Exposure–response relationship for ramucirumab from the randomized, double-blind, phase 3 REVEL trial (docetaxel versus docetaxel plus ramucirumab) in second-line treatment of metastatic non-small cell lung cancer

Abstract

Purpose

Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure–response relationship of ramucirumab from REVEL.

Methods

Patients received ramucirumab (10 mg/kg) or placebo plus docetaxel (75 mg/m²) every 3 weeks. Pharmacokinetic samples were collected. A population pharmacokinetic analysis predicted ramucirumab minimum concentration after first-dose administration (C_min,1) and average concentration at steady state (C_ave,ss). Predicted C_min,1 and C_ave,ss were used to evaluate the relationship between ramucirumab exposure and efficacy and safety, respectively. Exposure–efficacy was assessed by Kaplan–Meier and Cox regression analyses; exposure–safety was assessed by ordered categorical analyses.

Results

Analyses included 376 patients treated with ramucirumab plus docetaxel and 366 patients treated with placebo plus docetaxel (364 for safety population). After adjusting for corresponding prognostic factors, the association between overall survival (OS) and C_min,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (C_min,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by C_min,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab C_ave,ss and grade ≥ 3 febrile neutropenia and hypertension.

Conclusions

An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure–response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017).

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