Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study
Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition...
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| creator | Valle, Juan W Vogel, Arndt Denlinger, Crystal S He, Aiwu Ruth Bai, Li-Yuan Orlova, Rashida Van Cutsem, Eric Adeva, Jorge Chen, Li-Tzong Obermannova, Radka Ettrich, Thomas J Chen, Jen-Shi Wasan, Harpreet Girvan, Allicia C Zhang, Wei Liu, Jiangang Tang, Chunlao Ebert, Philip J Aggarwal, Amit McNeely, Samuel C Moser, Brian A Oliveira, Joana M Carlesi, Roberto Walgren, Richard A Oh, Do-Youn |
| description | Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin–gemcitabine in patients with locally advanced or metastatic biliary tract cancer.
We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing.
Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1–14·1). Median progression-free survival was 6·5 months (80% CI 5·7–7·1) in the ramucirumab group, 7·0 months (6·2–7·1) in the meresti |
| doi_str_mv | 10.1016/S1470-2045(21)00409-5 |
| format | Article |
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We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing.
Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1–14·1). Median progression-free survival was 6·5 months (80% CI 5·7–7·1) in the ramucirumab group, 7·0 months (6·2–7·1) in the merestinib group, and 6·6 months (5·6–6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90–1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73–1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]).
Adding ramucirumab or merestinib to first-line cisplatin–gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.
Eli Lilly and Company.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(21)00409-5</identifier><identifier>PMID: 34592180</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Adenocarcinoma ; Adenocarcinoma - drug therapy ; Adenocarcinoma - mortality ; Adenocarcinoma - secondary ; Adverse events ; Aged ; Angiogenesis ; Angiogenesis Inhibitors - administration & dosage ; Angiogenesis Inhibitors - adverse effects ; Antibodies, Monoclonal, Humanized - administration & dosage ; Antibodies, Monoclonal, Humanized - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Biliary tract ; Biliary Tract Neoplasms - drug therapy ; Biliary Tract Neoplasms - mortality ; Biliary Tract Neoplasms - pathology ; Cancer therapies ; Chemotherapy ; Cholangiocarcinoma ; Cisplatin ; Clinical trials ; Disease Progression ; Double-Blind Method ; Double-blind studies ; Drug Administration Schedule ; Embolism ; FDA approval ; Female ; Gemcitabine ; Humans ; Immunotherapy ; Indazoles - administration & dosage ; Indazoles - adverse effects ; Intravenous administration ; Kinases ; Life span ; Lung cancer ; Male ; Medical prognosis ; Metastases ; Metastasis ; Middle Aged ; Monoclonal antibodies ; Neutropenia ; Niacinamide - administration & dosage ; Niacinamide - adverse effects ; Niacinamide - analogs & derivatives ; Patients ; Placebos ; Progression-Free Survival ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - adverse effects ; Ramucirumab ; Response rates ; Safety ; Sepsis ; Solid tumors ; Survival ; Targeted cancer therapy ; Thrombocytopenia ; Time Factors ; Toxicity ; Tumors]]></subject><ispartof>The lancet oncology, 2021-10, Vol.22 (10), p.1468-1482</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><rights>2021. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-37e9cb3987d9148c1a3136311dbf1b0eea7e9f993cebf1c84c06205cc2ae8d4d3</citedby><cites>FETCH-LOGICAL-c445t-37e9cb3987d9148c1a3136311dbf1b0eea7e9f993cebf1c84c06205cc2ae8d4d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1470204521004095$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34592180$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Valle, Juan W</creatorcontrib><creatorcontrib>Vogel, Arndt</creatorcontrib><creatorcontrib>Denlinger, Crystal S</creatorcontrib><creatorcontrib>He, Aiwu Ruth</creatorcontrib><creatorcontrib>Bai, Li-Yuan</creatorcontrib><creatorcontrib>Orlova, Rashida</creatorcontrib><creatorcontrib>Van Cutsem, Eric</creatorcontrib><creatorcontrib>Adeva, Jorge</creatorcontrib><creatorcontrib>Chen, Li-Tzong</creatorcontrib><creatorcontrib>Obermannova, Radka</creatorcontrib><creatorcontrib>Ettrich, Thomas J</creatorcontrib><creatorcontrib>Chen, Jen-Shi</creatorcontrib><creatorcontrib>Wasan, Harpreet</creatorcontrib><creatorcontrib>Girvan, Allicia C</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Liu, Jiangang</creatorcontrib><creatorcontrib>Tang, Chunlao</creatorcontrib><creatorcontrib>Ebert, Philip J</creatorcontrib><creatorcontrib>Aggarwal, Amit</creatorcontrib><creatorcontrib>McNeely, Samuel C</creatorcontrib><creatorcontrib>Moser, Brian A</creatorcontrib><creatorcontrib>Oliveira, Joana M</creatorcontrib><creatorcontrib>Carlesi, Roberto</creatorcontrib><creatorcontrib>Walgren, Richard A</creatorcontrib><creatorcontrib>Oh, Do-Youn</creatorcontrib><title>Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin–gemcitabine in patients with locally advanced or metastatic biliary tract cancer.
