Efficacy and Safety of Cetuximab Dosing (biweekly vs weekly) in Patients with KRAS Wild-type Metastatic Colorectal Cancer: A Meta-analysis

Abstract

Background Cetuximab 500 mg/m2 biweekly (Q2W) plus chemotherapy is commonly used and recommended by NCCN guidelines. This meta-analysis compares efficacy and safety between Q2W versus weekly (Q1W) cetuximab dosing. Methods A systematic literature review was performed on Pubmed and RightFind (2007-2017) for patients with KRAS wild-type mCRC who received Q2W or Q1W cetuximab and other treatments. Observational studies and case reports were excluded. Randomized trials comparing Q2W and Q1W dosing, and single-arm trials with only Q2W schedule were included. CRYSTAL, a phase 3 randomized study with Q1W cetuximab dosing was paired with each single-arm study with a Q2W schedule and reweighted to achieve similar demographic/baseline characteristics. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HR), overall response rate (ORR) with odds ratios, and risk difference of adverse events of special interest (AESI) between Q2W versus Q1W cetuximab were analyzed. Results Five phase 2 studies with cetuximab Q2W/Q1W dosing schedules were identified: CECOG (phase 2; Q2W, n = 77; Q1W, n = 75), NORDIC 7.5 (phase 2; Q2W, n = 152) and NORDIC 7 (arm C of phase 3; Q1W, n = 109), CELINE (n = 60), OPTIMIX (n = 99), and APEC (n = 289) all phase 2, Q2W, single-arm studies paired with CRYSTAL Q1W dosing (n = 303). Efficacy was similar between Q2W versus Q1W administration; OS HR = 0.96, 95% confidence interval (CI) [0.89, 1.04]; PFS HR = 0.96, 95% CI [0.87, 1.05]; ORR odds ratio 1.16, 95% CI [0.96, 1.41]. Mean differences (Q2W-Q1W) across AESI rates were not clinically meaningful with no obvious directionality. Conclusion This meta-analysis demonstrated no significant differences in efficacy and safety between Q2W versus Q1W cetuximab administration in mCRC patients.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience

“…This was based on the evidence of comparable pharmacokinetic exposure, safety, efficacy, and survival outcomes between the two regimens. 10 Moreover, in the ongoing BREAKWATER study, patients with BRAF V600E-mut mCRC receive biweekly cetuximab in association with encorafenib with or without chemotherapy. 11 …”

Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs

“…This approach has been applied for several monoclonal antibodies for which it has been shown that these changes do not impact their efficacy and tolerance and can be applied for other drugs with no apparent association between peak concentration and toxicity. 9 , 15 , 21 , 26 For example, nivolumab was approved at a dose of 3 mg/kg every 2 weeks (Q2W). 20 Later, a flat dose of 240 mg Q2W and 480 mg every 4 weeks (Q4W) was approved based on similar average steady-state concentrations in modeling and simulation studies.…”

“… 4 Although many studies show the benefit of a variety of alternative dosing strategies compared with the standard approved dose, these strategies rarely find their way to routine clinical practice. 5 , 6 , 7 , 8 , 9 …”

Optimizing the Dosing Regimen of Cetuximab and Ramucirumab Using the Model‐Informed Drug Development Paradigm

“…This involved combining and analyzing low dimensionality data from multiple clinical studies to derive the overall drug efficacy and safety. 11 For both cetuximab and ramucirumab, the program followed a paired meeting approach. The objective of the initial engagement was to reach an agreement with the FDA on an approach and data package required to support labeling supplements.…”