Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

Abstract Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) i...

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Autores principales:	Laura M. Spring, Shealagh L. Clark, Tianyu Li, Shom Goel, Nabihah Tayob, Elene Viscosi, Elizabeth Abraham, Dejan Juric, Steven J. Isakoff, Erica Mayer, Beverly Moy, Jeffrey G. Supko, Sara M. Tolaney, Aditya Bardia
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/33e1b363efc046cc98162a97b34fb552
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spelling	oai:doaj.org-article:33e1b363efc046cc98162a97b34fb5522021-12-02T18:49:26ZPhase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer10.1038/s41523-021-00311-y2374-4677https://doaj.org/article/33e1b363efc046cc98162a97b34fb5522021-08-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00311-yhttps://doaj.org/toc/2374-4677Abstract Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1.Laura M. SpringShealagh L. ClarkTianyu LiShom GoelNabihah TayobElene ViscosiElizabeth AbrahamDejan JuricSteven J. IsakoffErica MayerBeverly MoyJeffrey G. SupkoSara M. TolaneyAditya BardiaNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laura M. Spring Shealagh L. Clark Tianyu Li Shom Goel Nabihah Tayob Elene Viscosi Elizabeth Abraham Dejan Juric Steven J. Isakoff Erica Mayer Beverly Moy Jeffrey G. Supko Sara M. Tolaney Aditya Bardia Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
description	Abstract Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1.
format	article
author	Laura M. Spring Shealagh L. Clark Tianyu Li Shom Goel Nabihah Tayob Elene Viscosi Elizabeth Abraham Dejan Juric Steven J. Isakoff Erica Mayer Beverly Moy Jeffrey G. Supko Sara M. Tolaney Aditya Bardia
author_facet	Laura M. Spring Shealagh L. Clark Tianyu Li Shom Goel Nabihah Tayob Elene Viscosi Elizabeth Abraham Dejan Juric Steven J. Isakoff Erica Mayer Beverly Moy Jeffrey G. Supko Sara M. Tolaney Aditya Bardia
author_sort	Laura M. Spring
title	Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
title_short	Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
title_full	Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
title_fullStr	Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
title_full_unstemmed	Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer
title_sort	phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for her2-positive metastatic breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/33e1b363efc046cc98162a97b34fb552
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Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

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