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.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/adverse effects , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Disease-Free Survival , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Rectal Neoplasms/drug therapyABSTRACT
Model-informed drug development (MIDD) is a process that integrates drug exposure-based, biological, and statistical models to enhance the benefit-risk balance in drug development. The US Food and Drug Administration (FDA) MIDD Paired Meeting Pilot Program provides a platform to apply MIDD approaches to drug development and to seek regulatory feedback in a collaborative and streamlined process prior to submission for approval. Eli Lilly and Company (Lilly) participated in the Pilot Program to seek agency alignment to enhance the initial approved dosing regimens of cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN) and ramucirumab (Cyramza; Eli Lilly and Company) without conducting additional clinical trials. Here, we describe the overall MIDD strategy at Lilly, the process with the FDA, and the impact of implementing the approach.