CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial

Yuankai Shi, Jin Li, Jianming Xu, Yan Sun, Liwei Wang, Ying Cheng, Wei Liu, Guoping Sun, Yigui Chen, Li Bai, Yiping Zhang, Xiaohui He, Yi Luo, Zhehai Wang, Yunpeng Liu, Qiang Yao, Yuhong Li, Shukui Qin, Xiaohua Hu, Feng Bi, Rongsheng Zheng, Xuenong Ouyang, Yuankai Shi, Jin Li, Jianming Xu, Yan Sun, Liwei Wang, Ying Cheng, Wei Liu, Guoping Sun, Yigui Chen, Li Bai, Yiping Zhang, Xiaohui He, Yi Luo, Zhehai Wang, Yunpeng Liu, Qiang Yao, Yuhong Li, Shukui Qin, Xiaohua Hu, Feng Bi, Rongsheng Zheng, Xuenong Ouyang

Abstract

Background: The 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first-line treatment for metastatic colorectal cancer (mCRC), however, the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients.

Methods: Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan-only. Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression-free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR).

Results: The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P < 0.001) and longer median PFS (169 days vs. 95 days; P < 0.001) as compared to the irinotecan-only arm. Patients receiving CMAB009 plus irinotecan also demonstrated improved DCR (80.1% vs. 65.2%, P < 0.001), CBR (30.0% vs. 14.6%, P < 0.001), and DOR (210 days vs. 109 days; P < 0.001) as compared to irinotecan-only. However, patients treated with CMAB009 had an increased risk of skin rash (66.9% vs. 5.5%, P < 0.001) and paronychia (9.8% vs. 0.0%, P < 0.001). Anti-drug antibodies (ADA) were detected in 3.6% of patients, and only 0.9% of patients who received CMAB009 experienced hypersensitivity reactions. In patients receiving sequential-CMAB009 therapy after failure with irinotecan, their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential-CMAB009 (P = 0.940).

Conclusions: Treatment with CMAB009 plus irinotecan was found to be a superior second-line regimen in comparison to irinotecan-only in KRAS wild-type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third-line of treatment after treatment failure with second-line irinotecan-only. Trial registration ClinicalTrials.gov: NCT01550055, retrospectively registered on March 9, 2012.

Keywords: CMAB009; Cetuximab; EGFR; Fluoropyrimidine; Immunogenicity; Irinotecan; KRAS; Oxaliplatin failure; Second-line; mCRC.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart illustrating the trial enrollment and patient outcomes
Fig. 2
Fig. 2
Kaplan-Meier analysis comparing the progression-free survival of patients from the CMAB009 plus irinotecan arm to those in the irinotecan-only arm only. PFS, progression free survival; HR, hazard ratio; CI, confidence intervals
Fig. 3
Fig. 3
Kaplan-Meier analysis comparing the overall survival of patients from the CMAB009 plus irinotecan arm to those in the sequential-CMAB009 arm. OS, overall survival; HR, hazard ratio; CI, confidence intervals
Fig. 4
Fig. 4
Kaplan–Meier analysis for the duration of treatment response. Median DOR was significantly longer in patients who received CMAB009 plus irinotecan compared with those who received irinotecan-only. DOR, duration of response

