Ramucirumab

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Edward B Garon - One of the best experts on this subject based on the ideXlab platform.

  • osimertinib plus Ramucirumab the best of both worlds
    Clinical Cancer Research, 2021
    Co-Authors: Edward B Garon
    Abstract:

    Both osimertinib and the combination of erlotinib plus Ramucirumab are approved for initial therapy of advanced EGFR mutation–positive non–small cell lung cancer. Osimertinib is also approved in previously treated T790M mutation–positive patients. The accompanying article reports on a study combining osimertinib with Ramucirumab. See related article by Yu et al., p. XXXX

  • patient reported outcomes in relay a phase 3 trial of Ramucirumab plus erlotinib versus placebo plus erlotinib in untreated egfr mutated metastatic non small cell lung cancer
    Current Medical Research and Opinion, 2020
    Co-Authors: Kiyotaka Yoh, Martin Reck, Edward B Garon, Annamaria Zimmermann, Denis Morosibilot, Santiago Ponce Aix, Shinji Atagi, Katherine B Winfree, Bente Frimodtmoller, Carla Visserengrul
    Abstract:

    In the phase 3 RELAY trial, Ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus...

  • relay exploratory study of Ramucirumab plus gefitinib in untreated patients pts with epidermal growth factor receptor egfr mutated metastatic non small cell lung cancer nsclc
    Journal of Clinical Oncology, 2020
    Co-Authors: Makoto Nishio, Martin Reck, Edward B Garon, Kazuto Nishio, Fumio Imamura, Tomoya Kawaguchi, Hiroyuki Yamaguchi, Satoshi Ikeda, Katsuya Hirano, Carla Visserengrul
    Abstract:

    9564Background: The phase III randomized part of the RELAY study (Part B; RELAY; NCT02411448) showed a significant improvement in progression-free survival (PFS) for Ramucirumab (RAM) plus erlotini...

  • Ramucirumab plus erlotinib in patients with untreated egfr mutated advanced non small cell lung cancer relay a randomised double blind placebo controlled phase 3 trial
    Lancet Oncology, 2019
    Co-Authors: Kazuhiko Nakagawa, Edward B Garon, Makoto Nishio, L Pazares, Keunchil Park, Takashi Seto, Santiago Ponce Aix, Chaohua Chiu, Silvia Novello, Ernest Nadal
    Abstract:

    Summary Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus Ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. Methods This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous Ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. Findings Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with Ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8–27·2). At the time of primary analysis, progression-free survival was significantly longer in the Ramucirumab plus erlotinib group (19·4 months [95% CI 15·4–21·6]) than in the placebo plus erlotinib group (12·4 months [11·0–13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46–0·76; p Interpretation Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. Funding Eli Lilly.

  • 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 Chemotherapy and Pharmacology, 2018
    Co-Authors: Egbert F Smit, Martin Reck, Edward B Garon, Ling Gao, Federico Cappuzzo, Paolo Bidoli, Roger B Cohen, Lisa Obrien, Pablo Lee, Annamaria Zimmermann
    Abstract:

    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. 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. 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. 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).

Josep Tabernero - One of the best experts on this subject based on the ideXlab platform.

  • meta analysis of individual patient safety data from six randomized placebo controlled trials with the antiangiogenic vegfr2 binding monoclonal antibody Ramucirumab
    Annals of Oncology, 2017
    Co-Authors: Dirk Arnold, Andrew X. Zhu, Ari David Baron, Charles S Fuchs, Josep Tabernero, A Ohtsu, Edward B Garon, John R Mackey, Luis Pazares, Takuji Okusaka
    Abstract:

    Abstract Background Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of Ramucirumab across a large patient population. Materials and methods An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. Results A total of 4996 treated patients (N = 2748 in the Ramucirumab arm andN = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5–1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5–1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5–1.1; high-grade, RR: 0.7, 95% CI 0.4–1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8–1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7–1.7) did not demonstrate a definite increased risk with Ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1–2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the Ramucirumab arm compared with the control arm. Conclusions Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

  • exposure response analyses of Ramucirumab from two randomized phase iii trials of second line treatment for advanced gastric or gastroesophageal junction cancer
    Molecular Cancer Therapeutics, 2017
    Co-Authors: Josep Tabernero, Gyorgy Bodoky, Kei Muro, Eric Van Cutsem, Atsushi Ohtsu, Yasuhiro Shimada, Shuichi Hironaka, Jaffer A Ajani, Jiri Tomasek, Howard Safran
    Abstract:

    Ramucirumab is an IgG1 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 (Cmin,ss). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the Ramucirumab exposure (Cmin,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 Cmin,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 Cmin,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.

  • analysis of angiogenesis biomarkers for Ramucirumab efficacy in patients with metastatic colorectal cancer from raise a global randomized double blind phase iii study
    Annals of Oncology, 2017
    Co-Authors: Gyorgy Bodoky, Josep Tabernero, Allen Lee Cohn, Takayuki Yoshino, Radka Obermannova, R Garciacarbonero, Tudor Ciuleanu, Rebecca R Hozak, David Craig Portnoy
    Abstract:

    Abstract Background The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody Ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with Ramucirumab efficacy outcomes. Patients and methods Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of Ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the Ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for Ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration NCT01183780.

  • biomarker analyses in regard gastric gej carcinoma patients treated with vegfr2 targeted antibody Ramucirumab
    British Journal of Cancer, 2016
    Co-Authors: Charles S Fuchs, Mustapha Tehfe, Josep Tabernero, Howard Safran, Ian Chau, Jiři Tomasek, Bohuslav Melichar, Dumitru Filip, Eldar Topuzov, Luis Schlittler
    Abstract:

    Background: Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. Methods: A total of 152 out of 355 (43%) patients randomised to Ramucirumab or placebo had >= 1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. Results: None of the biomarkers tested were associated with Ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI = 0.84,3.23). Treatment with Ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI = 0.38, 1.22) and low (HR = 0.73, 95% CI = 0.42, 1.26) VEGFR2 subgroups. The benefit associated with Ramucirumab did not appear to differ by tumoural HER2 expression. Conclusions: REGARD exploratory analyses did not identify a strong potentially predictive biomarker of Ramucirumab efficacy; however, statistical power was limited.

  • a randomized double blind placebo controlled phase iii study of cisplatin plus a fluoropyrimidine with or without Ramucirumab as first line therapy in patients with metastatic gastric or gastroesophogeal junction gej adenocarcinoma rainfall nct02314117
    Journal of Clinical Oncology, 2015
    Co-Authors: Charles S Fuchs, Josep Tabernero, Eric Van Cutsem, Ian Chau, David Ferry, Salaheddin Albatran, David H Ilson, Michael Emig, Allen S Melemed, Veerle Vanvoorden
    Abstract:

    TPS178 Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving Ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive Ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression...

Martin Reck - One of the best experts on this subject based on the ideXlab platform.

  • Ramucirumab and durvalumab for previously treated advanced non small cell lung cancer gastric gastro oesophageal junction adenocarcinoma or hepatocellular carcinoma an open label phase ia b study jvdj
    European Journal of Cancer, 2020
    Co-Authors: Yungjue Bang, Martin Reck, Zev A Wainberg, Keunchil Park, Talia Golan, Laetitia Dahan, Victor Moreno, Ravit Geva, Filippo De Braud, Laura W Goff
    Abstract:

    Abstract Background Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of Ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti–PD-L1 IgG1, in previously treated patients with advanced non–small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC). Patients and methods A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0–1, progression on prior therapy, no prior Ramucirumab or immunotherapy and any PD-L1 status. Patients received Ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or Ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC). Results Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment–related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression. Conclusion Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression.

  • patient reported outcomes in relay a phase 3 trial of Ramucirumab plus erlotinib versus placebo plus erlotinib in untreated egfr mutated metastatic non small cell lung cancer
    Current Medical Research and Opinion, 2020
    Co-Authors: Kiyotaka Yoh, Martin Reck, Edward B Garon, Annamaria Zimmermann, Denis Morosibilot, Santiago Ponce Aix, Shinji Atagi, Katherine B Winfree, Bente Frimodtmoller, Carla Visserengrul
    Abstract:

    In the phase 3 RELAY trial, Ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus...

  • relay exploratory study of Ramucirumab plus gefitinib in untreated patients pts with epidermal growth factor receptor egfr mutated metastatic non small cell lung cancer nsclc
    Journal of Clinical Oncology, 2020
    Co-Authors: Makoto Nishio, Martin Reck, Edward B Garon, Kazuto Nishio, Fumio Imamura, Tomoya Kawaguchi, Hiroyuki Yamaguchi, Satoshi Ikeda, Katsuya Hirano, Carla Visserengrul
    Abstract:

    9564Background: The phase III randomized part of the RELAY study (Part B; RELAY; NCT02411448) showed a significant improvement in progression-free survival (PFS) for Ramucirumab (RAM) plus erlotini...

