Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial)

Eiji Oki, Yasunori Emi, Takeharu Yamanaka, Hiroyuki Uetake, Kei Muro, Takao Takahashi, Takeshi Nagasaka, Etsuro Hatano, Hitoshi Ojima, Dai Manaka, Tetsuya Kusumoto, Yu Katayose, Toshiyoshi Fujiwara, Kazuhiro Yoshida, Michiaki Unno, Ichinosuke Hyodo, Naohiro Tomita, Kenichi Sugihara, Yoshihiko Maehara, Eiji Oki, Yasunori Emi, Takeharu Yamanaka, Hiroyuki Uetake, Kei Muro, Takao Takahashi, Takeshi Nagasaka, Etsuro Hatano, Hitoshi Ojima, Dai Manaka, Tetsuya Kusumoto, Yu Katayose, Toshiyoshi Fujiwara, Kazuhiro Yoshida, Michiaki Unno, Ichinosuke Hyodo, Naohiro Tomita, Kenichi Sugihara, Yoshihiko Maehara

Abstract

Background: Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET).

Methods: The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS).

Results: Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively.

Conclusion: Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions.

Trial registration: This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

Conflict of interest statement

E.O. received grants from Chugai Pharmaceutical Co., Ltd., and received lecture fee from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly, Bayer Japan, Yakult Honsha Co., Ltd., Merck Serono, and Takeda Pharmaceutical Co., Ltd. Y.E. received honoraria from Chugai Pharmaceutical Co., Ltd. T.Y. reports grants and received lecture fee from Chugai, Takeda, and Taiho and grants from Pfizer, Merck Serono, Astra Zeneca, Yakult Honsha, Bristol Myers Squibb, Daiichi-Sankyo, Gilead Sciences, Huya Biosciences, Bayer, and Sysmex. H.U. reports grants from Taiho Pharm., Chugai Pharm., Takeda Pharm., and Yakult. K.M. received grants from Chugai, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Sanofi, Pfizer and Merck Serono, and personal fees from Taiho, Takeda, Bayer, and Eli Lilly. T.T. received lecture fees from Chugai Pharmaceutical Co., Ltd., Takeda Pharm,Sanofi, Taiho Pharm, Merck Serono, and Yakult Honsha. T.F. received grants from Astellas Pharma Inc., Otsuka Pharmaceutical Co., Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical Co., Chugai Pharmaceutical Co., Eli Lilly Japan K.K., and Yakult Honsha Co. K.Y. received grants and personal fees from Chugai Pharm. Co., Ltd., Merck Serono Co., Ltd., and Yakult Honsha Co., Ltd., grants from Kyowa Hakko Kirin, grants and personal fees from Nippon Kayaku Co., Ltd. during the conduct of the study, grants and personal fees from Johnson & Johnson K.K., Taiho Pharm. Co., Ltd., Daiichi Sankyo Co., Ltd., Tsumura, Takeda Pharmaceutical Co., Ltd., Asahi Kasei, Eisai, Sanofi, Eli Lilly Japan K.K., Covidient Japan, Novartis Pharma, EA Pharma Co., Ltd. and Ono Pharm. Co., Ltd, grants from Toyama Chemical, Abbott Japan, Otsuka Pharma Co., Ltd., Toray Medical Co., Ltd, KCI, Astellas, Sumitomo Dainippon Pharma, and Bristol Myers Japan and personal fees from Olympus, Terumo, Denka, MSD K.K., Bayer Yakuhin, Ltd., and Intuitive Surgical. M.U. received grants from Chugai, Yakult Honsha, and Takeda and received personal fees from Merck Serono, Chugai, Yakult Honsha, and Takeda during the conduct of the study, grants from Taiho, Novartis, Asahi Kasei, Asteras, Toyama Chem, and Pfizer and personal fees from Taiho, Novatis, Asahi Kasei, Pfizer, Teijin Pharm, Eisai, Daiichi Sankyo, Johnson & Johnson, Boston Scientific, Covidien/Medtronic, Nobelpharma, Ono Pharmaceutical, and Mylan. I.H. reports grants and personal fees from Taiho Pharma, Chugai Pharma, Daiichi-Sankyo Pharma, Yakult-Honsha Pharma, Lilly, Takeda Pharma, and Ono Pharma. N.T. received grants from Taiho Pharmaceutical Co. and Chugai Pharmaceutical Co., outside the submitted work. K.S. received honoraria from Chugai Pharm, Taiho, Takeda, Merck Serono, Yakult Honsha, Bristol-Meyers Japan, Bayer Yakuhin, and Eli Lilly Co. and received grants from Chugai, Taiho and Takeda. Y.M. received grants from Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., and Merck Serono Co. Ltd. during the conduct of the study and grants from Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED., Pfizer Japan Inc., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Eisai Co., Ltd., Shionogi & Co., Ltd., and Novartis Pharma K.K. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Consort flow diagram. Primary analysis was evaluated in the full analysis set (FAS), which was defined as all patients who were eligible for study inclusion, as well as those who received at least one dose of the protocol treatment
Fig. 2
Fig. 2
Kaplan–Meier estimates of a progression-free survival by central assessment and b overall survival. Solid black line: mFOLFOX6+bevacizumab, dotted black line: mFOLFOX6+cetuximab
Fig. 3
Fig. 3
Forest plots show hazard ratios for progression-free survival in patients with colorectal to liver metastases, using mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab
Fig. 4
Fig. 4
Waterfall plot shows the best change in target lesion size for individual patients by central assessment. CR complete response, NE not evaluable, PD progressive disease, PR partial response, SD stable disease. a mFOLFOX6+bevacizumab and b mFOLFOX6+cetuximab

