Background: FOLFOXIRI plus bevacizumab (BEV) is a first-line treatment option for patients with unresectable or metastatic CRC. However, there are no clear recommendations for second-line therapy after failure of FOLFOXIRI plus BEV. The EFFORT study investigated whether FOLFIRI plus aflibercept is active following FOLFOXIRI plus BEV in unresectable/metastatic CRC. Methods: EFFORT was an open-label, multicenter, single arm phase II study. Patients with unresectable/metastatic CRC who failed FOLFOXIRI plus BEV as a first-line therapy received aflibercept plus FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m² IV over 90 min, with levofolinate 200 mg/m² IV over 2 hours, followed by fluorouracil 400 mg/m² bolus and fluorouracil 2400 mg/m² continuous infusion over 46 hours) every 2 weeks on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). To achieve 80% power to show a significant benefit with a one-sided alpha level of 0.10, assuming a threshold PFS of 3 months and an expected value of at least 5.4 months, 32 patients needed to be enrolled. Major secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Results: From April 2019 to May 2021, 35 patients were enrolled and FAS included 34 patients (one patient who did not met eligibility criteria was excluded). Of them, 18 were males, median age was 63 years (range: 32-78) and ECOG Performance Status was either 0 (n = 28) or 1 (n = 6). The primary tumor was left-sided in most patients (23/34) and 27 patients had liver metastases. And 23 patients had RAS mutation. The primary endpoint was met with a median PFS of 4.3 months [80% CI: 3.7-5.1]. The median OS was 15.2 months [95% CI: 8.9-22.7]. Objective tumor responses were CR (n = 1), PR (n = 4), SD (n = 21) or PD (n = 8). ORR was 14.7% (5/34) [95% CI: 5.0-31.1], and disease control rate was 76.5% (26/34) [95% CI: 58.8–89.3]. Main grade 3 or 4 adverse events were neutropenia (7/35, 20.0%), thrombopenia (3/35, 8.6%), leucopenia (2/35, 5.7%), and hypertension (3/35, 8.6%). No severe proteinuria and no treatment-related death were reported. Conclusions: Aflibercept plus FOLFIRI given after failure of FOLFOXIRI plus BEV is active and shows a manageable safety profile. This regimen maybe a useful as second-line treatment option in such patients. Clinical trial information: jRCTs071190003.