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Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial

IMPORTANCE: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. OBJECTIVE: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine i...

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Autores principales: Cortés, Javier, Diéras, Véronique, Lorenzen, Sylvie, Montemurro, Filippo, Riera-Knorrenschild, Jorge, Thuss-Patience, Peter, Allegrini, Giacomo, De Laurentiis, Michelino, Lohrisch, Caroline, Oravcová, Eva, Perez-Garcia, Jose M., Ricci, Francesco, Sakaeva, Dina, Serpanchy, Rosanne, Šufliarský, Jozef, Vidal, Maria, Irahara, Natsumi, Wohlfarth, Christine, Aout, Mounir, Gelmon, Karen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317656/
https://www.ncbi.nlm.nih.gov/pubmed/32584367
http://dx.doi.org/10.1001/jamaoncol.2020.1796
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author Cortés, Javier
Diéras, Véronique
Lorenzen, Sylvie
Montemurro, Filippo
Riera-Knorrenschild, Jorge
Thuss-Patience, Peter
Allegrini, Giacomo
De Laurentiis, Michelino
Lohrisch, Caroline
Oravcová, Eva
Perez-Garcia, Jose M.
Ricci, Francesco
Sakaeva, Dina
Serpanchy, Rosanne
Šufliarský, Jozef
Vidal, Maria
Irahara, Natsumi
Wohlfarth, Christine
Aout, Mounir
Gelmon, Karen
author_facet Cortés, Javier
Diéras, Véronique
Lorenzen, Sylvie
Montemurro, Filippo
Riera-Knorrenschild, Jorge
Thuss-Patience, Peter
Allegrini, Giacomo
De Laurentiis, Michelino
Lohrisch, Caroline
Oravcová, Eva
Perez-Garcia, Jose M.
Ricci, Francesco
Sakaeva, Dina
Serpanchy, Rosanne
Šufliarský, Jozef
Vidal, Maria
Irahara, Natsumi
Wohlfarth, Christine
Aout, Mounir
Gelmon, Karen
author_sort Cortés, Javier
collection PubMed
description IMPORTANCE: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. OBJECTIVE: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). DESIGN, SETTING, AND PARTICIPANTS: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. INTERVENTIONS: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m(2), 700 mg/m(2), or 650 mg/m(2) twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. MAIN OUTCOMES AND MEASURES: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). RESULTS: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m(2) in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, −4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. CONCLUSIONS AND RELEVANCE: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01702558
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spelling pubmed-73176562020-06-29 Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial Cortés, Javier Diéras, Véronique Lorenzen, Sylvie Montemurro, Filippo Riera-Knorrenschild, Jorge Thuss-Patience, Peter Allegrini, Giacomo De Laurentiis, Michelino Lohrisch, Caroline Oravcová, Eva Perez-Garcia, Jose M. Ricci, Francesco Sakaeva, Dina Serpanchy, Rosanne Šufliarský, Jozef Vidal, Maria Irahara, Natsumi Wohlfarth, Christine Aout, Mounir Gelmon, Karen JAMA Oncol Original Investigation IMPORTANCE: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. OBJECTIVE: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). DESIGN, SETTING, AND PARTICIPANTS: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. INTERVENTIONS: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m(2), 700 mg/m(2), or 650 mg/m(2) twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. MAIN OUTCOMES AND MEASURES: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). RESULTS: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m(2) in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, −4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. CONCLUSIONS AND RELEVANCE: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01702558 American Medical Association 2020-08 2020-06-25 /pmc/articles/PMC7317656/ /pubmed/32584367 http://dx.doi.org/10.1001/jamaoncol.2020.1796 Text en Copyright 2020 Cortés J et al. JAMA Oncology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the CC-BY-NC-ND License.
spellingShingle Original Investigation
Cortés, Javier
Diéras, Véronique
Lorenzen, Sylvie
Montemurro, Filippo
Riera-Knorrenschild, Jorge
Thuss-Patience, Peter
Allegrini, Giacomo
De Laurentiis, Michelino
Lohrisch, Caroline
Oravcová, Eva
Perez-Garcia, Jose M.
Ricci, Francesco
Sakaeva, Dina
Serpanchy, Rosanne
Šufliarský, Jozef
Vidal, Maria
Irahara, Natsumi
Wohlfarth, Christine
Aout, Mounir
Gelmon, Karen
Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title_full Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title_fullStr Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title_full_unstemmed Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title_short Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial
title_sort efficacy and safety of trastuzumab emtansine plus capecitabine vs trastuzumab emtansine alone in patients with previously treated erbb2 (her2)-positive metastatic breast cancer: a phase 1 and randomized phase 2 trial
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317656/
https://www.ncbi.nlm.nih.gov/pubmed/32584367
http://dx.doi.org/10.1001/jamaoncol.2020.1796
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