  • 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 Chemotherapy and Pharmacology, 2018
    Co-Authors: Egbert F Smit, Martin Reck, Edward B Garon, Ling Gao, Federico Cappuzzo, Paolo Bidoli, Roger B Cohen, Lisa Obrien, Pablo Lee, Annamaria Zimmermann
    Abstract:

    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. 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. 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. 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).

  • randomized double blind phase ib iii study of erlotinib with Ramucirumab or placebo in previously untreated egfr mutant metastatic non small cell lung cancer relay phase ib results
    Clinical Lung Cancer, 2017
    Co-Authors: Martin Reck, Edward B Garon, Ryan C Widau, L Pazares, Santiago Ponce, Jesus Corral Jaime, O Juan, Ernest Nadal, Katsuyuki Kiura, R P Dalal
    Abstract:

    Abstract Background Despite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non–small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with Ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC. Patients and Methods Eligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received Ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles. Results Fourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment. Conclusion Ramucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining Ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.

Andrew X. Zhu - One of the best experts on this subject based on the ideXlab platform.

  • serum alpha fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with Ramucirumab
    British Journal of Cancer, 2021
    Co-Authors: Andrew X. Zhu, Kenta Motomura, Eric Assenat, Josep M Llovet, Richard S Finn, Peter R Galle, Giovanni Brandi, Chia Jui Yen, Yoon Koo Kang, Izumi Ohno
    Abstract:

    Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for Ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured Ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with Ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001). AFP is an important prognostic factor and a predictive biomarker for Ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for Ramucirumab. ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

  • Ramucirumab in the second line for patients with hepatocellular carcinoma and elevated alpha fetoprotein patient reported outcomes across two randomised clinical trials
    ESMO Open, 2020
    Co-Authors: Andrew X. Zhu, Josep M Llovet, Richard S Finn, Peter R Galle, Takuji Okusaka, Ian Chau, Jean Frederic Blanc, Ryan D Nipp, David Cella, Allicia C Girvan
    Abstract:

    ABSTRACT Background Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line Ramucirumab. Patients and methods Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received Ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted. Results In the pooled population with AFP ≥400 ng/mL (n=542; Ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with Ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between Ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings. Conclusions Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated Ramucirumab-driven survival benefits in this setting, these data may inform patient–clinician discussions about the benefit–risk profile of this therapy. Trial registration number NCT01140347 ; NCT02435433 , NCT02435433 .

  • a phase ib ii study of Ramucirumab in combination with emibetuzumab in patients with advanced cancer
    Clinical Cancer Research, 2019
    Co-Authors: Andrew X. Zhu, James J Harding, Todd M Bauer, T K Choueiri, Alexander Drilon, Martin H Voss, Charles S Fuchs
    Abstract:

    Purpose: Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of Ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab. Patients and Methods: A 3+3 dose escalation of emibetuzumab plus Ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC). Results: A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non–small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus Ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug–drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64–8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression. Conclusions: Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.

  • meta analysis of individual patient safety data from six randomized placebo controlled trials with the antiangiogenic vegfr2 binding monoclonal antibody Ramucirumab
    Annals of Oncology, 2017
    Co-Authors: Dirk Arnold, Andrew X. Zhu, Ari David Baron, Charles S Fuchs, Josep Tabernero, A Ohtsu, Edward B Garon, John R Mackey, Luis Pazares, Takuji Okusaka
    Abstract:

    Abstract Background Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of Ramucirumab across a large patient population. Materials and methods An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. Results A total of 4996 treated patients (N = 2748 in the Ramucirumab arm andN = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5–1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5–1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5–1.1; high-grade, RR: 0.7, 95% CI 0.4–1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8–1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7–1.7) did not demonstrate a definite increased risk with Ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1–2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the Ramucirumab arm compared with the control arm. Conclusions Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

  • Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score
    JAMA oncology, 2017
    Co-Authors: Andrew X. Zhu, Masatoshi Kudo, Giovanni Brandi, Ari David Baron, Peter Malfertheiner, Seiji Kawazoe, Denis Pezet, Florian Weissinger, Carlo Barone, Takuji Okusaka
    Abstract:

    Importance REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential Ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). Objective To assess treatment effects and tolerability of Ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. Design, Settings, and Participants Randomized, double-blind, phase 3 trial of Ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). Interventions Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. Main Outcomes and Measures Overall survival (OS), defined as time from randomization to death from any cause. Results In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential Ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P  = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a Ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P  = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P  = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of Ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment–emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. Conclusions and Relevance In unselected patients, a trend for Ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a Ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of Ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more. Trial Registration clinicaltrials.gov Identifier:NCT01140347

