1. 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
- Author
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Jorge Riera-Knorrenschild, Mounir Aout, Jose Perez-Garcia, Rosanne Serpanchy, Jozef Šufliarský, Christine Wohlfarth, Peter C. Thuss-Patience, Javier Cortes, Michelino De Laurentiis, Sylvie Lorenzen, Dina Sakaeva, Filippo Montemurro, Giacomo Allegrini, Véronique Diéras, Natsumi Irahara, Francesco Ricci, Caroline Lohrisch, Maria Vidal, Karen A. Gelmon, Eva Oravcová, Cortes, J., Dieras, V., Lorenzen, S., Montemurro, F., Riera-Knorrenschild, J., Thuss-Patience, P., Allegrini, G., De Laurentiis, M., Lohrisch, C., Oravcova, E., Perez-Garcia, J. M., Ricci, F., Sakaeva, D., Serpanchy, R., Sufliarsky, J., Vidal, M., Irahara, N., Wohlfarth, C., Aout, M., and Gelmon, K.
- Subjects
Male ,Cancer Research ,Receptor, ErbB-2 ,medicine.medical_treatment ,Ado-Trastuzumab Emtansine ,Gastroenterology ,law.invention ,Metastasis ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Breast cancer ,Randomized controlled trial ,law ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,030212 general & internal medicine ,skin and connective tissue diseases ,Original Investigation ,Aged, 80 and over ,Middle Aged ,Metastatic breast cancer ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Breast Neoplasm ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Combination therapy ,Breast Neoplasms ,Càncer de mama ,Capecitabine ,03 medical and health sciences ,Gastrointestinal cancer ,Metàstasi ,Internal medicine ,Humans ,Càncer gastrointestinal ,Adverse effect ,neoplasms ,Aged ,Chemotherapy ,Antineoplastic Combined Chemotherapy Protocol ,Minimum bactericidal concentration ,business.industry ,medicine.disease ,chemistry ,Trastuzumab emtansine ,business - Abstract
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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- 2020