References

    1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210.
    1. Kato T, Yasui K, Hirai T, Kanemitsu Y, Mori T, Sugihara K, et al. Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis. Colon Rectum. 2003;46(10 Suppl):S22–S31.
    1. Cancer statistics in JAPAN-2016. (2018).
    1. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann. Surg. 2004;240:644–657. doi: 10.1097/01.sla.0000145964.08365.01.
    1. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann. Oncol. 2005;16:1311–1319. doi: 10.1093/annonc/mdi246.
    1. Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J. Clin. Oncol. 2005;23:9243–9249. doi: 10.1200/JCO.2005.07.740.
    1. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47. doi: 10.1016/S1470-2045(09)70330-4.
    1. Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br. J. Cancer. 2010;103:1542–1547. doi: 10.1038/sj.bjc.6605940.
    1. Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan S, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann. Oncol. 2015;26:702–708. doi: 10.1093/annonc/mdu580.
    1. Wong R, Cunningham D, Barbachano Y, Saffery C, Valle J, Hickish T, et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann. Oncol. 2011;22:2042–2048. doi: 10.1093/annonc/mdq714.
    1. Oki E, Emi Y, Miyamoto Y, Kabashima A, Higashi H, Ogata Y, et al. Phase II trial of S-1 and oxaliplatin plus cetuximab for colorectal cancer patients with initially unresectable or not optimally resectable liver metastases (KSCC1002) Ann. Surg. Oncol. 2015;22(Suppl 3):S1067–S1074. doi: 10.1245/s10434-015-4771-1.
    1. Beppu T, Emi Y, Tokunaga S, Oki E, Shirabe K, Ueno S, et al. Liver resectability of advanced liver-limited colorectal liver metastases following mFOLFOX6 with bevacizumab (KSCC0802 Study) Anticancer Res. 2014;34:6655–6662.
    1. Shindoh J, Loyer EM, Kopetz S, Boonsirikamchai P, Maru DM, Chun YS, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J. Clin. Oncol. 2012;30:4566–4572. doi: 10.1200/JCO.2012.45.2854.
    1. Hatano E, Okuno M, Nakamura K, Ishii T, Seo S, Taura K, et al. Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study) J. Hepatobiliary Pancreat. Sci. 2015;22:634–645. doi: 10.1002/jhbp.254.
    1. Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17:1426–1434. doi: 10.1016/S1470-2045(16)30269-8.
    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. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol. 2014;32:2240–2247. doi: 10.1200/JCO.2013.53.2473.
    1. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–1075. doi: 10.1016/S1470-2045(14)70330-4.
    1. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317:2392–2401. doi: 10.1001/jama.2017.7105.
    1. Primrose J, Falk S, Finch-Jones M, Valle J, O’Reilly D, Siriwardena A, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15:601–611. doi: 10.1016/S1470-2045(14)70105-6.
    1. Ciombor KK, Goldberg RM. Highlights in gastrointestinal (colorectal) cancer treatment: the primary tumor sidedness debate and advances in immunotherapy. JAMA Oncol. 2016;2:1537–1538. doi: 10.1001/jamaoncol.2016.3642.
    1. Sunakawa Y, Tsuji A, Fujii M, Ichikawa W. No benefit from the addition of anti-EGFR antibody in all right-sided metastatic colorectal cancer? Ann. Oncol. 2017;28:2030–2031. doi: 10.1093/annonc/mdx231.
    1. Ribero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110:2761–2767. doi: 10.1002/cncr.23099.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner