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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.

Purpose: The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug-drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI)., Methods: Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis., Results: Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83-1.05) for AUC(0-∞) and 1.04 (90 % CI 0.97-1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88-1.04) for AUC(0-∞) and 0.97 (90 % CI 0.85-1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients., Conclusions: There was no PK drug-drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns.