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Background: Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice., Methods: REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies., Findings: Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures., Interpretation: REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024., Funding: Bayer HealthCare., Competing Interests: All authors report support for the present manuscript from Bayer for medical writing funding to Open Health. Celestia S. Higano reports support for the present manuscript from Bayer for clinical trial funding to institution; grants or contracts from AbbVie (Contract to develop unbranded educational slide set), Vaccitech (Clinical trial consulting contract, no payments yet), and Verity; consulting fees from the Prostate Cancer Clinical Trials Consortium (Consulting PCCCTC medical monitor for trials sponsored by ESSA and Bayer), Prostate Cancer Supportive Care Program (Consulting Medical Director), and Astellas, AstraZeneca, Ferring, Genentech, Merck Sharp & Dohme, Myovant, Pfizer, Tolmar, and Vaccitech (all advisory boards); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tolmar (medical writing); payment for expert testimony from Ferring; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Exelixis, Advantagene/Candel, and Alliance Foundation (all DSMBs). Daniel J. George reports grants or contracts from Astellas, AstraZeneca, BMS, Calithera, Exelixis, J&J, Pfizer, Novartis, and Sanofi (all paid to his institution); royalties or licenses from Up-to-Date (paid to self); consulting fees from Bayer, Ideo Oncology, Merck, Michael J Hennessey, Myovant, Propella, RevHealth, Seattle Genetics, WebMD, and Xcures (all paid to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Exelixis, and Sanofi (all paid to self); payment for expert testimony from Wilmer Hale (paid to self); support for attending meetings and/or travel from Bayer, Exelixis, and Sanofi (paid to self); participation on a Data Safety Monitoring Board or Advisory Board for Janssen and AstraZeneca (both paid to self); and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for AACR (senior editor), Millennium Med Pub, and CAHO (Co-Editor-in-Chief) (all paid to self). Neal D. Shore reports consulting fees from AbbVie, Alessa Therapeutics, Akido, Arquer, Asieris, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clarity, Cold Genesys, Dendreon, Exact Images, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Photocure, Pfizer, PlatformQ, Profound, Promaxo, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar, Vaxiion; payment for expert testimony from Ferring. Oliver Sartor reports grants or contracts from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio; consulting fees from Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien, Merck, Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., NorthStar, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien, Merck, Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., NorthStar, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics; patents planned, issued or pending: Koochekpour, Sartor AO, inventors. Saposin C and receptors as targets for treatment of benign and malignant disorders. US patent awarded January 23, 2007 (patent no. 7,166,691); participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Jannsen, Pfizer, and Myovant; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Louisiana Cancer Research Consortium – Board, LA. Cancer and Lung Trust; and stock or stock options in Clarity Pharmaceuticals, Noria Therapeutics, Inc., Lilly, Clovis, Glaxo Smith Kline, Abbvie, Cardinal Health, and United Health Group. Kurt Miller reports consulting fees from Accord, Janssen, Novartis, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Accord, Janssen, Novartis, Pfizer, and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Myovant. Peter S. Conti reports no other conflicts to declare. Cora N. Sternberg reports consulting fees from Pfizer, MSD, AZ, Astellas, Sanofi, Genzyme, Roche-Genentech, BMS, Bayer, Foundation Medicine, Gilead, Medscape, UroToday, CCN Clinical, Janssen, NCI (all ad boards over at least 5 years). Fred Saad reports grants or contracts from Astellas, AstraZeneca, Janssen, Myovant, Merck, Novartis, Sanofi, and Pfizer (payment to institution); consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Myovant, Merck, Novartis, Sanofi, Pfizer, Tolmar (payment to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Myovant, Merck, Novartis, Sanofi, Pfizer, Tolmar (payment to self). Juan Pablo Sade reports no other conflicts to declare. Joaquim Bellmunt reports royalties or licenses from UpToDate; consulting fees from Pfizer/MSD, Genentech, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer/MSD, Genentech, AstraZeneca, and Merck; support for attending meetings and/or travel from Pfizer; participation on a Data Safety Monitoring Board or Advisory Board from Pfizer/MSD, Genentech, AstraZeneca, and Merck. Matthew R. Smith reports grants or contracts from Bayer for the present study (paid to self and institution) and from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to institution); consulting fees from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to self); and participation on a Data Safety Monitoring Board or Advisory Board for Bayer, Janssen, and Lilly (all paid to self). Kumari Chandrawansa reports stock or stock options in Bayer; other financial or non-financial interests: employee of Bayer. Per Sandström reports other financial or non-financial interests: employee of Bayer. Frank Verholen reports other financial or non-financial interests: employee of Bayer. Bertrand Tombal reports support for the present manuscript from Bayer (support of study); grants or contracts from Bayer (grant for studies); consulting fees from Astellas, Bayer, Novartis, Janssen, Accor, and MSD (all payments to his company: UROADVISE); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer (paid to his company: UROADVISE) and Astellas., (© 2023 Published by Elsevier Ltd.)