We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing.
Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1–14·1). Median progression-free survival was 6·5 months (80% CI 5·7–7·1) in the ramucirumab group, 7·0 months (6·2–7·1) in the merestinib group, and 6·6 months (5·6–6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90–1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73–1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]).
Adding ramucirumab or merestinib to first-line cisplatin–gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.
Eli Lilly and Company.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - mortality</subject><subject>Adenocarcinoma - secondary</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Angiogenesis</subject><subject>Angiogenesis Inhibitors - administration & dosage</subject><subject>Angiogenesis Inhibitors - adverse effects</subject><subject>Antibodies, Monoclonal, Humanized - administration & dosage</subject><subject>Antibodies, Monoclonal, Humanized - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Biliary tract</subject><subject>Biliary Tract Neoplasms - drug therapy</subject><subject>Biliary Tract Neoplasms - mortality</subject><subject>Biliary Tract Neoplasms - pathology</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Cholangiocarcinoma</subject><subject>Cisplatin</subject><subject>Clinical trials</subject><subject>Disease Progression</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug Administration Schedule</subject><subject>Embolism</subject><subject>FDA approval</subject><subject>Female</subject><subject>Gemcitabine</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Indazoles - administration & dosage</subject><subject>Indazoles - adverse effects</subject><subject>Intravenous administration</subject><subject>Kinases</subject><subject>Life span</subject><subject>Lung cancer</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Neutropenia</subject><subject>Niacinamide - administration & dosage</subject><subject>Niacinamide - adverse effects</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Patients</subject><subject>Placebos</subject><subject>Progression-Free Survival</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Ramucirumab</subject><subject>Response rates</subject><subject>Safety</subject><subject>Sepsis</subject><subject>Solid tumors</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Thrombocytopenia</subject><subject>Time Factors</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkcuKFTEQhoMozjj6CErAjcK05tqX2cgweIMBF-o65FLNydDdOVbSA-fRfDtzTo9uXSUpvr_-VP2EvOTsHWe8ff-dq441gin9RvC3jCk2NPoROa9l1WjV949P9w05I89yvmOMd5zpp-RMKj0I3rNz8vs6hFhiWmgaKdp59RHX2TqakM6AkEtcoqMl0VzsEiwGOkbMpZniAtTvYE5lB2j3BzpWyZS8naYDteHeLh7C1qbYKi7RUxenaPFAC1pfqD8ieEVtNV5CmmOGcElDWt0EjasG9TWvUxXCUhAu6X5nM1BRv7KGw3PyZLRThhcP5wX5-enjj5svze23z19vrm8br5Qujexg8E4OfRcGrnrPreSylZwHN3LHAGwFxmGQHmrB98qzVjDtvbDQBxXkBXm99d1j-rXWhZi7tOJSLY3QXdt3olWyUnqjPKacEUazxzjXWQ1n5hiYOQVmjmkYwc0pMKOr7tVD99XNEP6p_iZUgQ8bAHXG-whoso9w3G1E8MWEFP9j8Qcdj6ls</recordid><startdate>202110</startdate><enddate>202110</enddate><creator>Valle, Juan W</creator><creator>Vogel, Arndt</creator><creator>Denlinger, Crystal S</creator><creator>He, 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Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope></search><sort><creationdate>202110</creationdate><title>Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study</title><author>Valle, Juan W ; Vogel, Arndt ; Denlinger, Crystal S ; He, Aiwu Ruth ; Bai, Li-Yuan ; Orlova, Rashida ; Van Cutsem, Eric ; Adeva, Jorge ; Chen, Li-Tzong ; Obermannova, Radka ; Ettrich, Thomas J ; Chen, Jen-Shi ; Wasan, Harpreet ; Girvan, Allicia C ; Zhang, Wei ; Liu, Jiangang ; Tang, Chunlao ; Ebert, Philip J ; Aggarwal, Amit ; McNeely, Samuel C ; Moser, Brian A ; Oliveira, Joana M ; Carlesi, Roberto ; Walgren, Richard A ; Oh, Do-Youn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-37e9cb3987d9148c1a3136311dbf1b0eea7e9f993cebf1c84c06205cc2ae8d4d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - mortality</topic><topic>Adenocarcinoma - secondary</topic><topic>Adverse events</topic><topic>Aged</topic><topic>Angiogenesis</topic><topic>Angiogenesis Inhibitors - administration & dosage</topic><topic>Angiogenesis Inhibitors - adverse effects</topic><topic>Antibodies, Monoclonal, Humanized - administration & dosage</topic><topic>Antibodies, Monoclonal, Humanized - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Biliary tract</topic><topic>Biliary Tract Neoplasms - drug therapy</topic><topic>Biliary Tract Neoplasms - mortality</topic><topic>Biliary Tract Neoplasms - pathology</topic><topic>Cancer therapies</topic><topic>Chemotherapy</topic><topic>Cholangiocarcinoma</topic><topic>Cisplatin</topic><topic>Clinical trials</topic><topic>Disease Progression</topic><topic>Double-Blind Method</topic><topic>Double-blind studies</topic><topic>Drug Administration Schedule</topic><topic>Embolism</topic><topic>FDA approval</topic><topic>Female</topic><topic>Gemcitabine</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Indazoles - administration & dosage</topic><topic>Indazoles - adverse effects</topic><topic>Intravenous administration</topic><topic>Kinases</topic><topic>Life span</topic><topic>Lung cancer</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Neutropenia</topic><topic>Niacinamide - administration & dosage</topic><topic>Niacinamide - adverse effects</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Patients</topic><topic>Placebos</topic><topic>Progression-Free Survival</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Ramucirumab</topic><topic>Response rates</topic><topic>Safety</topic><topic>Sepsis</topic><topic>Solid tumors</topic><topic>Survival</topic><topic>Targeted cancer therapy</topic><topic>Thrombocytopenia</topic><topic>Time Factors</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valle, Juan W</creatorcontrib><creatorcontrib>Vogel, Arndt</creatorcontrib><creatorcontrib>Denlinger, Crystal S</creatorcontrib><creatorcontrib>He, Aiwu Ruth</creatorcontrib><creatorcontrib>Bai, Li-Yuan</creatorcontrib><creatorcontrib>Orlova, Rashida</creatorcontrib><creatorcontrib>Van Cutsem, Eric</creatorcontrib><creatorcontrib>Adeva, Jorge</creatorcontrib><creatorcontrib>Chen, Li-Tzong</creatorcontrib><creatorcontrib>Obermannova, Radka</creatorcontrib><creatorcontrib>Ettrich, Thomas J</creatorcontrib><creatorcontrib>Chen, Jen-Shi</creatorcontrib><creatorcontrib>Wasan, Harpreet</creatorcontrib><creatorcontrib>Girvan, Allicia C</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Liu, Jiangang</creatorcontrib><creatorcontrib>Tang, Chunlao</creatorcontrib><creatorcontrib>Ebert, Philip J</creatorcontrib><creatorcontrib>Aggarwal, Amit</creatorcontrib><creatorcontrib>McNeely, Samuel C</creatorcontrib><creatorcontrib>Moser, Brian A</creatorcontrib><creatorcontrib>Oliveira, Joana M</creatorcontrib><creatorcontrib>Carlesi, Roberto</creatorcontrib><creatorcontrib>Walgren, Richard A</creatorcontrib><creatorcontrib>Oh, Do-Youn</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valle, Juan W</au><au>Vogel, Arndt</au><au>Denlinger, Crystal S</au><au>He, Aiwu Ruth</au><au>Bai, Li-Yuan</au><au>Orlova, Rashida</au><au>Van Cutsem, Eric</au><au>Adeva, Jorge</au><au>Chen, Li-Tzong</au><au>Obermannova, Radka</au><au>Ettrich, Thomas J</au><au>Chen, Jen-Shi</au><au>Wasan, Harpreet</au><au>Girvan, Allicia C</au><au>Zhang, Wei</au><au>Liu, Jiangang</au><au>Tang, Chunlao</au><au>Ebert, Philip J</au><au>Aggarwal, Amit</au><au>McNeely, Samuel C</au><au>Moser, Brian A</au><au>Oliveira, Joana M</au><au>Carlesi, Roberto</au><au>Walgren, Richard A</au><au>Oh, Do-Youn</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2021-10</date><risdate>2021</risdate><volume>22</volume><issue>10</issue><spage>1468</spage><epage>1482</epage><pages>1468-1482</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin–gemcitabine in patients with locally advanced or metastatic biliary tract cancer.
We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing.
Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1–14·1). Median progression-free survival was 6·5 months (80% CI 5·7–7·1) in the ramucirumab group, 7·0 months (6·2–7·1) in the merestinib group, and 6·6 months (5·6–6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90–1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73–1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]).
Adding ramucirumab or merestinib to first-line cisplatin–gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.
Eli Lilly and Company.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34592180</pmid><doi>10.1016/S1470-2045(21)00409-5</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2021-10, Vol.22 (10), p.1468-1482 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_proquest_journals_2576872643 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adenocarcinoma Adenocarcinoma - drug therapy Adenocarcinoma - mortality Adenocarcinoma - secondary Adverse events Aged Angiogenesis Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - adverse effects Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Biliary tract Biliary Tract Neoplasms - drug therapy Biliary Tract Neoplasms - mortality Biliary Tract Neoplasms - pathology Cancer therapies Chemotherapy Cholangiocarcinoma Cisplatin Clinical trials Disease Progression Double-Blind Method Double-blind studies Drug Administration Schedule Embolism FDA approval Female Gemcitabine Humans Immunotherapy Indazoles - administration & dosage Indazoles - adverse effects Intravenous administration Kinases Life span Lung cancer Male Medical prognosis Metastases Metastasis Middle Aged Monoclonal antibodies Neutropenia Niacinamide - administration & dosage Niacinamide - adverse effects Niacinamide - analogs & derivatives Patients Placebos Progression-Free Survival Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - adverse effects Ramucirumab Response rates Safety Sepsis Solid tumors Survival Targeted cancer therapy Thrombocytopenia Time Factors Toxicity Tumors |
| title | Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study |
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