Aflibercept in Combination With FOLFIRI as First-line Chemotherapy in Patients With Metastatic Colorectal Cancer (mCRC): A Phase II Study (FFCD 1302).

FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line. Patients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H0: 55% and H1= 75%. Data were analyzed in intention to treat. Forty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification. Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.

Lapeyre-Prost A ，Pernot S ，Sigrand J ，Le Malicot K ，Mary F ，Aparicio T ，Dahan L ，Caroli-Bosc FX ，Lecomte T ，Doat S ，Marthey L ，Desrame J ，Lepage C ，Taieb J ... -  《-》

Efficacy and Safety of Aflibercept in Combination With Chemotherapy Beyond Second-Line Therapy in Metastatic Colorectal Carcinoma Patients: An AGEO Multicenter Study.

Although no data have been reported beyond second-line therapy, aflibercept is approved in this setting in many countries. We conducted a multicenter study to analyze the efficacy and safety of a aflibercept-chemotherapy regimen beyond second-line therapy in patients with metastatic colorectal cancer. Metastatic colorectal cancer patients treated with aflibercept beyond second-line therapy were included. Objective response rate, overall survival (OS), and progression-free survival (PFS) were assessed. A total of 130 patients were included. Median OS and PFS were 7.6 months (95% confidence interval, 6.2-9.3) and 3.3 months (95% confidence interval, 2.7-3.8), respectively. The best response rates were partial response 6.9%, stable disease 38.5%, progressive disease 42.5%, and not evaluable 12%. According to whether patients received previous FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin)-bevacizumab or not, OS was 7.7 and 8.1 months (P = .31), and PFS was 2.9 and 3.9 months (P = .02), respectively. Interestingly, PFS and OS were both significantly improved by 4% and 5% per month, respectively, without antiangiogenic treatment before the initiation of the aflibercept regimen. The negative effect of prior FOLFIRI-bevacizumab or shorter time since last bevacizumab was maintained in multivariate analysis for both OS and PFS. The aflibercept-chemotherapy regimen is a therapeutic option in patients with chemorefractory disease beyond second-line therapy, in particular in patients with an antiangiogenic-free interval.

Auvray M ，Tougeron D ，Auclin E ，Moulin V ，Artru P ，Hautefeuille V ，Hammel P ，Lecomte T ，Locher C ，Sickersen G ，Coriat R ，Lecaille C ，Vernerey D ，Taieb J ，Pernot S ... -  《-》

Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial.

Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age. Efficacy and safety were analyzed by treatment arm and age (≥ or <65years). Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1). A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients. clinicaltrials.govNCT00561470.

Ruff P ，Van Cutsem E ，Lakomy R ，Prausova J ，van Hazel GA ，Moiseyenko VM ，Soussan-Lazard K ，Dochy E ，Magherini E ，Macarulla T ，Papamichael D ... -  《-》

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of

Wade R ，Duarte A ，Simmonds M ，Rodriguez-Lopez R ，Duffy S ，Woolacott N ，Spackman E ... -  《-》

Safety and efficacy of aflibercept in combination with fluorouracil, leucovorin and irinotecan in the treatment of Asian patients with metastatic colorectal cancer.

To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan (FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed after oxaliplatin-based chemotherapy. This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept (4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singapore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software. The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with 63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%) achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6 months [95% confidence interval (CI), 2.2-13.1 months], the median OS was 11.6 months (95% CI, 6.1 to not-estimable), and median PFS was 4.1 months (95% CI, 2.2-5.9). Majority of the toxicities were grade 1-2, and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%). All adverse events resolved with supportive management. The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian patients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen.

Chong DQ ，Manalo M ，Imperial M ，Teo P ，Yong G ，Ng M ，Tan IB ，Choo SP ，Chua C ... -  《-》