526PDTRIUMPH: Primary efficacy of a phase II trial of trastuzumab (T) and pertuzumab (P) in patients (pts) with metastatic colorectal cancer (mCRC) with HER2 (ERBB2) amplification (amp) in tumour tissue or circulating tumour DNA (ctDNA): A GOZILA sub-study

Abstract Background ERBB2 amp occurs in approximately 4% of pts with mCRC. We conducted a phase II trial to evaluate the efficacy and safety of T and P in pts with ERBB2-amplified mCRC identified by tissue and/or ctDNA analysis. Methods We enrolled pts with central tissue and/or ctDNA (Guardant360) confirmed wild-type RAS and ERBB2-amplified mCRC, refractory or intolerant to standard chemotherapy including EGFR blockade. Pts received T and P every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: tissue-positive and ctDNA-positive. The required sample size for each group was 25 (one-sided α = 2.5%, β = 10%) to test the threshold ORR of 5% against the expected ORR of 30%; 5 confirmed responses were needed to determine statistical significance. Results The first response evaluation was done on Jan 7, 2019. Of 19 pts enrolled at 7 sites, 18 were evaluable for response. ERBB2-amp was confirmed in both tissue and ctDNA for 14 pts, in tissue alone for 3, and in ctDNA alone for 1; therefore, 17 and 15 pts were assigned to the tissue-positive and the ctDNA-positive group, respectively. With median follow-up of 5.4 months, there were 6 confirmed responders in the tissue-positive group (ORR = 35%, 95% confidence interval [CI] 14-62%; 1 CR and 5 PR) and 5 in the ctDNA positive group (ORR = 33%, 95% CI 12-62%; 1 CR and 4 PR). Median progression-free survival for both groups was 4.0 months (95% CI = 1.4-5.6 months and 1.3-5.6 months, respectively). Clonal ctDNA mutations in KRAS, BRAF, PIK3CA, or ERBB2 at baseline were observed only in pts with disease progression as best response. The safety profile of T and P was consistent with prior reports. Severe adverse events were reported in 2 pts: Gr 3 decreased ejection fraction and Gr 3 infusion related reaction. Conclusions The TRIUMPH study met its primary endpoint, demonstrating that combination of T and P has promising activity, with an acceptable toxicity profile, in treatment-refractory mCRC pts with ERBB2 amp in tissue and/or ctDNA. Clonal oncogenic ctDNA driver mutations may predict for primary resistance. Clinical trial identification UMIN000027887. Legal entity responsible for the study SCRUM-Japan GI-SCREEN. Funding Japan Agency for Medical Research and Development. Disclosure Y. Nakamura: Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical. W. Okamoto: Research grant / Funding (self): MSD. T. Kato: Honoraria (self), Research grant / Funding (self): Chugai Pharma; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Lilly; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi. K. Kato: Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy: MSD; Advisory / Consultancy: Oncolys BioPharma; Research grant / Funding (self): Shionogi; Research grant / Funding (self): MSD Oncology. S. Iwasa: Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Ono Pharmaceutical; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bayer. T. Esaki: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Eisai; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): Takeda; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Sanofi; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Nihonkayaku; Research grant / Funding (institution): Pfizer. Y. Komatsu: Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharma; Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (institution), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: TOWA; Speaker Bureau / Expert testimony: Nipro Corporation; Research grant / Funding (self): MSD; Research grant / Funding (self): Yakult Pharmaceutical; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Sysmex. T. Masuishi: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): Lilly; Honoraria (self): Bayer Yakuhin; Honoraria (self): Sanofi. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Lilly; Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Nihonkayaku; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Ono Pharmaceutical. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. S. Olsen: Full / Part-time employment: Guardant Health AMEA; Shareholder / Stockholder / Stock options: Guardant Health; Shareholder / Stockholder / Stock options: AstraZeneca. T. Yoshino: Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Sanofi. K.K.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Research grant / Funding (institution): Parexel International Inc.; Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd.; Research grant / Funding (institution): MSD. K. K. All other authors have declared no conflicts of interest.