HER2 amplification is identified in approximately 5% out of RAS wild-type metastatic colorectal cancer (mCRC) and likely related to the resistance to EGFR blockade. Some preclinical and clinical studies have shown the efficacy of HER2-targeted therapy against HER2-positive mCRC. To identify this orphan-fractionated mCRC, we collaborate with the nationwide cancer genome screening project (SCRUM-Japan GI-SCREEN) by means of tissue/circulating tumor DNA (ctDNA) screening.
TRIUMPH study is a multicenter phase II study to evaluate efficacy and safety of combination therapy with trastuzumab and pertuzumab in patients with HER2-positive mCRC confirmed by either tissue or ctDNA analysis. Eligibility criteria includes histologically confirmed mCRC; ECOG PS ≤ 1; RAS wild-type and HER2-positive defined as IHC 3+ or FISH positive (HER2/CEP17 ratio ≥ 2.0) by means of tissue screening, or HER2-amplified and RAS wild-type identified from ctDNA (Guardant360); and refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and anti-EGFR antibody. Enrolled patients will receive intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and pertuzumab (840 mg loading dose, followed by 420 mg) every 3 weeks. In addition, the natural history data of patients with HER2-positive and RAS wild-type who do not meet the eligibility will be followed as a historical control. The primary endpoint is objective response rate (ORR) by investigator’s assessment in patients with HER2 positive tumor confirmed by tissue analysis as well as ctDNA analysis, respectively. A sample size for each group is calculated to be 18 on the basis of a power of 80% to test the null hypothesis of ORR of less than 5% versus the alternative hypothesis of ORR of over 30%, at a one-sided alpha level of 0.025. Furthermore, ctDNA will be serially analyzed to investigate the resistance mechanisms; a key focus of current research is to provide clinically meaningful thresholds which may be used for identifying and implementing treatment changes.
Clinical trial identification
Legal entity responsible for the study
The Japan Agency for Medical Research and Development
W. Okamoto: Research funding from MSD. Y. Komatsu: Speakers\' Bureau: Taiho Pharmaceutical, Lilly, Chugai Pharma, Merck Serono, Novartis, Pfizer, Bayer. Honoraria: Novartis, Pfizer, Bayer. Research funding: Taiho Pharmaceutical, Lilly, MSD, Ono Pharmaceutical, Novartis, Bayer, Chugai Pharma, Yakult. K. Kato: Research funding: ONO, MSD, Shionogi. H. Taniguchi: Honoraria: Chugai Pharma. T. Kato: Speakers\' bureau: Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Eli Lilly and Company, Bayer Yakuhin, Ltd., Sanofi S.A., Yakult Honsha Company, Limited. T. Nishina: Honoraria: Chugai Pharmaceutical Co. Ltd. T. Esaki: Honoraria: Chugai, Eli Lilly, Taiho, Merck Serono, Ono, Nihon Kayaku, Eisai. Research funding: Eli Lilly, Taiho, Novartis, Daiichi-Sankyo, DS pharma, AstraZeneca, Merck Serono, Ono, Boehringer, MSD. H. Nomura: Employment: Asahi-Kasei Pharma. A. Ohtsu: Research funding: Bristol-Myers Squibb. T. Yoshino: Research funding: GlaxoSmithKline K.K. and Boehringer-Ingelheim GmbH. All other authors have declared no conflicts of interest.