Cargando…
Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study
OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086500/ https://www.ncbi.nlm.nih.gov/pubmed/36564099 http://dx.doi.org/10.1136/ijgc-2022-003927 |
_version_ | 1785022167187980288 |
---|---|
author | Santin, Alessandro D Vergote, Ignace González-Martín, Antonio Moore, Kathleen Oaknin, Ana Romero, Ignacio Diab, Sami Copeland, Larry J Monk, Bradley J Coleman, Robert L Herzog, Thomas J Siegel, Jonathan Kasten, Linda Schlicker, Andreas Schulz, Anke Köchert, Karl Walter, Annette O Childs, Barrett H Elbi, Cem Bulat, Iurie |
author_facet | Santin, Alessandro D Vergote, Ignace González-Martín, Antonio Moore, Kathleen Oaknin, Ana Romero, Ignacio Diab, Sami Copeland, Larry J Monk, Bradley J Coleman, Robert L Herzog, Thomas J Siegel, Jonathan Kasten, Linda Schlicker, Andreas Schulz, Anke Köchert, Karl Walter, Annette O Childs, Barrett H Elbi, Cem Bulat, Iurie |
author_sort | Santin, Alessandro D |
collection | PubMed |
description | OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. METHODS: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m(2)) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. RESULTS: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. CONCLUSIONS: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02751918. |
format | Online Article Text |
id | pubmed-10086500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-100865002023-04-12 Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study Santin, Alessandro D Vergote, Ignace González-Martín, Antonio Moore, Kathleen Oaknin, Ana Romero, Ignacio Diab, Sami Copeland, Larry J Monk, Bradley J Coleman, Robert L Herzog, Thomas J Siegel, Jonathan Kasten, Linda Schlicker, Andreas Schulz, Anke Köchert, Karl Walter, Annette O Childs, Barrett H Elbi, Cem Bulat, Iurie Int J Gynecol Cancer Original Research OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. METHODS: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m(2)) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. RESULTS: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. CONCLUSIONS: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02751918. BMJ Publishing Group 2023-04 2022-12-23 /pmc/articles/PMC10086500/ /pubmed/36564099 http://dx.doi.org/10.1136/ijgc-2022-003927 Text en © IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Original Research Santin, Alessandro D Vergote, Ignace González-Martín, Antonio Moore, Kathleen Oaknin, Ana Romero, Ignacio Diab, Sami Copeland, Larry J Monk, Bradley J Coleman, Robert L Herzog, Thomas J Siegel, Jonathan Kasten, Linda Schlicker, Andreas Schulz, Anke Köchert, Karl Walter, Annette O Childs, Barrett H Elbi, Cem Bulat, Iurie Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title | Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title_full | Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title_fullStr | Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title_full_unstemmed | Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title_short | Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study |
title_sort | safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase ib dose escalation and expansion study |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086500/ https://www.ncbi.nlm.nih.gov/pubmed/36564099 http://dx.doi.org/10.1136/ijgc-2022-003927 |
work_keys_str_mv | AT santinalessandrod safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT vergoteignace safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT gonzalezmartinantonio safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT moorekathleen safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT oakninana safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT romeroignacio safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT diabsami safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT copelandlarryj safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT monkbradleyj safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT colemanrobertl safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT herzogthomasj safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT siegeljonathan safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT kastenlinda safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT schlickerandreas safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT schulzanke safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT kochertkarl safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT walterannetteo safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT childsbarretth safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT elbicem safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy AT bulatiurie safetyandactivityofantimesothelinantibodydrugconjugateanetumabravtansineincombinationwithpegylatedliposomaldoxorubicininplatinumresistantovariancancermulticenterphaseibdoseescalationandexpansionstudy |