Abstract 1813
Background
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.
Methods
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.
Results
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).
Conclusions
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
Funding
Japan Clinical Cancer Research Organization: JACCRO
Disclosure
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.