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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

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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).

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Acknowledgements

We thank the patients, their families, the study sites, and the study personnel who participated in this clinical trial. Eli Lilly and Company contracted with Syneos Health for writing support provided by Andrea D. Humphries, PhD, and Ira Ayene, PhD, and editing support provided by Angela C. Lorio, ELS.

Funding

Funded by: Eli Lilly and Company.

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Egbert F. Smit

  2. David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA

    Edward B. Garon

  3. Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany

    Martin Reck

  4. Ospedale San Gerardo, Via Pergolesi, 33, Monza, Italy

    Federico Cappuzzo

  5. Nuovo Ospedale San Gerardo, Via Pergolesi, Milano, Italy

    Paolo Bidoli

  6. Perelman School of Medicine, Philadelphia, PA, USA

    Roger B. Cohen

  7. Eli Lilly and Company, Bridgewater, NJ, USA

    Ling Gao & Pablo Lee

  8. Eli Lilly and Company, Indianapolis, IN, USA

    Lisa M. O’Brien, Annamaria Zimmermann, David R. Ferry & Allen S. Melemed

  9. Département de Cancérologie Médicale Centre Léon-Bérard, Lyon, France

    Maurice Pérol

  10. Department of Pulmonary Diseases, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Egbert F. Smit

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  1. Egbert F. Smit
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Corresponding author

Correspondence to Egbert F. Smit.

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Conflict of interest

Ling Gao, Lisa M. O’Brien, Pablo Lee, Annamaria Zimmermann, David R. Ferry, and Allen S. Melemed are full-time employees and stockholders of Eli Lilly and Company. Egbert F. Smit has received honoraria from Eli Lilly and Company. Edward B. Garon received research funding from AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Mirati, Pfizer, Novartis, Boehringer Ingelheim, and Eli Lilly and Company. Martin Reck has received honoraria for lectures and consultancy from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Merck, Merck Sharp & Dohme, Novartis, Pfizer, and Roche/Genentech. Federico Cappuzzo has received consultancy fees from Eli Lilly and Company. Maurice Pérol has received honoraria as a consultant/advisory board member for Eli Lilly and Company. Paolo Bidoli is on the advisory board for Boehringer Ingelheim, Bristol-Myers Squibb, and Eli Lilly and Company. Roger B. Cohen declares grant support to his institution from ImClone. This study is funded by Eli Lilly and Company.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Smit, E.F., Garon, E.B., Reck, M. et al. 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. Cancer Chemother Pharmacol 82, 77–86 (2018). https://doi.org/10.1007/s00280-018-3560-5

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