Egbert F Smit1,2, Edward B Garon3, Martin Reck4, Federico Cappuzzo5, Paolo Bidoli6, Roger B Cohen7, Ling Gao8, Lisa M O'Brien9, Pablo Lee8, Annamaria Zimmermann9, David R Ferry9, Allen S Melemed9, Maurice Pérol10. 1. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. ef.smit@vumc.nl. 2. Department of Pulmonary Diseases, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. ef.smit@vumc.nl. 3. David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA. 4. Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. 5. Ospedale San Gerardo, Via Pergolesi, 33, Monza, Italy. 6. Nuovo Ospedale San Gerardo, Via Pergolesi, Milano, Italy. 7. Perelman School of Medicine, Philadelphia, PA, USA. 8. Eli Lilly and Company, Bridgewater, NJ, USA. 9. Eli Lilly and Company, Indianapolis, IN, USA. 10. Département de Cancérologie Médicale Centre Léon-Bérard, Lyon, France.
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 withramucirumab plus docetaxeland 366 patients treated withplacebo 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).
RCT Entities:
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).
Authors: René J Boosman; Jacobus A Burgers; Egbert F Smit; Neeltje Steeghs; Anthonie J van der Wekken; Jos H Beijnen; Alwin D R Huitema; Rob Ter Heine Journal: Drugs Date: 2021-12-11 Impact factor: 9.546
Authors: Kazuhiko Nakagawa; Edward B Garon; Ling Gao; Sophie Callies; Annamaria Zimmermann; Richard Walgren; Carla Visseren-Grul; Martin Reck Journal: Cancer Chemother Pharmacol Date: 2022-07-16 Impact factor: 3.288
Authors: Ronald de Wit; Thomas Powles; Daniel Castellano; Andrea Necchi; Jae-Lyun Lee; Michiel S van der Heijden; Nobuaki Matsubara; Aristotelis Bamias; Aude Fléchon; Cora N Sternberg; Alexandra Drakaki; Evan Y Yu; Annamaria H Zimmermann; Amanda Long; Richard A Walgren; Ling Gao; Katherine M Bell-McGuinn; Daniel P Petrylak Journal: Br J Clin Pharmacol Date: 2022-02-07 Impact factor: 3.716
Authors: Maxim Sorokin; Elena Poddubskaya; Madina Baranova; Alex Glusker; Lali Kogoniya; Ekaterina Markarova; Daria Allina; Maria Suntsova; Victor Tkachev; Andrew Garazha; Marina Sekacheva; Anton Buzdin Journal: Cold Spring Harb Mol Case Stud Date: 2020-04-01