PFS is the time before the disease gets worse, ie, progresses and becomes worse. The patients on T-DM1 had a 35% longer PFS than those of comparator medicine--a very significant and welcome finding.
What is T-DM1 (trastuzumab emtansine)
T-DM1 is an antibody-drug conjugate (ADC in short) that combines Trastuzumab (aka Herceptin) antibody with a Derivative of a tubulin binding agent called Maytansine (ie, DM1 or emantasine). While trastuzumab bind the cell surface receptor and block proliferative signalling, emtansine is an intracellular poison that binds tubulin and disrupts the intracellular microtubule-based skeleton. Emtansine technology belongs to ImmunoGen, Inc., a Waltham Massachusetts-based company (Nasdaq: IMGN), and is licenced by Genentech/Roche.
Protocol# EMILIA (TDM4370g/BO21977)
Clinical study: EMILIA trial is an international, Phase III, randomised, open-label study comparing trastuzumab emtansine alone to lapatinib in combination with Xeloda
Patients: HER2-positive with locally advanced or metastatic breast cancer whose disease had progressed (ie, they had relapsed) after an initial treatment with Herceptin and a taxane-based chemotherapy, such as docetaxel.
Number of patients: 991 patients
- T-DM1 arm (n=495 patients) received 3.6 mg/kg dose every three weeks (q3w).
- Lapatinib plus Xeloda (L plus X) arm (n=496 patients) received Lapatinib 1250 mg dose daily, every three weeks (between days 1 and 21), and Xeloda 1000 mg/m2 dose, twice daily (between days 1 and 14), every three weeks.
PFS (as assessed by an independent review committee,) overall survival (OS), and Safety.
- One-year and two-year survival rates
- Safety profile
- PFS as assessed by investigator
- Objective response rate (ORR)
- Duration of response
- Quality of life (QOL).
203 sites in 22 countries; enrollment began in February 2009.
At the ASCO conference, the final analysis on PFS and interim data on OS was presented:
- Patients receiving T-DM1 lived 3.2 months longer without getting their disease worse than those on L-plus-X. PFS, as assessed by independent review committee, was 9.6 months vs 6.4 months, respectively. The difference of 35% (ie, Hazard ratio [HR] of 0.65) was very significant (p<.0001).
- The first interim analysis of OS was also presented. There was a trend towards better overall survival in T-DM1 group. The median survival in L-plus-X group was 23.3 months , but has not been reached for T-DM1 group, ie, those on T-DM1 are living longer and more than 50% of them are alive today. A longer follow-up is required for T-DM1 group (HR=0.62; P=0.0005). The final analysis is expected to take place by 2014.
- The one-year survival for T-DM1 group was 84.7%, whereas 77.0% of L-plus-X patients were alive after one year. After two years, 65.4% of T-DM1 patients were alive vs 47.5% of those on L-plus-X.
- The response rate (the percentage of patients with tumour shrinkage) was 43.6 percent for those who received T-DM1 versus 30.8 percent of patients who received L-plus-X.
- One quality of life measure, time-to-symptom progression, which was reported by patients was 7.1 months in T-DM1 patients versus 4.6 months in L-plus-X patients. In other words, T-DM1 patients were almost twice as long as the other group to be free of painful symptoms.
- T-DM1 was much less toxic with 40.8% patients experiencing Grade 3 or higher adverse events (AEs) compared to 57% patients in L-plus-X group.
Types of AEs reported in the study:
"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)."
--From: Roche Press Release. June 3, 2012.
ASCO 2012 Abstract
- Kimberly L. Blackwell, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol 30, 2012 (suppl; abstr LBA1)
- Roche’s targeted investigational breast cancer medicine, trastuzumab emtansine (T-DM1), reduced the risk of cancer worsening or death by 35 percent in pivotal phase III trial. Roche Media Release. Basel, 3 June 2012.
- ImmunoGen, Inc. Announces Results from Trastuzumab Emtansine (T-DM1) EMILIA Phase III Trial. Press Release. ImmunoGen, Inc. June 3, 2012.
Last year's (ASCO 2011) Abstract:
- Verma, S., et al. EMILIA: A phase III, randomized, multicenter study of trastuzumab-DM1 (T-DM1) compared with lapatinib (L) plus capecitabine (X) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC) and previously treated with a trastuzumab-based regimen. J Clin Oncol 29: 2011 (suppl; abstr TPS116)
- T-DM1 Shows a Way to Deliver Chemo Without Side Effects. June 1, 2012.
- EMILIA Study Results: Roche's Trastuzumab Emtansine (T-DM1) Delays Metastatic Breast Cancer Progression. March 31, 2012.
- One-Two Punch: Curbing HER-2 Positive Breast Cancer with Herceptin-Tykerb Combo. January 19, 2012.
- San Antonio Breast Cancer Symposium 2011: Clinical Trials Report. December 8, 2011.
- Breast Cancer Tweets From AACR 2012 Annual Meeting. April 4, 2012.