E Van Cutsem1, K Muro2, D Cunningham3, G Bodoky4, A Sobrero5, S Cascinu6, J Ajani7, S C Oh8, S E Al-Batran9, Z A Wainberg10, S R Wijayawardana11, S Melemed11, D Ferry12, R R Hozak11, A Ohtsu13. 1. Digestive Oncology, University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium. Electronic address: Eric.VanCutsem@uzleuven.be. 2. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 3. Royal Marsden Hospital, Sutton, UK. 4. Department of Oncology, St. László Hospital, Budapest, Hungary. 5. Medical Oncology, IRCCS Ospedale San Martino IST, Genova, Italy. 6. Department of Medical Oncology, Università Politecnica Delle Marche, Ancona, Italy. 7. Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. 8. Korea University Guro Hospital, Seoul, South Korea. 9. Institute of Clinical Cancer Research (IKF), UCT- University Cancer Center, Frankfurt, Germany. 10. Medical Hematology and Oncology, University of California Los Angeles, Los Angeles, CA, USA. 11. Eli Lilly and Company, Indianapolis, IN, USA. 12. Eli Lilly and Company, Bridgewater, NJ, USA. 13. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Abstract
BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.
RCT Entities:
BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.