Efficacy and safety of triweekly cetuximab in combination with capecitabine as first-line maintenance treatment for KRAS/BRAF wild-type metastatic colorectal cancer: A phase Ib dose-escalation study.

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124 Background: The every-two-weeks (Q2W) dosing schedule of cetuximab plus fluorouracil-based agents is a commonly used maintenance therapy for KRAS/BRAF wild-type metastatic colorectal cancer (mCRC), but current regimens are limited by infusion burden and schedule misalignment. A triweekly cetuximab schedule synchronized with capecitabine may offer greater convenience, and warrants further investigation. Methods: In this phase Ib, 3+3 dose-escalation study, patients with KRAS/BRAF wild-type mCRC who had completed first-line induction therapy without progression received cetuximab every-three-weeks (Q3W) at 400, 500, 600 or 700 mg/m², combined with capecitabine (1000 mg/m² twice daily, days 1-14, Q3W). The primary objective was to evaluate the pharmacokinetic (PK), assess safety and determine the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT) within six weeks. Secondary objectives included PFS, OS, ORR and DCR. A parallel 500 mg/m² Q2W cohort served as a pharmacokinetic reference. Treatment continued until progression, unacceptable toxicity or withdrawal. Dose escalation followed standard 3+3 rules. Results: A total of twenty-four patients were enrolled (Q3W cohort, N=18; Q2W cohort, N=6). No MTD was reached up to 700 mg/m² Q3W. Safety profiles were consistent across cohorts, with no unexpected adverse events observed. Median PFS in the four cetuximab Q3W cohorts was 9.7 months, 14.3 months, 8.6 months, and not reached, respectively. Pharmacokinetic analysis showed that trough serum concentrations of cetuximab at 700 mg/m² Q3W were comparable to those achieved with the standard 500 mg/m² Q2W regimen. Conclusions: Cetuximab combined with capecitabine can be safely administered on a Q3W schedule, and the 700 mg/m² Q3W regimen provided the most favorable profile in terms of safety, pharmacokinetic exposure and preliminary efficacy, supporting its further evaluation in subsequent studies. Clinical trial information: NCT05775900 . Pharmacokinetic parameters of cetuximab at steady state. Pharmacokinetic parameters Triweekly cetuximab Biweekly cetuximab 400mg/m 2 (N=3) 500mg/m 2 (N=3) 600mg/m 2 (N=6) 700mg/m 2 (N=6) 500mg/m 2 (N=6) AUC 0-τ, ss (mg*h/L) Mean (SD) 67526.9 (26858.9) 59779.5 (10164.8) 73381.1 (31175.4) 115209.9 (24433.6) 92864.6 (38509.6) Median 61223.4 59981.7 70400.1 112078.4 85982.5 Geomean (CV%) 64110.0 (39.8%) 59195.8 (17.0%) 67669.8 (42.5%) 113188.9 (21.2%) 86118.4 (41.5%) C max, ss (mg/L) Mean (SD) 312.1 (28.4) 282.5 (50.9) 312.0 (63.0) 458.0 (114.9) 359.9 (80.1) Median 326.9 261.3 287.3 421.1 345.4 Geomean (CV%) 311.2 (9.1%) 279.6 (18.0%) 307.5 (20.2%) 447.2 (25.1%) 353.0 (22.2%) C min, ss (mg/L) Mean (SD) 18.3 (15.8) 4.7 (6.2)

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