Gene mutation status in circulating tumor DNA (ctDNA) and first-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) harboring RAS mutation
Authors: Y. Sunakawa, J. Usher, H. Satake, Y. Jaimes, Y. Miyamoto, M. Nakamura, M. Kataoka, M. Shiozawa, A. Takagane, T. Terazawa, T. Watanabe, K. Ishigure, C. Tanaka, T. Sekikawa, M. Takeuchi, M. Fujii, K. Danenberg, P.V. Danenberg, H.-J. Lenz, W. Ichikawa
Journal: Annals of Oncology (2018)

Background: We have conducted a phase II trial of 1st-line modified (m)-FOLFOXIRI plus bev for RAS mutant mCRC, which included a biomarker study using liquid biopsies [Oncotarget 2018]. There are few reports on monitoring changes in gene mutation (mt) status in mCRC harboring RAS mt. Therefore, the pre-planned analysis was performed to investigate a number of genes in ctDNA during therapy that might be determinants of therapeutic efficacy. Methods: Sixty-two patients (pts) with unresectable/measurable tumors received protocol treatment with m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², levofolinate [LV] 200 mg/m², and fluorouracil 2400 mg/m² repeated biweekly) plus bev. The phase II trial included objective response rate (ORR) for primary endpoint and progression-free survival (PFS), overall survival, early tumor shrinkage, depth of response (DpR), and safety for secondary endpoints. In 53 pts who enrolled in the biomarker study, plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8wks, and progression) and analyzed for specific KRAS and NRAS variants with real-time PCR assays. Results: Fifty-three pts had the following clinical data: median age of 61yrs, 57% male, 91% PS0, 28% right-sided tumors, ORR of 72%, median DpR of 49%, and median PFS of 10.8 months. RAS mt was detected in pre-treatment plasma in 79% (42/53) of pts. Among pts with mt in ctDNA at pre-treatment, 76% changed to mt-negative 8wks after treatment. ORR and DpR were higher in pts of mt-negative at 8wks compared to pts of mt-positive (81% vs. 50% and 55% vs. 34%, respectively). Median PFS was 11.9 and 8.8 months in pts who were mt-negative and mt-positive, respectively (HR 0.58, 95%CI 0.25-1.33, P = 0.20). Interestingly, in 26 pts who experienced progressive disease (PD) and were evaluable for ctDNA analysis, 52% (11/21) of pts with mt at pre-treatment still had no mt in plasma at PD. Pts of mt-negative at PD had longer survival time from PD compared to pts of mt-positive (9.3 vs. 7.0 months). Conclusions: Gene mt status in ctDNA during therapy may predict clinical outcome of triplet plus bev treatment in RAS mutant mCRC. Our study suggests that pts with no mt in plasma at PD may have more favorable post-treatment. Clinical trial identification: UMIN000015152. Editorial acknowledgement: We acknowledge Sachika Koyama and Yasushi Ohtake (JACCRO) for editorial assistance. Legal entity responsible for the study: Wataru Ichikawa. Funding: Japan Clinical Cancer Research Organization (JACCRO). Disclosure: Y. Sunakawa: Honoraria for talks: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, Merck Serono, Bayer Yakuhin, Sanofi. H. Satake: Honoraria: Bayer, Chugai Pharma, Eli Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, Yakult Honsha. M. Nakamura: Honoraria: Chugai Pharma, Taiho Pharmaceutical, Yakult Honsha. M. Takeuchi: Consulting fees: Hisamitsu Pharmaceutical, Kowa, Shionogi Pharma, Abbvie, Astellas. H-J. Lenz: Consulting or advisory role, travel expenses, honoraria: Roche. W. Ichikawa: Consulting fees: Ono Pharmaceutical; Research funding: Takeda, Taiho Pharmaceutical, Eisai, Chugai Pharma, Merck Serono, Shionogi Pharma, Daiichi Sankyo; Honoraria: Merck Serono, Taiho Pharmaceutical, Chugai Pharma, Takeda, Ono Pharmaceutical, Lilly. All other authors have declared no conflicts of interest.