Date: 2012-08-27
Type of information:
phase: 3
Announcement: results
Company: Roche (Switzerland)
Product: trastuzumab emtansine (T-DM1)
Action mechanism: Trastuzumab emtansine is an antibody-drug conjugate (ADC). It is comprised of the antibody trastuzumab and the chemotherapy DM1 attached together using a stable linker. Trastuzumab emtansine is designed to target and inhibit HER2 signalling and deliver the chemotherapy directly inside HER2-positive cancer cells.
Disease: HER2-positive metastatic breast cancer
Therapeutic area: Cancer Oncology
Country:
Trial
details: EMILIA (TDM4370g/BO21977) is an international, Phase III, randomised, open-label study comparing trastuzumab emtansine alone to lapatinib in combination with Xeloda® in 991 patients with HER2-positive locally advanced or metastatic breast cancer whose disease progressed after initial treatment with Herceptin® and a taxane-based chemotherapy.
Participants in the trastuzumab emtansine arm received:
Trastuzumab emtansine 3.6 mg/kg dose every three weeks
Participants in the lapatinib plus Xeloda arm received:
Lapatinib 1250 mg dose daily, every three weeks.
Xeloda 1000 mg/m2 dose, twice daily, days 1 – 14, every three weeks.
The co-primary efficacy endpoints of the study are PFS (as assessed by an independent review committee) and OS. Safety is also a primary endpoint of the study. Other study endpoints include and one-year and two-year survival rates, safety profile, PFS as assessed by investigator, objective response rate, duration of response and quality of life.
Latest
news: * On August 27, 2012, Roche has announced updated results from the Phase III EMILIA study, which showed that trastuzumab emtansine (T-DM1) significantly extended the lives (improved overall survival) of people with HER2-positive metastatic breast cancer (mBC) compared to the combination of lapatinib and Xeloda® (capecitabine). The EMILIA study, in people with HER2-positive mBC who had previously received Herceptin® (trastuzumab) and taxane chemotherapy, has now met both co-primary efficacy endpoints of significant improvements in overall survival and progression-free survival (PFS). These data will be presented at an upcoming medical meeting.
Updated EMILIA overall survival results : This confirmatory analysis of overall survival in the Phase III EMILIA study crossed the pre-specified boundary that showed trastuzumab emtansine significantly extended the lives of people with HER2-positive mBC compared to the combination of lapatinib and Xeloda®.
Previously presented EMILIA results
Results from the EMILIA study were also presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2012:
• There was a significant improvement in the time people receiving trastuzumab emtansine (n=495) lived without their disease getting worse (PFS) compared to those who received lapatinib plus Xeloda® (n=496), as assessed by independent review.
• The risk of disease worsening was reduced by 35 percent for people who received trastuzumab emtansine compared to those who received lapatinib plus Xeloda® (HR=0.65, p<0.0001; median PFS 9.6 months vs. 6.4 months, respectively).
• Fewer people who received trastuzumab emtansine experienced Grade 3 or higher (severe) adverse events (AEs) than those who received lapatinib plus Xeloda, at 40.8 percent compared to 57.0 percent, respectively. For people receiving trastuzumab emtansine, compared to those receiving lapatinib plus Xeloda®, the most common (occurring in more than 2 percent of participants) Grade 3 or higher AEs were low platelet count (12.9 percent vs. 0.2 percent), increased levels of enzymes released by the liver and other organs (aspartate aminotransferase: 4.3 percent vs. 0.8 percent; alanine aminotransferase: 2.9 percent vs. 1.4 percent; in most people, these levels had returned to normal by the time of the next dose of trastuzumab emtansine), and anaemia (2.7 percent vs. 1.6 percent).
• A previous interim analysis of overall survival demonstrated a trend towards improved overall survival in people receiving trastuzumab emtansine compared to those who received lapatinib plus Xeloda®. However, the data were not considered statistically significant at that time.
Based on these updated overall survival results, people in the lapatinib and Xeloda® arm of EMILIA will be offered the option to receive trastuzumab emtansine.
Genentech has submitted a Biologics License Application (BLA) for trastuzumab emtansine to the FDA and Roche will shortly be submitting a Marketing Authorisation Application to the EMA.
