Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options.
TH3RESA trial has compared Trastuzumab Emtansine ( Kadcyla ), an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to Trastuzumab, with treatment of physician's choice in this population of patients.
This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients ( greater than or equal to 18 years, left ventricular ejection fraction greater than or equal to 50%, Eastern Cooperative Oncology Group performance status 0-2 ) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including Trastuzumab and Lapatinib ( Tykerb, Tyverb ), and previous taxane therapy in any setting, were randomly assigned ( in a 2:1 ratio ) to Trastuzumab Emtansine ( 3.6 mg/kg intravenously every 21 days ) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system.
Patients were stratified according to world region ( USA vs western Europe vs other ), number of previous regimens ( excluding single-agent hormonal therapy ) for the treatment of advanced disease ( two to three vs more than three ), and presence of visceral disease ( any vs none ).
Coprimary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.
Researchers have reported the final progression-free survival analysis and the first interim overall survival analysis.
From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned ( 404 to Trastuzumab Emtansine and 198 to physician's choice ).
At data cutoff ( Feb 11, 2013 ), 44 patients assigned to physician's choice had crossed over to Trastuzumab Emtansine. After a median follow-up of 7.2 months in the Trastuzumab Emtansine group and 6.5 months in the physician's choice group, 219 ( 54% ) patients in the Trastuzumab Emtansine group and 129 ( 65% ) of patients in the physician's choice group had progression-free survival events.
Progression-free survival was significantly improved with Trastuzumab Emtansine compared with physician's choice ( median 6.2 months vs 3.3 months; stratified hazard ratio, HR=0.528; p less than 0.0001 ).
Interim overall survival analysis showed a trend favouring Trastuzumab Emtansine ( stratified HR 0.552; p=0.0034 ), but the stopping boundary was not crossed.
A lower incidence of grade 3 or worse adverse events was reported with Trastuzumab Emtansine than with physician's choice ( 130 events [ 32% ] in 403 patients vs 80 events [ 43% ] in 184 patients ).
Neutropenia ( 2% vs 16% ), diarrhoea ( less than 1% vs 4% ), and febrile neutropenia ( less than 1% vs 4% ) were grade 3 or worse adverse events that were more common in the physician's choice group than in the Trastuzumab Emtansine group.
Thrombocytopenia ( 5% vs 2% ) was the grade 3 or worse adverse event that was more common in the Trastuzumab Emtansine group.
74 ( 18% ) patients in the Trastuzumab Emtansine group and 38 ( 21% ) in the physician's choice group reported a serious adverse event.
In conclusion, Trastuzumab Emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received Trastuzumab and Lapatinib. ( Xagena )
Krop IE et al, The Lancet Oncology 2014; 15: 689 – 699