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  • Ramucirumab in patients with previously treated advanced hepatocellular carcinoma impact of liver disease aetiology
    Liver International, 2021
    Co-Authors: Peter R Galle, Josep M Llovet, Masatoshi Kudo, Richard S Finn, Denis Pezet, Taeyou Kim, Mark Karwal, Tsai Sheng Yang, Sara Lonardi
    Abstract:

    BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating Ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (Ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

  • effect of Ramucirumab on albi grade in patients with advanced hcc results from reach and reach 2
    JHEP reports : innovation in hepatology, 2021
    Co-Authors: Masatoshi Kudo, Eric Assenat, Josep M Llovet, Richard S Finn, Peter R Galle, Giovanni Brandi, Chia Jui Yen, Yoon Koo Kang, Philippe Merle
    Abstract:

    Background & aims The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with Ramucirumab or placebo using the ALBI score in patients with advanced HCC. Methods Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive Ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle. Results Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]). Conclusions Compared with placebo, Ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade. Lay summary Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with Ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate Ramucirumab did not impair liver function when compared with placebo.

  • Ramucirumab in patients with advanced hepatocellular carcinoma and elevated α fetoprotein outcomes by treatment emergent ascites
    Hepatology Research, 2021
    Co-Authors: Masatoshi Kudo, Richard S Finn, Peter R Galle, Tatsuya Yamashita, Masafumi Ikeda, Kun Liang, Chunxiao Wang, Sachi Sakaguchi, Paolo Abada, Ryan C Widau
    Abstract:

    Aim The REACH and REACH-2 trials investigated Ramucirumab versus placebo in patients with advanced hepatocellular carcinoma (HCC). Ascites is common in HCC and is associated with poorer outcomes. This exploratory, pooled meta-analysis of patients with baseline α-fetoprotein (AFP) ≥400 ng/ml investigated outcomes by treatment-emergent (TE) ascites in REACH and REACH-2. Methods A pooled meta-analysis of independent patient data for participants (N = 542) with baseline AFP ≥400 ng/ml (stratified by study) from REACH and REACH-2 was carried out. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator, and OS further assessed by Cox models. The effect of TE ascites on OS was evaluated by multivariate Cox models. Results Treatment-emergent ascites developed in 66 patients (20.9%) in the Ramucirumab group and 33 patients (14.8%) in the placebo group. When adjusted for treatment duration, the incidence rates per 100 patient-years of any grade TE ascites were 59.1 and 71.9 for the Ramucirumab and placebo groups, respectively, and the incidence of grade ≥3 TE ascites were 13.4 and 19.6, respectively. Treatment-emergent ascites was associated with TE hypoalbuminemia (odds ratio 4.9; 95% confidence interval 2.5-9.3), but not TE proteinuria or hypertension. One patient discontinued Ramucirumab treatment due to TE ascites. Ramucirumab treatment improved OS and PFS compared with placebo, irrespective of TE ascites. Conclusions When adjusted for treatment duration, the incidence of TE ascites was no higher in patients who received Ramucirumab than in those who received placebo. Ramucirumab was well tolerated and provided a survival benefit irrespective of the development of TE ascites.

  • pattern of progression in advanced hepatocellular carcinoma treated with Ramucirumab
    Liver International, 2021
    Co-Authors: Maria Reig, Josep M Llovet, Masatoshi Kudo, Richard S Finn, Peter R Galle, Kun Liang, Andrea L Metti, William Schelman, Chunxiao Wang
    Abstract:

    Background & aims Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with Ramucirumab or placebo. Methods Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive Ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. Results Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. Conclusions The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of Ramucirumab for overall survival was consistent across progression patterns.

  • efficacy and safety of Ramucirumab in asian and non asian patients with advanced hepatocellular carcinoma and elevated alpha fetoprotein pooled individual data analysis of two randomized studies
    Liver cancer, 2020
    Co-Authors: Chia Jui Yen, Masatoshi Kudo, Arndt Vogel, Giovanni Brandi, Paolo Abada, Ho Yeong Lim, Chihhung Hsu, Rebecca Cheng, Ioana Simona Nitu, Yanzhi Hsu
    Abstract:

    Objective: REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of Ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of Ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH. Methods: We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model. Results: In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive Ramucirumab (n = 168) or placebo (n = 123), and 251 non-Asian patients received Ramucirumab (n = 148) or placebo (n = 103). The median OS was significantly longer in the Ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56–0.95], p = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49–0.86], p = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the Ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the Ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients. Discussion and Conclusion: This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of Ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.