Ramucirumab is an IgG 1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss ). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (C min,ss )-efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure-safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure-efficacy analysis showed ramucirumab C min,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with C min,ss , with increased exposure leading to increased incidence. Exploratory exposure-response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215-22. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer., Materials and Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters., Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor., Conclusions: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies., Competing Interests: Conflict of Interest: Drs. Emig, Ferry, Chandrawansa, Hsu, Sashegyi, and Liepa are full-time employees and stockholders of Eli Lilly and Company. Dr. Ferry additionally received honoraria from Eli Lilly and Company, Sanofi, and Roche; he also held an advisory role for Eli Lilly and Company, Sanofi, and Roche; he received research funding from Eli Lilly and Company and Sanofi; he gave expert testimony for Eli Lilly and Company; he received travel support from Sanofi and Roche. Dr. Fuchs served as a consultant for Eli Lilly and Company, Pfizer, Entrinsic Health, Genentech, Merck, Gilead Sciences, Macrogenics, Sanofi, Dicerna, Frive Prime Therapeutics, Bristol Myers Squibb, Bayer, Merrimack, and Celgene. Dr. Muro received honoraria from Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, and Taiho Pharmaceutical. Dr. Tomasek received honoraria from Roche, Bayer, Merck, Amgen, and Eli Lilly and Company; he served in an advisory role for Ipsen, Amgen, and Roche; he received research funding from Amgen, Novartis, and Eli Lilly and Company; and he received travel support from Pfizer, Eli Lily and Company, Novartis, and Roche. Dr. Van Cutsem received research support from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Merck Serono, Novartis, Roche, Sanofi, Celgene, and Ipsen. Dr. Chau would like to acknowledge United Kingdom National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. Dr. Shimada received research funding from Eli Lilly and Company, Taiho Pharmaceutical, and Chugai Pharma. Dr. Al-Batran received honoraria and served as an advisor for Eli Lilly and Company. Dr. Passalacqua received honoraria from Eli Lilly and Company, Roche, and Novartis; he served as an advisor for Eli Lilly and Company; he is on the Speakers' bureau for Astellas Pharma; and he receives research funding from Amgen. Dr. Ohtsu is related to an employee of Celgene and he receives research funding from Bristol-Myers Squibb. Dr. Wilke received honoraria from Eli Lilly and Company and served as an advisor for Eli Lilly and Company.

Background: We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial., Methods: Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations., Results: The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %)., Conclusions: Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. CLINICALTRIALS., Gov Identifier: NCT01170663.

Background and Aim: East Asia has higher gastric cancer incidence and mortality rates than other regions. We present a subgroup analysis of East Asians in the positive study RAINBOW., Methods: Patients with advanced gastric or gastroesophageal junction adenocarcinoma previously treated with platinum and fluoropyrimidine received ramucirumab 8 mg/kg or placebo on days 1 and 15 plus paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle., Results: Of 665 intention-to-treat patients, 223 were East Asian. Median overall survival was 12.1 months for ramucirumab plus paclitaxel and 10.5 months for placebo plus paclitaxel (hazard ratio: 0.986, 95% confidence interval: 0.727-1.337, P = 0.929). Median progression-free survival was 5.5 months for ramucirumab plus paclitaxel and 2.8 months for placebo plus paclitaxel (hazard ratio: 0.628, 95% confidence interval: 0.473-0.834, P = 0.001). Objective response rates were 34% for ramucirumab plus paclitaxel and 20% for placebo plus paclitaxel. Grade ≥ 3 neutropenia (60% vs 28%) and leukopenia (34% vs 13%) were higher for ramucirumab plus paclitaxel. The rate of febrile neutropenia was low (4% vs 4%). Special interest adverse events included any grade bleeding/hemorrhage (55% vs 25%), proteinuria (27% vs 7%), and hypertension (22% vs 2%)., Conclusions: Ramucirumab plus paclitaxel significantly improves progression-free survival and response rate, with prolonged median overall survival and an acceptable safety profile in East Asians with advanced gastric cancer., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel., Methods: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase., Findings: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%])., Interpretation: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer., Funding: Eli Lilly and Company., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer., Methods: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R., Results: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients)., Conclusion: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.