VIENNA – T-DM1 resulted in a significant 5-month overall survival benefit over capecitabine plus lapatinib in the treatment of metastatic breast cancer that had progressed following treatment with trastuzumab plus a taxane in a phase III trial.
Updated results from the open-label, EMILIA trial showed that the median overall survival was 25.1 months with capecitabine (Xeloda) plus lapatinib (XL), but 30.9 months with T-DM1. The hazard ratio for the survival benefit was 0.68 (P =.0006), indicating a 32% reduction in the risk of dying if treated with T-DM1 versus XL.
The findings were presented at the European Society for Medical Oncology Congress, with simultaneous online publication in the New England Journal of Medicine (doi:10.1056/NEJMoa1209124).
"The second overall survival interim analysis saw that the patients who received T-DM1 lived longer," said Dr. Javier Cortes, the invited discussant who commented on the significance of the findings.
"I do not remember any clinical trial in the history of metastatic breast cancer with these numbers," observed Dr. Cortes of the Vall d’Hebron Institute of Oncology in Barcelona.
Overall survival was a co-primary end point of the EMILIA study, but was not initially statistically better with T-DM1 than with XL. Indeed, results of the first interim analysis, which were presented at ASCO in June, showed that there was a trend, but not a definite overall survival benefit. In the T-DM1 vs. the XL arms, overall survival was 84.1% and 77% at 1 year and 65.4% and 47.5% at 2 years.
Those data were based on a data cut-off of Jan. 14, at a median follow up of 12.4 and 12.9 months in the T-DM1 and XL arms, when the progression-free analysis was also performed. This showed a clear progression-free survival benefit in favor of T-DM1 (9.6 months vs. 6.4 months, P less than .0001).
The second interim overall survival analysis performed up to the end of July 31 accounts for 18.6 months and 19.1 months of median follow-up. Estimated 1-year survival rates were 85.2% in the T-DM1 arm and 78.4% in the XL arm, with 2-year survival rates of 67.6% and 51.8%.
"A decision was made to conduct a second interim overall survival analysis after 50% of the targeted number of OS events had taken place," study investigator Dr. Sunil Verma of Sunnybrook Odette Cancer Center in Toronto explained.
"The final overall survival analysis is expected in 2014," he added, but this will only be descriptive, since following the beneficial findings of the second interim overall survival analysis, patients in the XL arm are now allowed to cross over to the T-DM1 arm.
Results for all additional secondary end points favored treatment with T-DM1 over XL. The objective response rate was 43.6% and 30.8% (P less than .001), and the median duration of response was 12.6 months versus 6.5 months. There were also greater improvements in patient-reported outcomes, such as symptom worsening assessed by the Functional Assessment of Cancer Therapy–Breast (FACT-B).
As with any new agent, toxicity is a potential concern, but data so far show that there are no untoward safety concerns. Specifically, cardiotoxicity was not increased in the T-DM1 arm. Cardiac events of grade 3 or higher occurred in 1 (0.2%) of 490 patients vs. 2 (0.4%) of 488 XL-treated patients. Other side effects increased in the T-DM1 arm were thrombocytopenia (12.9%) and altered liver enzymes and anemia. Adverse events in the XL arm were similar to those seen in clinical practice, including diarrhea and hand-foot syndrome.
Patient choice will also be a deciding factor when it comes to how T-DM1 could be used in routine practice. As an intravenous therapy – given every 3 weeks until progression – patients may prefer to stick to an oral regimen such as XL – although some patients may not like to take the multiple, and in the case of capecitabine, large pills to swallow.
Further trials with T-DM1 are ongoing and will help determine its role in the management of women with metastatic disease. The MARIANNE trial, for example, is investigating the use of T-DM1 in combination with taxanes after failure of taxane-based chemotherapy plus trastuzumab or pertuzumab in patients with HER-2–positive metastatic breast cancer. In the trial, T-DM1 plus taxanes are being compared with T-DM1 alone and with T-DM1 plus pertuzumab.
The EMILIA study was funded by F. Hoffmann–La Roche/Genentech. Dr. Verma disclosed receiving compensation for consultancy/advisory services and honoraria from both Roche and GlaxoSmithKline, and research funding from Roche/Genentech. Dr. Javier Cortes has received honoraria from Roche.