR-10-2273.
    1. Tuccillo C, Romano M, Troiani T, Martinelli E, Morgillo F, De Vita F, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor. Clin Cancer Res. 2005;11:1268–1276.
    1. Vallbohmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, et al. Molecular determinants of cetuximab efficacy. J Clin Oncol. 2005;23:3536–3544. doi: 10.1200/JCO.2005.09.100.
    1. Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61:5090–5101.
    1. Bianco R, Troiani T, Tortora G, Ciardiello F. Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy. Endocr Relat Cancer. 2005;12(Suppl 1):S159–S171. doi: 10.1677/erc.1.00999.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다