* On June 3, 2012, Roche has announced that the Phase III EMILIA study of trastuzumab emtansine (T-DM1) met its co-primary endpoint, of a significant improvement in the time patients with HER2-positive metastatic breast cancer (mBC) lived without their disease getting worse (progression-free survival; PFS). The study showed that the risk of disease worsening or death was reduced by 35 percent for people who received trastuzumab emtansine compared to those who received lapatinib plus Xeloda® (capecitabine) chemotherapy (HR=0.65, p-value <.0001).
There was also a trend for patients who received trastuzumab emtansine to live longer (overall survival, or OS, the other co-primary endpoint of the study) than those who received lapatinib plus Xeloda®, but these data are currently not mature. The safety profile of trastuzumab emtansine was consistent with that seen in previous studies, with fewer patients who received trastuzumab emtansine experiencing Grade 3 or higher (severe) adverse events (AEs) than those who received lapatinib plus Xeloda® (40.8 percent compared to 57 percent).
The results presented at ASCO represent the final analysis of PFS and the first interim analysis of OS.
There was a significant improvement in the time patients receiving trastuzumab emtansine (n=495) lived without their disease getting worse compared to those who received lapatinib plus Xeloda® (n=496), as assessed by an independent review committee: median PFS was 9.6 months versus 6.4 months, respectively.
The first interim OS analysis demonstrated a trend towards improved OS in patients receiving trastuzumab emtansine versus those who received lapatinib plus Xeloda®: median OS was 23.3 months for patients who received lapatinib plus Xeloda® but had not been reached for patients receiving trastuzumab emtansine and requires longer follow-up (HR=0.62; P=0.0005).
As the hazard ratio for OS did not cross the pre-specified stopping boundary for the study, the OS analysis is not considered statistically significant at this time. The final analysis is expected to take place by 2014.
One-year survival in patients who received trastuzumab emtansine was 84.7 percent versus 77.0 percent for patients who received lapatinib plus Xeloda®. Two-year survival was 65.4 percent versus 47.5 percent, respectively.
The response rate (the percentage of patients with tumour shrinkage) was 43.6 percent for those who received trastuzumab emtansine versus 30.8 percent of patients who received lapatinib plus Xeloda®.
The time-to-symptom progression, a patient-reported measure of quality of life, was also improved in patients who received trastuzumab emtansine: 7.1 months in patients who received trastuzumab emtansine versus 4.6 months in patients who received lapatinib plus Xeloda®.
Fewer patients who received trastuzumab emtansine experienced Grade 3 or higher (severe) AEs than those who received lapatinib plus Xeloda®, at 40.8 percent versus 57 percent, respectively. For people receiving trastuzumab emtansine, compared to those receiving lapatinib plus Xeloda, the most common (occurring in more than 2 percent of patients) Grade 3 or higher AEs were low platelet count (12.9 percent versus 0.2 percent), increased levels of enzymes released by the liver and other organs (in most patients these levels had returned to normal by the time of the next dose of trastuzumab emtansine; aspartate aminotransferase: 4.3 percent versus 0.8 percent; alanine aminotransferase: 2.9 percent versus 1.4 percent) and anaemia (2.7 percent versus 1.6 percent).
For those patients receiving lapatinib plus Xeloda® compared to those receiving trastuzumab emtansine, the most common Grade 3 or higher AEs were diarrhoea (20.7 percent versus 1.6 percent), hand-foot syndrome (16.4 percent versus 0) and vomiting (4.5 percent versus 0.8 percent).
* On March 30, 2012, Roche has announced topline results of EMILIA, the first randomised Phase III study of trastuzumab emtansine (T-DM1). The study enrolled people with HER2-positive metastatic breast cancer (mBC) who had previously received treatment with Herceptin® and a taxane (chemotherapy). The study showed people who received trastuzumab emtansine lived significantly longer without their disease getting worse (progression-free survival, PFS) compared to those who received lapatinib plus Xeloda® (capecitabine).
Final results for overall survival (OS), a co-primary efficacy endpoint of EMILIA, are not yet mature. The safety profile of trastuzumab emtansine was consistent with that seen in previous studies. These data will be submitted for presentation at an upcoming medical meeting.
