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Exposure-Response Analyses of Ramucirumab from Two Published OnlineFirst July 17, 2017; DOI: 10.1158/1535-7163.MCT-16-0895 Large Molecule Therapeutics Molecular Cancer Therapeutics Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer Josep Tabernero1, Atsushi Ohtsu2, Kei Muro3, Eric Van Cutsem4, Sang Cheul Oh5, Gyorgy€ Bodoky6, Yasuhiro Shimada7, Shuichi Hironaka8, Jaffer A. Ajani9, Jiri Tomasek10, Howard Safran11, Kumari Chandrawansa12, Yanzhi Hsu12, Michael Heathman13, Azhar Khan14, Lan Ni13, Allen S. Melemed13, Ling Gao12, David Ferry13, and Charles S. Fuchs15 Abstract Ramucirumab is an IgG1 monoclonal antibody specific for the and 335 placebo þ paclitaxel patients from RAINBOW and vascular endothelial growth factor receptor-2. Ramucirumab, 72 ramucirumab and 35 placebo patients from REGARD. Expo- 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) sure–efficacy analysis showed ramucirumab Cmin,ss was a signif- or in combination with paclitaxel (RAINBOW), was safe and icant predictor of OS and PFS in both trials. Higher ramucirumab effective in patients with previously treated advanced gastric or exposure was associated with longer OS and PFS. In RAINBOW, gastroesophageal junction (GEJ) cancer. We evaluated exposure– grade 3 hypertension, leukopenia, and neutropenia, but efficacy and exposure–safety relationships of ramucirumab from not febrile neutropenia, significantly correlated with Cmin,ss, two randomized, placebo-controlled phase III trials. Sparse phar- with increased exposure leading to increased incidence. macokinetic samples were collected, and a population pharma- Exploratory exposure–response analyses suggest a positive rela- cokinetic analysis was conducted to predict ramucirumab mini- tionship between efficacy and ramucirumab exposure with man- mum trough concentration at steady state (Cmin,ss). Kaplan–Meier ageable toxicities at exposures generated from a dose of 8 mg/kg methods and Cox proportional hazards models were used to ramucirumab given every 2 weeks for patients with advanced evaluate the ramucirumab exposure (Cmin,ss)–efficacy relation- gastric/GEJ cancer. These findings suggest an opportunity to ship to overall survival (OS) and progression-free survival (PFS). further optimize benefit versus risk profiles of ramucirumab Logistic regression analyses were used to evaluate exposure–safety treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; relationships. Analyses included 321 ramucirumab þ paclitaxel 16(10); 2215–22. Ó2017 AACR. 1Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Uni- Introduction versitat Autonoma de Barcelona, Barcelona, Spain. 2National Cancer Center Ramucirumab is a recombinant human IgG1-neutralizing 3 HospitalEast,Kashiwa,Chiba,Japan. Aichi Cancer Center Hospital, Nagoya, monoclonal antibody (mAb) with a 50 pmol/L Kd specific for Japan. 4University Hospitals Leuven and KU Leuven, Leuven, Belgium. 5Korea the ectodomain of the vascular endothelial growth factor recep- University Guro Hospital, Seoul, Korea. 6St. Laszlo Hospital, Budapest, Hungary. 7National Cancer Center Hospital, Tokyo, Japan. 8Chiba Cancer tor-2 (VEGFR-2; ref. 1). The maximum tolerated dose of single- Center,Chiba,Japan.9MD Anderson Cancer Center, Houston, Texas. agent ramucirumab determined in a phase I trial was 13 mg/kg/ 10Masaryk Memorial Cancer Institute, Brno, Czech Republic. 11Rhode Island week (1). Safety and efficacy of ramucirumab in patients with Hospital, Providence, Rhode Island. 12Eli Lilly and Company, Bridgewater, previously treated advanced gastric or gastroesophageal junction 13 14 New Jersey. Eli Lilly and Company, Indianapolis, Indiana. Eli Lilly and (GEJ) cancer were evaluated in two randomized, double-blind Company, Windlesham, Surrey, United Kingdom. 15Dana-FarberCancerInsti- phase III trials (REGARD and RAINBOW; refs. 2, 3). In both the tute, Boston, Massachusetts. REGARD (ramucirumab 8 mg/kg versus placebo every 2 weeks) Note: Supplementary data for this article are available at Molecular Cancer and RAINBOW (ramucirumab 8 mg/kg or placebo every 2 weeks Therapeutics Online (http://mct.aacrjournals.org/). in combination with weekly paclitaxel 80 mg/m2) studies, overall Current address for K. Chandrawansa: Bayer HealthCare, Whippany, New survival (OS) and progression-free survival (PFS) were signifi- Jersey; current address for C.S. Fuchs: Yale School of Medicine, New Haven, cantly improved in the ramucirumab arm. The most common Connecticut. grade 3 adverse events (AE) in patients treated with ramucir- Trial registration IDs: NCT01170663 (RAINBOW) and NCT00917384 (REGARD). umab included neutropenia, leukopenia, hypertension, fatigue, Corresponding Author: Josep Tabernero, Vall d'Hebron University