TY - JOUR
T1 - 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.
AU - Cortés, Javier
AU - Diéras, Véronique
AU - Lorenzen, Sylvie
AU - Montemurro, Filippo
AU - Riera-Knorrenschild, Jorge
AU - Thuss-Patience, Peter
AU - Allegrini, Giacomo
AU - De Laurentiis, Michelino
AU - Lohrisch, Caroline
AU - Oravcová, Eva
AU - Perez-Garcia, Jose M
AU - Ricci, Francesco
AU - Sakaeva, Dina
AU - Serpanchy, Rosanne
AU - Šufliarský, Jozef
AU - Vidal, Maria
AU - Irahara, Natsumi
AU - Wohlfarth, Christine
AU - Aout, Mounir
AU - Gelmon, Karen
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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. 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). 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. 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. 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). 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/m2 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. 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. ClinicalTrials.gov Identifier: NCT01702558.
AB - 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. 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). 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. 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. 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). 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/m2 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. 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. ClinicalTrials.gov Identifier: NCT01702558.
KW - Ado-Trastuzumab Emtansine
KW - administration & dosage
KW - adverse effects
KW - Adult
KW - Aged
KW - 80 and over
KW - Antineoplastic Agents
KW - Immunological
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Breast Neoplasms
KW - drug therapy
KW - Capecitabine
KW - Female
KW - Humans
KW - Male
KW - Middle Aged
KW - Receptor
KW - ErbB-2
KW - Treatment Outcome
U2 - 10.1001/jamaoncol.2020.1796
DO - 10.1001/jamaoncol.2020.1796
M3 - Articolo
VL - 6
SP - 1203
EP - 1209
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
ER -