References

    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi: 10.3322/caac.21262.
    1. Zheng R, Zeng H, Zhang S, Chen W. Estimates of cancer incidence and mortality in China, 2013. Chin J Cancer. 2017;36(1):66. doi: 10.1186/s40880-017-0234-3.
    1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–132. doi: 10.3322/caac.21338.
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. doi: 10.3322/caac.21387.
    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 doi: 10.3322/caac.21492.
    1. Lucas AS, O’Neil BH, Goldberg RM. A decade of advances in cytotoxic chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2011;10(4):238–244. doi: 10.1016/j.clcc.2011.06.012.
    1. Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, et al. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14(1):1–10. doi: 10.1016/j.clcc.2014.11.002.
    1. Thirion P, Michiels S, Pignon J, Buyse M, Braud A, Carlson R, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol. 2004;22(18):3766–3775. doi: 10.1200/JCO.2004.03.104.
    1. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil–leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000;18(1):136. doi: 10.1200/JCO.2000.18.1.136.
    1. Bokemeyer C, Bondarenko I, Hartmann J, De Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22(7):1535–1546. doi: 10.1093/annonc/mdq632.
    1. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30. doi: 10.1200/JCO.2004.09.046.
    1. Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010;277(2):301–308. doi: 10.1111/j.1742-4658.2009.07448.x.
    1. Lee SY, Oh SC. Advances of targeted therapy in treatment of unresectable metastatic colorectal cancer. Biomed Res Int. 2016;2016:7590245. doi: 10.1155/2016/7590245.
    1. Chung CH, Mirakhur B, Chan E, Le Q-T, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1, 3-galactose. N Engl J Med. 2008;358(11):1109–1117. doi: 10.1056/NEJMoa074943.
    1. Wang C, Guo H. Characterization of N-glycosylation in an anti-EGFR monoclonal antibody produced by different expression systems. Sheng Wu Gong Cheng Xue Bao. 2017;33(6):1018–1027. doi: 10.13345/j.cjb.170074.
    1. van Bueren JJL, Rispens T, Verploegen S, van der Palen-Merkus T, Stapel S, Workman LJ, et al. Anti-galactose-α-1,3-galactose IgE from allergic patients does not bind α-galactosylated glycans on intact therapeutic antibody Fc domains. Nat Biotechnol. 2011;29(7):574. doi: 10.1038/nbt.1912.
    1. He X, Shi Y, Qin Y, Yang S, Sun Y. Phase I study of anti-EGFR monoclonal antibody (CMAB009) in patients with advanced cancer. Zhonghua yi xue za zhi. 2011;91(33):2333–2335.
    1. Whitcombe D, Theaker J, Guy SP, Brown T, Little S. Detection of PCR products using self-probing amplicons and fluorescence. Nat Biotechnol. 1999;17(8):804. doi: 10.1038/11751.
    1. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634. doi: 10.1200/JCO.2007.14.7116.
    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(14):2311–2319. doi: 10.1200/JCO.2007.13.1193.
    1. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–3995. doi: 10.1158/0008-5472.CAN-06-0191.
    1. Gill S, Goldberg RM. Targeted therapies: cetuximab, chemotherapy and KRAS status in mCRC. Nat Rev Clin Oncol. 2009;6(7):379. doi: 10.1038/nrclinonc.2009.83.
    1. Van Cutsem E, Kohne C-H, Láng I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–2019. doi: 10.1200/JCO.2010.33.5091.
    1. McLellan E, Owen R, Stepniewska K, Sheffield J, Lemoine N. High frequency of K-ras mutations in sporadic colorectal adenomas. Gut. 1993;34(3):392–396. doi: 10.1136/gut.34.3.392.
    1. Arber N, Shapira I, Ratan J, Stern B, Hibshoosh H, Moshkowitz M, et al. Activation of cK-ras mutations in human gastrointestinal tumors. Gastroenterology. 2000;118(6):1045–1050. doi: 10.1016/S0016-5085(00)70357-X.
    1. Van Cutsem E, Köhne C-H, Hitre E, Zaluski J, Chang Chien C-R, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–1417. doi: 10.1056/NEJMoa0805019.
    1. Jonker DJ, O’callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–2048. doi: 10.1056/NEJMoa071834.
    1. Xu R-H, Muro K, Morita S, Iwasa S, Han SW, Wang W, et al. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018;19(5):660–671. doi: 10.1016/S1470-2045(18)30140-2.
    1. Cremolini C, Rossini D, Dell’Aquila E, Lonardi S, Conca E, Del Re M, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA oncol. 2019;5(3):343–350. doi: 10.1001/jamaoncol.2018.5080.
    1. Schirripa M, Cremolini C, Loupakis F, Morvillo M, Bergamo F, Zoratto F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer. 2015;136(1):83–90. doi: 10.1002/ijc.28955.
    1. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol. 2014;53(7):852–864. doi: 10.3109/0284186X.2014.895036.
    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(4):337–345. doi: 10.1056/NEJMoa033025.
    1. Lenz HJ. Cetuximab in the management of colorectal cancer. Biol Targets Ther. 2007;1(2):77.
    1. Zhang P, Woen S, Wang T, Liau B, Zhao S, Chen C, et al. Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs. Drug Disc Today. 2016;21(5):740–765. doi: 10.1016/j.drudis.2016.01.006.
    1. Kawasaki N, Itoh S, Hashii N, Takakura D, Qin Y, Huang X, et al. The significance of glycosylation analysis in development of biopharmaceuticals. Biol Pharm Bull. 2009;32(5):796–800. doi: 10.1248/bpb.32.796.
    1. Batra J, Rathore AS. Glycosylation of monoclonal antibody products: current status and future prospects. Biotechnol Prog. 2016;32(5):1091–1102. doi: 10.1002/btpr.2366.

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