Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study
The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who p...
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creator | Douma, Li-Anne H Lalezari, Ferry van der Noort, Vincent de Vries, Jeltje F Monkhorst, Kim Smesseim, Illaa Baas, Paul Schilder, Bodien Vermeulen, Marrit Burgers, Jacobus A de Gooijer, Cornedine J |
description | The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0–1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65–75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8–19·4), 22 (58%; 95% CI 41–74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29–62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and le |
doi_str_mv | 10.1016/S1470-2045(23)00446-1 |
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In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0–1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65–75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8–19·4), 22 (58%; 95% CI 41–74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29–62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
Merck Sharp & Dohme.</description><identifier>ISSN: 1470-2045</identifier><identifier>ISSN: 1474-5488</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(23)00446-1</identifier><identifier>PMID: 37844598</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Adverse events ; Aged ; Anorexia ; Antineoplastic Agents, Immunological - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Cancer therapies ; Chemotherapy ; Consent ; Drug dosages ; Drug withdrawal ; Female ; Humans ; Immunotherapy ; Lymphopenia ; Male ; Mesothelioma ; Mesothelioma - pathology ; Mesothelioma, Malignant - drug therapy ; Monoclonal antibodies ; Myocardial infarction ; Oncology ; Patients ; PD-1 protein ; Pembrolizumab ; Pleural Neoplasms - pathology ; Response rates ; Solid tumors ; Targeted cancer therapy ; Toxicity ; Tumors ; Vascular endothelial growth factor</subject><ispartof>The lancet oncology, 2023-11, Vol.24 (11), p.1219-1228</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><rights>2023. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-694382841113fe47a6e800aac7dc52994c5946fb360d4ca4355347baec325b5d3</citedby><cites>FETCH-LOGICAL-c393t-694382841113fe47a6e800aac7dc52994c5946fb360d4ca4355347baec325b5d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2884672423?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,781,785,3551,27926,27927,45997,64387,64389,64391,72471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37844598$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Douma, Li-Anne H</creatorcontrib><creatorcontrib>Lalezari, Ferry</creatorcontrib><creatorcontrib>van der Noort, Vincent</creatorcontrib><creatorcontrib>de Vries, Jeltje F</creatorcontrib><creatorcontrib>Monkhorst, Kim</creatorcontrib><creatorcontrib>Smesseim, Illaa</creatorcontrib><creatorcontrib>Baas, Paul</creatorcontrib><creatorcontrib>Schilder, Bodien</creatorcontrib><creatorcontrib>Vermeulen, Marrit</creatorcontrib><creatorcontrib>Burgers, Jacobus A</creatorcontrib><creatorcontrib>de Gooijer, Cornedine J</creatorcontrib><title>Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0–1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65–75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8–19·4), 22 (58%; 95% CI 41–74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29–62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
Merck Sharp & Dohme.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Anorexia</subject><subject>Antineoplastic Agents, Immunological - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Consent</subject><subject>Drug dosages</subject><subject>Drug withdrawal</subject><subject>Female</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Lymphopenia</subject><subject>Male</subject><subject>Mesothelioma</subject><subject>Mesothelioma - pathology</subject><subject>Mesothelioma, Malignant - drug therapy</subject><subject>Monoclonal antibodies</subject><subject>Myocardial infarction</subject><subject>Oncology</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>Pembrolizumab</subject><subject>Pleural Neoplasms - pathology</subject><subject>Response rates</subject><subject>Solid tumors</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><issn>1470-2045</issn><issn>1474-5488</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkUtv1DAURi0EoqXwE0CW2EwXAT8Thw2qquEhTUUlYG059h3GlWMHOykqa3447szAgg0rP3S-e6_uQeg5Ja8ooe3rz1R0pGFEyBXj54QI0Tb0ATqt36KRQqmH-_sBOUFPSrkhhHaUyMfohHdKCNmrU_TrGsYhp-B_LqMZ8BSWggPEWzP76AfsIy5gU3RN8BGwiQ7PO5-Pz6lSEOeCf_h5V7OwZBPwCCXNOwg-jQavrtdXV-vNxfkbbHDx8VuAxuQRTztTADNc5sXdPUWPtiYUeHY8z9DXd-svlx-azaf3Hy8vNo3lPZ-bthdcMSUopXwLojMtKEKMsZ2zkvW9sLIX7XbgLXHCGsGl5KIbDFjO5CAdP0OrQ90pp-8LlFmPvlgIwURIS9FMdYr1tHap6Mt_0Ju05Finq5QSbccE45WSB8rmVEqGrZ6yH02-05Toe016r0nfO9CM670mTWvuxbH6Mozg_qb-eKnA2wMAdR23HrIutq7agvMZ7Kxd8v9p8RvqlaEr</recordid><startdate>202311</startdate><enddate>202311</enddate><creator>Douma, Li-Anne