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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 (Cmin,1) and average concentration at steady state (Cave,ss). Predicted Cmin,1 and Cave,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 Cmin,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (Cmin,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by Cmin,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab Cave,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).

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Smit EF,Garon EB,Reck M,Cappuzzo F,Bidoli P,Cohen RB,Gao L,O'Brien LM,Lee P,Zimmermann A,Ferry DR,Melemed AS,Pérol M

doi

10.1007/s00280-018-3560-5

subject

Has Abstract

pub_date

2018-07-01 00:00:00

pages

77-86

issue

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-018-3560-5

journal_volume

pub_type

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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.