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Poster display session

1813 - Dynamic changes in levels of gene mutations using circulating tumor DNA (ctDNA) and efficacy of 1st-line modified (m)-FOLFOXIRI plus bevacizumab (bev) for metastatic colorectal cancer (mCRC) harboring RAS mutation (mt) (JACCRO CC-11)


09 Sep 2017


Poster display session


Yu Sunakawa


Annals of Oncology (2017) 28 (suppl_5): v158-v208. 10.1093/annonc/mdx393


Y. Sunakawa1, T. Sekikawa2, J. Usher3, H. Satake4, Y. Jaimes3, Y. Miyamoto5, M. Nakamura6, H. Nakayama7, K. Kazama8, A. Takagane9, A. Makiyama10, K. Kobayashi11, Y. Kubota12, M. Mori13, M. Kotaka14, M. Takeuchi15, M. Fujii16, K. Danenberg3, H. Lenz17, W. Ichikawa2

Author affiliations

  • 1 Division Of Medical Oncology, Showa University Northern Yokohama Hospital, 224-8503 - Yokohama/JP
  • 2 Division Of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama/JP
  • 3 Molecular Diagnostics, Liquid Genomics, Inc., 90501 - Los Angeles/US
  • 4 Department Of Medical Oncology, Kobe City Medical Center General Hospital, Kobe/JP
  • 5 Department Of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto/JP
  • 6 Aizawa Comprehensive Cancer Center, Aizawa Hospital, 390-8510 - Matsumoto/JP
  • 7 Department Of Surgery, National Hospital Organization Nagoya Medical Center, Nagoya/JP
  • 8 Department Of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama/JP
  • 9 Department Of Surgery, Hakodate Goryoukaku Hospital, Hakodate/JP
  • 10 Department Of Hematology/oncology, Japan Community Healthcare Organization Kyushu Hospital, Kita-Kyusyu/JP
  • 11 Department Of Surgery, Nagasaki University Graduate School of Biomedical, Nagasaki/JP
  • 12 Department Of Medical Oncology, Showa University Hospital, Tokyo/JP
  • 13 Division Of Clinical Oncology, Jichi Medical University, Shimotsuke/JP
  • 14 Gastrointestinal Cancer Center, Sano Hospital, Kobe/JP
  • 15 Department Of Clinical Medicine (biostatistics), Kitasato University School of Pharmacy, Tokyo/JP
  • 16 Department Of Digestive Surgery, Nihon University School of Medicine, Tokyo/JP
  • 17 Division Of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, 90033 - Los Angeles/US


Abstract 1813


FOLFOXIRI plus bev is a standard initial therapy for mCRC but toxic in Japanese patients (pts) due to frequent febrile neutropenia (FN). We performed a phase II trial to assess the safety and activity of 1st-line m-FOLFOXIRI plus bev for mCRC with RAS mt. In addition, pre-planned analysis of a number of genes in ctDNA during therapy that might be determinants of therapeutic efficacy was performed.


Pts with unresectable/measurable tumors received bev and m-FOLFOXIRI [irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate (LV) 200 mg/m2, and fluorouracil 2400 mg/m2 repeated biweekly]. After induction therapy for a maximum of 12 cycles, maintenance therapy with fluorouracil/LV plus bev was administered. The primary endpoint was objective response rate (ORR). Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8w, and progression) and analyzed for specific KRAS, NRAS, BRAF, and PIK3CA variants with real-time PCR assays.


Sixty-two of 64 participants evaluable for efficacy had the following characteristics: median age 63, 55% male, 92% PS0, and 27% right-sided tumors. Median follow-up time was 7.9 months. ORR and disease control rate were 74.2% and 96.8%, respectively. ETS was 74%, and median DpR was 48%. Median PFS was not reached. Common grade 3 or 4 adverse events were neutropenia (49%), hypertension (22%), diarrhea (13%), and FN (4.8%). No treatment-related deaths occurred. Analysis of ctDNA from pre-treatment plasma confirmed mts in 72% (38/53) of pts. Absence of mt at 8w correlated with ORR regardless of mt status at pre-treatment [no mt; 80% (32/40), any mt; 45% (5/11), P = 0.05, t-test]; moreover, pts with PIK3CA mt at pre-treatment had a poor response (43%, 3/7).


m-FOLFOXIRI plus bev is active and feasible for Japanese mCRC pts with RAS mt. KRAS, NRAS, and PIK3CA mt in ctDNA were associated with response to the triplet plus bev and might potentially be used to predict outcomes.

Clinical trial identification

UMIN000015152, Oct/1/2014

Legal entity responsible for the study

Japan Clinical Cancer Research Organization: JACCRO


Japan Clinical Cancer Research Organization: JACCRO


Y. Sunakawa: Honoraria from Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, and Merck Serono. H. Satake: Honoraria from Bayer, Chugai Pharma, Eli Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, and Yakult Honsha. M. Nakamura: Honoraria from Merck Serono, Taiho Pharmaceutical, Yakult Honsha. M. Kotaka: Honoraria from Chugai Pharma, Yakult Honsha, Daiichi Sankyo. M. Takeuchi: Honoraria from Mitsubishi Tanabe Pharma, consulting or advisory role from Hisamitsu Pharmaceutical, Kowa, Taiho Pharmaceutical, Shionogi Pharma, Abbvie, AstraZeneca Japan and EA Pharma, travel grants from AnGes MG, Inc. H-J. Lenz: Consulting or advisory role for Merck Serono, Roche, Bayer, and Pfizer, travel expenses form Merck Serono, Bayer, and Roche, honoraria from Merck Serono, Roche, Bayer and Boehringer-Ingelheim. W. Ichikawa: Consulting role from Daiichi Sankyo, Zeria Pharmaceutical, Ono Pharmaceutica, honoraria from Merck Serono, Taiho Pharmaceutical, Chugai Pharma and Takeda, research funding from Takeda, Taiho, Eisai, Merck Serono, Ono, Chugai and Shionogi. All other authors have declared no conflicts of interest.

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