Aflibercept-LV5FU2 as first-line treatment of non-resectable metastatic colorectal cancers: Results of the FOLFA randomized phase II trial.

3555 Background: Previous trials have demonstrated that bevacizumab and fluoropyrimidine combination is effective and well-tolerated in older patients (pts) with non-aggressive unresectable metastatic colorectal cancer. We evaluated in this trial safety and efficacy of aflibercept and infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) combination versus LV5FU2 alone in older pts, asymptomatic and/or frail, deemed unsuitable for doublet cytotoxic chemotherapy. Methods: The main eligibility criteria for this randomized phase II trial were age ≥ 65 and WHO performance status < 2. Randomization was stratified according to thymidylate synthase (TS)- 5’UTR germline polymorphism. Common (also called simplified) LV5FU2 regimen was preceded or not by aflibercept (4mg/kg). The primary endpoint was the 6-month progression-free survival (PFS) rate, achieved if > 40% in the experimental arm. Secondary objectives were safety, quality of life, overall survival (OS), and the prognostic impact of TS -5’UTR polymorphism. Results: 117 patients (pts) were included, 59 in arm A (5FU-aflibercept), 58 in arm B (5FU alone), of median age 81 years (range 67-91; > 75 years: 81%). RAS/ BRAF status (available in 112 pts [96%]) was mutated in 49% and 7%, respectively. The 6-month PFS was 54% in both arms (same 90% CI 42-65). The disease control rate was 83% in arm A and 87% in arm B. The median OS was 21.8 months in arm A and 25.1 months in arm B. The toxicities were more common in arm A: at least 1 grade 3-4 toxicity > 2 in 82% versus (vs) 58.2% pts, hypertension grade > 3 in 42% vs 18% pts, proteinuria (any grade) in 51% vs 11% pts, dysphonia (grade < 3) in 19% vs 2%, 1 colic perforation in arm A. Treatment delays for toxicities were required for 4% of the 753 courses in arm A vs 2% of the 780 courses in arm B , 5FU bolus suppression was decided for 29.8% pts vs 20% (arm A vs arm B), median 29 days vs 73 days after the first course (arm A vs B), without difference in the doses of infusional 5FU. A second and third line of treatment were received in 41% and 14% of pts in arm A vs 67% and 29% of pts in arm B, respectively. The TS 5’UTR polymorphism (3R3R vs 2R2R or 2R3R) had no impact on PFS or OS. Regarding the quality of life (QLQ C30 score), the difference of overall health score was on average -6.39 (SD = 26.68) in arm A vs -4.91 (SD = 27.15) in arm B, and was very similar in all components. The median time to definitive deterioration in quality of life was 15 months (95% CI: 9-22.8) in arm A vs 9.6 (95% CI: 5.1-19.4) in arm B. Conclusions: FOLFA trial meets is primary endpoint with 53.6% of 6-month PFS with LV5FU2-aflibercept. Nevertheless, as compared with LV5FU2 alone we observed no increase in PFS or OS and more toxicities. These results do not argue for an evaluation of LV5FU2-aflibercept combination in a randomized phase III trial. Clinical trial information: EudraCT 2014-001837-10.