Hospital, Vall abdominal pain, and anemia (2, 3). Based on the outcomes of d'Hebron Institute of Oncology (VHIO), P. Vall d'Hebron 119-129, 08035 Barce- these trials, ramucirumab has been approved for use as mono- lona, Spain. Phone: 34-93-489-4301; Fax 34-93-274-6059; E-mail: therapy or in combination with paclitaxel for the treatment of [email protected] patients with previously treated advanced gastric/GEJ cancer (4). doi: 10.1158/1535-7163.MCT-16-0895 Exposure–response analyses are the foundation for determin- Ó2017 American Association for Cancer Research. ing safety and efficacy of mAbs used for cancer treatments. www.aacrjournals.org 2215 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst July 17, 2017; DOI: 10.1158/1535-7163.MCT-16-0895 Tabernero et al. Assessing the pharmacokinetics (PK) of mAbs is challenging. Exposure–efficacy analyses Often the maximum tolerated dose is not determined in phase Univariate and multivariable Cox regression analyses were I trials, and measuring target occupancy in cancer tissues is not utilized to determine whether there was a significant relationship easily achieved; indeed many tumors show inhomogeneous between Cmin,ss and survival for each of the phase III trials. Only antibody penetration (5, 6). Several studies on mAbs used to patients with nonmissing ramucirumab concentration data were treat various types of cancer have demonstrated that the relation- included in each of the exposure populations. For the multivar- ship of efficacy and AEs with a defined drug exposure is critical to iable analyses, hazard ratios (HR) were adjusted for significant determining if a treatment is considered safe and effective and if baseline covariates. A stepwise Cox regression model was used to changes to dose or schedule could possibly improve the benefit select baseline covariates at an entry P value of 0.05 and exit P versus risk profile (7–11). value of 0.1. The list of factors evaluated for potential prognostic Although the REGARD and RAINBOW studies showed significance included geographical region, disease measurability, improved OS and PFS for ramucirumab 8 mg/kg alone or in time to progression on first-line therapy, gender, age, race, Eastern combination with paclitaxel versus placebo, exploratory expo- Cooperative Oncology Group performance status (ECOG PS), sure–response analyses were conducted to determine if increased weight loss in the 3 months prior to randomization, primary exposure to ramucirumab could maximize the potential thera- tumor location, prior first-line chemotherapy, histologic subtype, peutic benefit in patients with advanced gastric/GEJ cancer. We number of metastatic sites, peritoneal metastasis, liver metastasis, conducted separate exposure–response analyses of efficacy presence of ascites, tumor differentiation, number of previous and safety from patients on ramucirumab in the REGARD and treatment lines including neoadjuvant and adjuvant, and prior RAINBOW trials. The objectives of these analyses were to evaluate gastrectomy. the relationships between predicted ramucirumab exposure and To evaluate the exposure–response relationship compared with survival, as well as commonly reported AEs in previously treated the control groups for both studies, patients in the exposure patients with advanced gastric/GEJ cancer. populations were stratified into exposure groups by defined Cmin,ss quartiles (Q) (RAINBOW) or by the Cmin,ss median Materials and Methods (REGARD). The quartiles for the patients from the RAINBOW study were defined as: Q1 ¼ Cmin,ss 20.1 to 42.0 mg/mL (<25%); The details of the REGARD and RAINBOW trials, including Q2 ¼ Cmin,ss >42.0 to 53.8 mg/mL (25 to <50%); Q3 ¼ Cmin,ss fi informed consent, trial design, and clinical de nitions of OS, >53.8 to 72.2 mg/mL (50 to <75%); and Q4 ¼ Cmin,ss >72.2 to PFS, and objective response rate (ORR), were previously 227 mg/mL (75%). The REGARD exposure population was described (2, 3). Each center's institutional review board or divided by the median Cmin,ss of 65.35 mg/mL. The Kaplan–Meier independent ethics committee approved the study. The trial method was used to evaluate OS and PFS for each of the indi- followed the principles of the Declaration of Helsinki and the vidual exposure groups versus the control groups. The HR for each Good Clinical Practice Guidelines of the International Confer- exposure group versus the control arm was estimated using a Cox ence on Harmonization. All patients provided written informed proportional hazards model. All HRs for the multivariable anal- consent. yses were adjusted for the significant baseline covariates. Briefly, patients in the RAINBOW trial with advanced gastric/ For REGARD, the first post-baseline
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