A post-marketing safety study of ramucirumab with FOLFIRI in patients with metastatic colorectal cancer

Abstract

Background: Ramucirumab [human vascular endothelial growth factor (VEGF) receptor-2 monoclonal antibody] + levofolinate, fluorouracil, and irinotecan (FOLFIRI) was approved for the treatment of metastatic colorectal cancer (CRC) in Japan based on the results from the phase 3 RAISE trial (NCT01183780).However, safety information of ramucirumab + FOLFIRI in the real-world setting is limited. Therefore, the present study was conducted to evaluate the safety of ramucirumab + FOLFIRI under routine clinical practice in patients with metastatic CRC (mCRC) after first-line chemotherapy.Methods: A single-arm, prospective, multicenter, non-interventional, observational study was conducted between August 2016 and May 2020. Patients with mCRC treated with ramucirumab + FOLFIRI for the first time were included. Patients were observed for 12 months from the start of ramucirumab. Data were recorded using the electronic data capture system.Results: In total, 362 patients with a mean age of 64.1 years were evaluated for safety, of whom 355 patients were evaluated for effectiveness. A higher proportion of the patients were males (n=200; 55.2%), had metastases and recurrent sites (n=362, 100.0%), and had received prior anti-cancer treatment (n=355; 98.1%).Approximately 83.7% (n=303) and 25.4% (n=92) of patients had medication history of bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies, respectively. Overall, 84.3% (n=305) of patients experienced any grade adverse events (AEs). Neutrophil count decreased (n=138; 38.1%), hypertension (n=58; 16.0%), and diarrhea (n=57; 15.7%) were observed frequently. The clinically relevant grade ≥3 AEs of special interest (AESIs) with >2% incidence included neutropenia (n=101; 27.9%), hypertension (n=35; 9.7%), proteinuria (n=23; 6.4%), hepatic dysfunction (n=15; 4.1%), febrile neutropenia (n=10; 2.8%), and leukopenia (n=9; 2.5%). The presence of renal disease at baseline increased the risk of proteinuria [risk ratio: 2.1; 95% confidence interval (CI): 1.1-4.2]. Three deaths were reported due to AEs, of which 1 was study treatment related. The 12-month survival rate of the ramucirumab + FOLFIRI regimen was 59%, mortality mainly (90%) occurring due to progressive disease. Conclusions:Although the current observational study enrolled patients with various medication history, the regimen of ramucirumab + FOLFIRI was manageable under clinical practice. No new safety concerns beyond the findings observed in previous clinical trials were reported.

Post-Marketing Safety Study of Ramucirumab Plus FOLFIRI: Analysis of Age and Initial Dose of Irinotecan in Patients with Metastatic Colorectal Cancer

“… Data presented as n (%) unless otherwise indicated SD standard deviation a Data for the overall population are from Masuishi et al [ 11 ] b Only patients with available information regarding initial dose of irinotecan are included ( n = 13 excluded) c Patients could have more than one site …”

“… Data presented as median (minimum–maximum) a Data for the overall population are from Masuishi et al [ 11 ] …”

“… MedDRA version 23.0. The frequency (irinotecan ≤150 mg/m 2 vs >150 mg/m 2 ) of any grade diarrhea was 16.9% ( n = 44) vs 14.8% ( n = 13) and grade ≥ 3 diarrhea was 1.9% ( n = 5) vs 4.6% ( n = 4) AE adverse event, MedDRA Medical Dictionary for Regulatory Activities, SAE serious adverse event a Data for the overall population are from Masuishi et al [ 11 ] b Only patients with available information regarding initial dose of irinotecan are included ( n = 13 excluded) …”

“…Patients diagnosed with unresectable, advanced, or recurrent mCRC and treated for the first time with ramucirumab plus FOLFIRI under routine clinical practice were eligible for study inclusion. The study design has been previously described [ 11 ]. Briefly, on day 1 of each 2-week cycle, patients received intravenous ramucirumab 8 mg/kg followed by FOLFIRI (intravenous irinotecan 150 or 180 mg/m 2 , intravenous levofolinate 200 mg/m 2 , and fluorouracil 400 mg/m 2 given as an intravenous bolus injection followed by 2400 mg/m 2 given as a continuous infusion over 46 h).…”

“…We recently reported the safety profile of ramucirumab plus FOLFIRI in patients with mCRC in a post-marketing observational study conducted in clinical sites in Japan [ 11 ]. We demonstrated that the regimen of ramucirumab plus FOLFIRI was manageable in Japanese patients with mCRC in real-world settings, with no new safety concerns identified and a 12-month survival rate of 59.0%, which corresponds to findings from the RAISE trial (55.9%) [ 11 ]. Patient characteristics such as age and combination therapy affect the decision-making process concerning systemic therapy, with the risks and benefits requiring careful consideration by clinicians.…”