AMALTHEA: A prospective, single-arm study of the Hellenic Cooperative Oncology Group evaluating the efficacy and safety of 1st line FOLFIRI+Aflibercept in patients with metastatic colorectal cancer

Background: The efficacy and safety of the FOLFIRI regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC). Methods: In the context of a prospective single-arm trial, patients with mCRC received standard doses of Leucovorin, 5-Fluorouracil and Irinotecan (FOLFIRI) combined with aflibercept (4 mg/KBW iv) every 2 weeks until disease progression, unacceptable toxicity or completion of 12 cycles, followed by aflibercept maintenance. Endpoints were the 12-month Progression-Free Rate (PFR12), efficacy and toxicity. Results: 73 fit patients were enrolled in the study between 2014 and 2016. Fifty-five patients had tumors in the left colon, forty-four presented with synchronous metastases. Median relative dose intensities administered were 0.85 (95% CI 0.74-0.84) for 5-FU CI, 0.80 (95% CI 0.73-0.89) for Irinotecan and 1.0 (95% CI 0.92-0.98) for Aflibercept. In total, adverse events occurred in 70 patients (95.9%), with no toxic deaths. The most common grade 3 or 4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhoea (11 patients, 15%), hypertension (19 pts, 26%), proteinuria (8 pts, 11%), infections (8 pts, 11%), mucositis (6 pts, 8%). Among 85 adverse events of special interest (AESI) observed, 57 events ended with complete recovery. Among eight patients with severe proteinuria, improvement to grade 0/2 occurred in six at a median time of 4.8 months. The Objective Response Rate (ORR) was 46.6% in the ITT population (n = 73) and 51.5% in the evaluable population (n = 66). Among potential prognostic clinicopathological parameters (including RAS, BRAF status, primary site), the presence of synchronous metastases and a relapse-free interval <12 months were significantly associated with response (odds ratio 2.92 and 3.75 respectively), while a performance status of 0 with overall survival (hazard ratio 0.42). At a median follow-up of 20.9 months, the median OS was 24.7 months (95% CI 17.3-30.5), the median PFS 8.4 months (95% CI 7.44-9.44), while the 12-month PFS rate was 21.8%. Conclusions: The FOLFIRI + Aflibercept regimen is active and safe, however it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Clinical trial identification: EudraCT No.: 2013-002567-26 Legal entity responsible for the study: Hellenic Cooperative Oncology Group (HeCOG) Funding: Sanofi-Aventis Disclosure: V. Karavasilis: Advisory Board: Novartis, Roche, Astellas, Merck, Sanofi, Pfizer, Astra-Zeneca, Janssen. Honoraria: Novartis, Roche, Astellas, Merck, Sanofi, Pfizer, Astra-Zeneca, Janssen. G. Aravantinos: Honoraria: Genesis pharma SA Scientific Advisory Board: Amgen, Astra-Zeneca, BMS, GSK, Roche, Sanofi. I. Souglakos: Honoraria: Sanofi. Research grant: Sanofi. G. Fountzilas: Honoraria: Astra-Zeneca. Consulting or Advisory Role: Pfizer, Sanofi, Roche. Stock and other ownership interests (an Immediate family member): Ariad. All other authors have declared no conflicts of interest.