| Literature DB >> 32584367 |
Javier Cortés1,2,3, Véronique Diéras4,5, Sylvie Lorenzen6, Filippo Montemurro7, Jorge Riera-Knorrenschild8, Peter Thuss-Patience9, Giacomo Allegrini10, Michelino De Laurentiis11, Caroline Lohrisch12, Eva Oravcová13, Jose M Perez-Garcia2, Francesco Ricci5, Dina Sakaeva14, Rosanne Serpanchy12, Jozef Šufliarský13,15, Maria Vidal3,16, Natsumi Irahara17, Christine Wohlfarth17, Mounir Aout17,18, Karen Gelmon12,19.
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/m2, 700 mg/m2, or 650 mg/m2 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).Entities:
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Year: 2020 PMID: 32584367 PMCID: PMC7317656 DOI: 10.1001/jamaoncol.2020.1796
Source DB: PubMed Journal: JAMA Oncol ISSN: 2374-2437 Impact factor: 31.777
Figure 1. Patient Disposition in Phase 2
aOne patient randomized to the T-DM1 alone group also received capecitabine throughout the study and is included in the T-DM1 + capecitabine safety population.
bOne patient in the T-DM1 alone group was randomized in error and was not treated.
cPatients who completed the study were those patients in follow-up who had their last visit within the last 6 months prior to the clinical cutoff date (May 31, 2017).
ITT indicates intention-to-treat; T-DM1, trastuzumab emtansine.
Figure 2. Progression-Free Survival in Patients With Metastatic Breast Cancer From Phase 2
Patients without progression/death were censored at the date of the last tumor assessment. HR estimates and 90% CIs are from a Cox regression model stratified by the number of previous lines of treatment.
HR indicates hazard ratio; T-DM1, trastuzumab emtansine.
Efficacy Results From Phase 2
| T-DM1 + capecitabine (n = 81) | T-DM1 (n = 80) | |
|---|---|---|
| Overall response rate, No. (%) [90% CI] | 36 (44.4) [35.0 to 54.2] | 29 (36.3) [27.3 to 46.0] |
| Difference, % (90% CI) | 8.2 (−4.5 to 20.9) | |
|
| .34 | |
| Clinical benefit rate, No. (%) [90% CI] | 54 (66.7) [57.1 to 75.3] | 50 (62.5) [52.7 to 71.6] |
| Best overall response, No. (%) | ||
| Complete response | 2 (2) | 2 (3) |
| Partial response | 34 (42) | 27 (34) |
| Stable disease | 24 (30) | 26 (33) |
| Progressive disease | 14 (17) | 23 (29) |
| Not evaluable | 7 (9) | 2 (3) |
| Time to response, median (IQR), mo | 2.10 (1.99 to 3.24) | 2.10 (2.04 to 4.67) |
| Duration of response, median (IQR), mo | 11.30 (8.18 to NE) | 12.22 (8.25 to 19.88) |
| Time to treatment failure, median (IQR), mo | 9.86 (4.67 to 15.87) | 7.66 (4.27 to 14.52) |
| Time to progression, median (IQR), mo | 10.38 (4.93 to NE) | 10.32 (4.83 to 18.43) |
Abbreviations: IQR, interquartile range; NE, not estimable; T-DM1, trastuzumab emtansine.
Provided for responders only.