H</creator><creator>Lalezari, Ferry</creator><creator>van der Noort, Vincent</creator><creator>de Vries, Jeltje F</creator><creator>Monkhorst, Kim</creator><creator>Smesseim, Illaa</creator><creator>Baas, Paul</creator><creator>Schilder, Bodien</creator><creator>Vermeulen, Marrit</creator><creator>Burgers, Jacobus A</creator><creator>de Gooijer, Cornedine J</creator><general>Elsevier Ltd</general><general>Elsevier 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><scope>7X8</scope></search><sort><creationdate>202311</creationdate><title>Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study</title><author>Douma, Li-Anne H ; Lalezari, Ferry ; van der Noort, Vincent ; de Vries, Jeltje F ; Monkhorst, Kim ; Smesseim, Illaa ; Baas, Paul ; Schilder, Bodien ; Vermeulen, Marrit ; Burgers, Jacobus A ; de Gooijer, Cornedine J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-694382841113fe47a6e800aac7dc52994c5946fb360d4ca4355347baec325b5d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Adverse events</topic><topic>Aged</topic><topic>Anorexia</topic><topic>Antineoplastic Agents, Immunological - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Cancer therapies</topic><topic>Chemotherapy</topic><topic>Consent</topic><topic>Drug dosages</topic><topic>Drug withdrawal</topic><topic>Female</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Lymphopenia</topic><topic>Male</topic><topic>Mesothelioma</topic><topic>Mesothelioma - pathology</topic><topic>Mesothelioma, Malignant - drug therapy</topic><topic>Monoclonal antibodies</topic><topic>Myocardial infarction</topic><topic>Oncology</topic><topic>Patients</topic><topic>PD-1 protein</topic><topic>Pembrolizumab</topic><topic>Pleural Neoplasms - pathology</topic><topic>Response rates</topic><topic>Solid tumors</topic><topic>Targeted cancer therapy</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Douma, Li-Anne H</creatorcontrib><creatorcontrib>Lalezari, Ferry</creatorcontrib><creatorcontrib>van der Noort, Vincent</creatorcontrib><creatorcontrib>de Vries, Jeltje F</creatorcontrib><creatorcontrib>Monkhorst, Kim</creatorcontrib><creatorcontrib>Smesseim, Illaa</creatorcontrib><creatorcontrib>Baas, Paul</creatorcontrib><creatorcontrib>Schilder, Bodien</creatorcontrib><creatorcontrib>Vermeulen, Marrit</creatorcontrib><creatorcontrib>Burgers, Jacobus A</creatorcontrib><creatorcontrib>de Gooijer, Cornedine J</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>ProQuest 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)</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>PML(ProQuest Medical Library)</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><collection>MEDLINE - Academic</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Douma, Li-Anne H</au><au>Lalezari, Ferry</au><au>van der Noort, Vincent</au><au>de Vries, Jeltje F</au><au>Monkhorst, Kim</au><au>Smesseim, Illaa</au><au>Baas, Paul</au><au>Schilder, Bodien</au><au>Vermeulen, Marrit</au><au>Burgers, Jacobus A</au><au>de Gooijer, Cornedine J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2023-11</date><risdate>2023</risdate><volume>24</volume><issue>11</issue><spage>1219</spage><epage>1228</epage><pages>1219-1228</pages><issn>1470-2045</issn><issn>1474-5488</issn><eissn>1474-5488</eissn><abstract>The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0–1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65–75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8–19·4), 22 (58%; 95% CI 41–74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29–62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
Merck Sharp & Dohme.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>37844598</pmid><doi>10.1016/S1470-2045(23)00446-1</doi><tpages>10</tpages></addata></record> |
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subjects | Adolescent Adult Adverse events Aged Anorexia Antineoplastic Agents, Immunological - adverse effects Antineoplastic Combined Chemotherapy Protocols - adverse effects Cancer therapies Chemotherapy Consent Drug dosages Drug withdrawal Female Humans Immunotherapy Lymphopenia Male Mesothelioma Mesothelioma - pathology Mesothelioma, Malignant - drug therapy Monoclonal antibodies Myocardial infarction Oncology Patients PD-1 protein Pembrolizumab Pleural Neoplasms - pathology Response rates Solid tumors Targeted cancer therapy Toxicity Tumors Vascular endothelial growth factor |
title | Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study |
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