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.
4543 Background: Treatment (tx) of advanced gastric cancer (GC/GEJ) is highly heterogeneous, with substantial variability in tx patterns. Frontline tx choice may affect outcomes of subsequent tx, thereby influencing choice/efficacy of second-line (2L) tx. In RAINBOW, 2L ramucirumab(R) plus paclitaxel(P) significantly improved overall survival (OS) of patients (pts) with GC/GEJ. Here we explore efficacy, safety and quality of life (QoL) based on prior tx. Methods: Pts were grouped into doublet (DB) or triplet (TP) regimens based on prior cytotoxic tx received. OS and PFS were estimated using Kaplan-Meier method and tx effects on OS and PFS were evaluated by Cox PH model; safety and QoL were assessed descriptively for DB vs TP. Results: Use of DB and TP was similar between arms, with 23% in R+P and 26% in placebo (PB)+P arm receiving TP. Baseline characteristics were generally balanced between tx arms within DB and TP subgroups, with majority of TP administered in western regions (91%). Pts ≥65 years of age was 40% for DB and 28% for TP. DB pts (n = 498; 75%) received S1+cis (n = 97, 15%) and cape+ox (n = 71; 11%) as most common prior tx, while TP pts (n = 163; 25%) received epi+cape+ox (n = 74, 11%) and epi+cis+5FU (n = 53, 8%). Similar to ITT population, R+P improved OS and PFS in both DB and TP subgroups (Table). Patterns of overall and Grade ≥3 TEAEs between arms were similar regardless of prior tx. Higher rates of serious TEAEs were reported in TP pts (57%, 49%) than DB pts (44%, 40%) in R+P and PBO+P arms, respectively. Similar trend was observed for TEAEs leading to discontinuation for TP (40%, 30%) vs DB (29%, 22%) in respective tx arms. Baseline QoL scores were similar between tx arms within subgroups, but mean scores were > 5 points worse (range 0-100) for prior TP for role functioning, fatigue, pain, and appetite loss. Changes in mean scores were generally similar between arms and within subgroups. Conclusions: This exploratory analysis of RAINBOW suggests that although safety-related outcomes were less favorable in pts with prior TP, regardless of tx arm, similar improvements in efficacy were noted for R+P irrespective of prior DB or TP. Clinical trial information: NCT01170663 . [Table: see text]
after 4 months 80.4AE17.3. Also, fatigue, appetite loss, and nausea/vomiting did not deteriorate over time. Final QoL results will be presented at the ESMO Congress.Conclusions: Overall survival in almost 500 patients from start of FTD/TPI is comparable to other population-based studies. Our results suggest that fewer symptoms at start of FTD/TPI treatment are associated with longer treatment duration. QoL was maintained during FTD/TPI treatment, which supports its use in clinical practice.Legal entity responsible for the study: The authors.
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.
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