Regorafenib (REGO) plus FOLFIRINOX as frontline treatment in patients (pts) with RAS-mutated metastatic colorectal cancer (mCRC): A phase I/II, dose-escalation and dose-expansion study.

3561 Background: Standard treatment options for RAS-mutated mCRC pts include the combination of bevacizumab with FOLFIRINOX, a three-drug chemotherapy regimen. Unlike bevacizumab, REGO – an oral multi-tyrosine kinase agent - exhibits not only antiangiogenic properties with cytostatic effects but also true cytotoxic effects. We report the preliminary results of the FOLFIRINOX-R trial (NCT03828799), in which we evaluated the safety and the efficacy of REGO in combination with FOLFIRINOX in pts with RAS-mutated mCRC. Methods: FOLFIRINOX-R trial is a prospective, dose-finding, phase I/II study whose dose-escalation part has been completed. Dose escalation was implemented following a 3 + 3 design and included three dose levels (DL). FOLFIRINOX regimen includes oxaliplatin (85 mg/m²), folinic acid (400 mg/m²), irinotecan (150–180 mg/m²), 5-fluorouracil (400 mg/m² in bolus then 2400 mg/m² over 46h), and was administered every 14 days. REGO (80 to 160 mg per day, as per DL) was administered on days 4 to 10 of each cycle. Treatment was continued up to 12 cycles or until progression or unacceptable toxicity. The primary objectives of the dose-finding part of the study were to determine the maximum tolerated dose (MTD) using as endpoint the incidence of DLTs during the three first cycles of treatment, and to select the recommended phase 2 dose (RP2D). Key eligibility criteria include ECOG PS ≤1 and RAS-mutated mCRC not amenable to surgery with curative intent and not previously treated for metastatic disease. Patients with the 7/7 variant of the UGT1A1*28 polymorphism were not eligible. Prophylactic G-CSF was administered from Day-7 to Day-12. Results: Thirteen pts were enrolled across the 3 DL (DL 1: 3 pts, DL 2: 6 pts, DL 3: 4 pts); 46% of pts were female, the median age was 65 yo [range: 40 ; 76]. One pt (at DL 3) was not evaluable for DLT because of poor observance during the first 2 cycles. At data cut-off, median treatment duration and median follow-up were 4.6 mo. (range: 2.3; 10) and 13.4 mo. (range: 3.8; 18.0), respectively. One DLT (a grade 3 hypokalaemia related to grade 2 diarrhoea) occurred at DL 2. MTD was not reached at DL 3 (REGO 160 mg/day). The most common grade ≥3 TRAE per patient were grade 3 neutropenia (n = 1), grade 4 neutropenia (n = 1), grade 3 neuropathy (n = 2) and grade 3 diarrhoea (n = 7). Dose reductions/discontinuations due to grade ≥3 TRAE were necessary in 12/13 (92%) pts. The ORR was 62% (95% CI 32%-86%) and median PFS was 9.1 mo (range: 3.1; 15.4). Conclusions: Full-dose FOLFIRINOX plus full-dose REGO (160mg/day, days 4 to 10) can be administered safely. Due to the manageable toxicity profile and the promising efficacy observed in the dose-escalation stage, this regimen deserves to be evaluated in the dose-expansion stage. Clinical trial information: NCT03828799.