Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G).

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study.
Patients and Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety.
Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%).
Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.
Competing Interests: Conflict of interest statement DS reports grants from Yakult Honsha, Chugai, Ono, Eli Lilly, Daiichi Sankyo, Incyte and Taiho, and personal fee from Chugai, outside the submitted work. T.T. reports receiving personal fees from Merck Serono Co., Ltd, and Takeda Pharmaceutical Co., Ltd., during the conduct of the study, and receiving grants from Ono Pharmaceutical, Bristol-Myers Squibb and Japan AMED, outside the submitted work. N.S. reports receiving personal fees from Merck-Biopharm and Takeda Pharmaceutical Co.Ltd. , and ONO Pharmaceutical Co.,Ltd., MSD, Sanofi, Daiichi Sankyo, Parexel International, Sumitomo Dainippon Pharma, Bristol-Myers Squibb, Solasia Pharma, Chugai Parmaceutical, Taiho Pharmaceutical and Eli Lilly, outside the submitted work. T.N. reports grants and personal fees from Taiho pharma, grants and personal fees from Chugai pharma, grants from Daiichi sankyo pharma, grants from MSD, grants and personal fees from Ono pharma, grants and personal fees from Bristol myers squibb, grants and personal fees from Lilly pharma, grants from Dainippon sumitomo pharma, outside the submitted work. H.H. reports paid consulting or advisory roles for MSD and Ono; honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; and research funding from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Incyte, LSK BioPharma, Merck Biopharma, MSD, Ono, Pfizer, and Taiho, outside the submitted work. T.E. reports research funding from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Novartis, Astellas, Astellas Amgen Biopharma, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Dainippon Sumitomo, and honoraria from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Chugai, Nihon Kayaku, Sanofi, Takeda, Merck Serono, Bristol, Eisai. T.D. reports personal fees from SAWAI Pharmaceutical Co, personal fees from Sysmex, grants from MSD, grants from ONO Pharmaceutical, outside the submitted work. T.S. reports receiving personal fees from Merck-BioPharm and Takeda Pharmaceutical and grants and personal fees from Yakult Honsha and Daiichi-Sankyo, outside the submitted work. A.M. reports receiving personal fees from Lily, Chugai and Takeda, outside the submitted work. A.H. reports receiving personal fees from Taiho Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Novartis, Eisai, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Teijin Pharma, Sanofi and Merck Biopharma and grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eisai and Yakult Honsha, outside the submitted work.T.M. reports receiving grants and personal fees from Taiho Pharmaceutical, Yakult Honsha and Takeda Pharmaceutical; receiving personal fees from Chugai Pharmaceutical, Novelpharma, Merck Serono and Sanofi and receiving grants from Boehringer Ingelheim and Eisai, outside the submitted work. H.Y. reports research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Daiichi Sankyo, TERUMO, Eli Lilly Japan, Merk Biopharma, and Yakult Honsha, outside the submitted work. A.T. reports receiving personal fees from Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Merck Serono Co., Ltd. E.B. reports receiving grants and personal fees from Ono, Merck-Serono, Taiho, Chugai and Daiichi-Sankyo and personal fees from BMS, Takeda, Eli lilly, Tsumura, Kyowa-Kirin and Yakult, outside the submitted work. K.S. reports personal fees from SHIONOGI & CO., LTD., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Taiho Pharmaceutical Co Ltd, personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Merck Biopharma Co., Ltd, personal fees from NIPPON KAYAKU Co., Ltd., personal fees from Asahi Kasei Pharma, from Eisai Co., Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from CHUGAI PHARMACEUTICAL CO., LTD., personal fees from MOCHIDA PHARMACEUTICAL CO.,LTD., personal fees from Eli Lilly Japan K.K., personal fees from DAIICHI SANKYO COMPANY, LIMITED, outside the submitted work. M.G. reports receiving grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd., during the conduct of the study and personal fees and non-financial support from Takeda Pharmaceutical Co., Ltd., Novartis Pharmaceuticals and Bayer Yakuhin, Ltd., outside the submitted work. S.K. reports receiving grants and personal fees from Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb and personal fees from Chugai Pharma, Merck Serono, Bayer, Eisai and Yakult Honsha, outside the submitted work. Y.K. reports receiving research grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Ono Pharmaceutical, Bristol-Myers Squibb, and Tosoh Corp., research grants from MSD, Toppan Printing, Terumo and On-chip Biotechnologies, and personal fees from Thermo Fisher, and Lilly outside the submitted work. K.Y. reports receiving personal fees and other fees from Chugai, Bayer and MSD; personal fees from Takeda, Taiho, Yakult, Daiichi Sankyo, Merck Serono, Sanofi, Lily and other fees from Boehringer Ingelheim, outside the submitted work. S.H. reports receiving personal fees from Ono Pharm, Bristol-Myers Squibb, Taiho Pharm, Yakult Honsha, Daiichi Sankyo, Lilly, Chugai Pharm, Nihonkayaku and Tsumura & Co., outside the submitted work. N.B. reports receiving research grant from Ono, Bristol-Myers Squibb and Taiho and honorarium from Ono, Bristol-Myers Squibb, Taiho, Eli-Lilly and Chugai. I.H. reports receiving grants and personal fees from Chugai, Taiho, Takeda, Ono, Daiichi-Sankyo and Yakult-Honsha and personal fees from Merck-Serono, outside the submitted work. K.M. reports receiving grants and personal fees from ONO Pharmaceutical CO.,LTD. and Sanofi, and grants from Daiichi Sankyo, Parexel International, Shionogi Pharmaceutical, Sumitomo Dainippon Pharma, MSD, Pfizer, Mediscience Planning, Solasia Pharma, and Merck Serono. He also reports receiving personal fees from Eli Lilly, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, and Bayer; outside the submitted work. The other authors declare no conflicts of interest.
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