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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Veröffentlicht in:The lancet oncology 2023-11, Vol.24 (11), p.1219-1228
Hauptverfasser: 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
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container_end_page 1228
container_issue 11
container_start_page 1219
container_title The lancet oncology
container_volume 24
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
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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. 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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. 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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 &amp; 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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 &amp; 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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1474-5488
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source MEDLINE; Access via ScienceDirect (Elsevier); ProQuest Central UK/Ireland
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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