PURPOSE: To characterize ramucirumab exposure-response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study. METHODS: Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (C min,ss) and survival. Kaplan-Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,ss and safety outcomes. RESULTS: Pharmacokinetic samples from 906 patients were included in exposure-efficacy analyses; samples from 905 patients were included in exposure-safety analyses. A significant association was identified between C min,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure. CONCLUSIONS: Exploratory exposure-response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.

Eli Lilly and Company Bridgewater NJ USA

Eli Lilly and Company Buenos Aires Argentina

Eli Lilly and Company Indianapolis IN USA

Hospital General Universitario Gregorio Marañón Madrid Spain

Hospital Virgen del Rocio Seville Spain

Institutul Oncologic Cluj Napoca Cluj Napoca Romania

Istituto Oncologico Veneto IOV IRCCS Padua Italy

Kaiser Permanente San Diego San Diego CA USA

Ludwig Maximilians University Hospital Munich Munich Germany

Masaryk Memorial Cancer Institute Brno Czech Republic

National Cancer Center Hospital East Chiba Japan

Rocky Mountain Cancer Center 1800 Williams Street Denver CO 80218 USA

Shizuoka Cancer Center Shizuoka Japan

Southern Medical Day Care Centre Wollongong Australia

Szent László Hospital Budapest Hungary

University Hospital Motol Prague Czech Republic

University Hospitals Gasthuisberg Louvain Belgium

Vall d'Hebron University Hospital and Institute of Oncology Barcelona Spain

West Clinic Memphis TN USA

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