Optimal regimen of trastuzumab in combination with oxaliplatin/ capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phase II trial

Jifang Gong, Tianshu Liu, Qingxia Fan, Li Bai, Feng Bi, Shukui Qin, Jinwan Wang, Nong Xu, Ying Cheng, Yuxian Bai, Wei Liu, Liwei Wang, Lin Shen, Jifang Gong, Tianshu Liu, Qingxia Fan, Li Bai, Feng Bi, Shukui Qin, Jinwan Wang, Nong Xu, Ying Cheng, Yuxian Bai, Wei Liu, Liwei Wang, Lin Shen

Abstract

Background: The ToGA study showed that trastuzumab plus chemotherapy prolonged median survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Among chemotherapy options, oxaliplatin might be as effective as cisplatin but has shown to be more tolerable. To further improve treatment options for patients with advanced gastric cancer, we initiated a study to evaluate the efficacy and safety of trastuzumab plus oxaliplatin/capecitabine in patients with HER2-positive advanced gastric cancer.

Methods: CGOG1001 was an open-label, multicenter, prospective phase II study. Patients with chemotherapy-naive HER2-positive advanced gastric cancer were eligible. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg infusion every 3 weeks (q3w). Oxaliplatin was administrated as a 130 mg/m(2) infusion, q3w, for up to 6 cycles. Capecitabine 1000 mg/m(2) was given orally twice daily on days 1-14 followed by a 7-day rest interval. Trastuzumab and capecitabine were continued until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Simon two-stage design (H0 = 40%, H1 = 60%, α = 0.05, β = 0.2) by Response Evaluation Criteria In Solid Tumors 1.0 was applied.

Results: Fifty-one patients were enrolled. Confirmed response was recorded in 46 patients. One patient achieved complete response and 33 patients achieved partial response (response rate 34/51 [66.7%] in the intent-to-treat population). Median follow-up time was 28.6 months, with a median progression-free survival of 9.2 months (95% confidence interval [CI]: 6.5-11.6) and a median overall survival (OS) of 19.5 months (95% CI: 15.5-26.0). Patients with a HER2/CEP17 ratio of greater than five achieved improved OS (20.9 vs 19.5 months, p = 0.001). The most common adverse events of grade 3 or above were thrombocytopenia (21.6%), neutropenia (13.7%), anemia (5.9 %) and leucopenia (3.9%).

Conclusion: The addition of trastuzumab to oxaliplatin/capecitabine was well tolerated and the results demonstrated encouraging efficacy.

Trial registration: ClinicalTrials.gov NCT01364493.

Figures

Fig. 1
Fig. 1
Study flow diagram showing all patients screened for inclusion in the study and reasons for ineligibility
Fig. 2
Fig. 2
Waterfall plot of overall response of the target lesions measured by RECIST 1.0
Fig. 3
Fig. 3
Kaplan–Meier curves for progression-free survival (a) and overall survival (b)

References

    1. Bang YJ, Van Cutsem E, Feyereislova A, Feyereislova A, Chung HC, Shen L, 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;376:687–97. doi: 10.1016/S0140-6736(10)61121-X.
    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. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666–73. doi: 10.1093/annonc/mdn717.
    1. Okines A, Norman A, McCloud P, Kang YK, Cunningham D. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol. 2009;20:1529–34. doi: 10.1093/annonc/mdp047.
    1. Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14:e535–47. doi: 10.1016/S1470-2045(13)70436-4.
    1. Ding XD, Qu XJ, Fan YB, Che XF, Qu JL, Xu L, et al. Trastuzumab and oxaliplatin exhibit a synergistic antitumor effect in HER2-postive gastric cancer cells. Anticancer Drugs. 2014;25:315–22. doi: 10.1097/CAD.0000000000000048.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10. doi: 10.1016/0197-2456(89)90015-9.
    1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand. 1965;64:31–49.
    1. Pazo Cid R, Antón A. Advanced HER2-positive gastric cancer: Current and future targeted therapies. Crit Rev Oncol Hematol. 2013;85:350–62. doi: 10.1016/j.critrevonc.2012.08.008.
    1. Ryu MH, Yoo C, Kim JG, Ryoo BY, Park YS, Park SR, et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer. 2015;51:482–8. doi: 10.1016/j.ejca.2014.12.015.
    1. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–21. doi: 10.1016/S0140-6736(11)61873-4.
    1. Gomez-Martin C, Plaza JC, Pazo-Cid R, Salud A, Pons F, Fonseca P, et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J Clin Oncol. 2013;31:4445–52. doi: 10.1200/JCO.2013.48.9070.
    1. Sakamoto Y, Ohyama S, Yamamoto J, Yamada K, Seki M, Ohta KI, et al. Surgical resection of liver metastases of gastric cancer: an analysis of a 17-year experience with 22 patients. Surgery. 2003;133:507–11. doi: 10.1067/msy.2003.147.
    1. Okano K, Maeba T, Ishimura K, Karasawa Y, Goda F, Wakabayashi H, et al. Hepatic resection for metastatic tumours from gastric cancer. Ann Surg. 2002;235:86–91. doi: 10.1097/00000658-200201000-00011.
    1. Zacherl J, Zacherl M, Scheuba C, Steininger R, Wenzl E, Mülbacher F, et al. Analysis of hepatic resection of metastases originating from gastric adenocarcinoma. J Gastrointest Surg. 2002;6:682–9. doi: 10.1016/S1091-255X(01)00075-0.
    1. Li J, Lu M, Zhang X, Li Y, Zhan X, Shen L, et al. The assessment of clinicopathological features, therapy pattern and survival benefit of 162 gastric cancers with liver metastases. Hepatogastroenterology. 2013;60:628–32.
    1. Tournigard C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol. 2006;24:394–400. doi: 10.1200/JCO.2005.03.0106.
    1. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432–40. doi: 10.1016/S0140-6736(09)61497-5.
    1. Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, et al. 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;13:466–75. doi: 10.1016/S1470-2045(12)70117-1.
    1. Gong J, Hu B, Zhang X, Zhang F, Zhang J, Xu N, et al. The multicenter, phase II, prospective study of paclitaxel plus capecitabine as first-line chemotherapy in advanced gastric carcinoma. Oncologist. 2014;19:173–4. doi: 10.1634/theoncologist.2013-0137.

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