September 26, 2011 (Stockholm, Sweden) — The first randomized trial to compare the novel agent trastuzumab emtansine (T-DM1) with standard therapy shows that it significantly increased progression-free survival in women with metastatic breast cancer.
"First-line treatment with T-DM1 was associated with a statistically significant improvement in progression-free survival, and was also associated with a reduction in the risk of toxicity," said lead author Sara Hurvitz, MD, director of the breast oncology program, division of hematology/oncology, University of California, Los Angeles.
"These results validate the hypothesis that the unique targeted delivery of chemotherapy through T-DM1 may lead to an improved therapeutic index," she said.
Dr. Hurvitz presented the results of the study here at the 2011 European Multidisciplinary Cancer Congress.
Median progression-free survival was 14.2 months for women who received T-DM1, and 9.2 months for those who received standard therapy with trastuzumab (Herceptin) plus docetaxel. The hazard ratio was 0.59, indicating that treatment with T-DM1 reduced the probability of disease progression or death by 41%, compared with standard therapy, noted Dr. Hurvitz.
T-DM1 is a novel HER2-targeted antibody–drug conjugate, developed by Genentech, for the treatment of HER2-positive cancer. Dr. Hurvitz emphasized that it provides intracellular delivery of the cytotoxic agent DM1, while maintaining the antitumor activities of trastuzumab and sparing normal cells.
Trastuzumab targets the product to the cancer cell, she explained, while the attached emtansine acts as a "bullet", she said.
In this study, Dr. Hurvitz and colleagues randomized 137 patients with metastatic breast cancer to either T-DM1 or to the combination of trastuzumab 75 or 100 mg/m2 plus docetaxel (control group) to evaluate the safety and efficacy of the experimental agent. In the majority of patients in the control group (74.2%), trastuzumab was initiated at 75 mg/m2.
The median durations of follow-up were 13.5 months for the control group and 13.8 months for the T-DM1 group. The primary end point was progression-free survival.
Patient characteristics were balanced between the 2 groups, and the majority of patients were enrolled outside of the United States. Dr. Hurvitz pointed out that relatively few patients received adjuvant trastuzumab. "This is likely due to the international nature of the study and the lack of availably at some centers," she said.
The majority of patients who discontinued treatment did so because of disease progression, but the rate was much lower in the T-DM1 group than in the control group (61% vs 42%).
The overall response rates were similar in the T-DM1 and control groups (64% vs 58%).
In the control group, the duration of response was 9.5 months; in the T-DM1 group, the duration of response has not been reached. "This suggest that it will be durable, but we will need further follow-up to know what it will be," said Dr. Hurvitz.
There was a difference in toxicity — a measure that is "clinically meaningful" to patients, she said.
Lower Rate of Toxicity
Patients in the T-DM1 group had significantly fewer common and grade 3 or higher adverse events. The T-DM1 group had approximately half the incidence of severe adverse events as the control group (46.4% vs 89.4%). Discontinuation of treatment because of toxicity was markedly lower in the T-DM1 group than in the control group (7.2% vs 28.8%).
The majority of serious events were related to neutropenia, and the rate was much higher in the control group than in the T-DM1 group (60.6% vs 5.8%). In addition, 13.6% of patients in the control group experienced febrile neutropenia; there were no cases in the T-DM1 group.
Also, said Dr. Hurvitz, the rate of alopecia — an adverse effect that is very important to patients — was much lower in the T-DM1 group than in the control group (4.0% vs 66.7%).
The median duration of treatment was longer in the T-DM1 group (10.0 vs 5.5 months), most likely because of the toxicity in the control group. There were 2 deaths in the study not related to disease progression — 1 in each group.
Overall survival data are not mature and are, therefore, not available.
Phase 3 Results Coming
"This is the first study to evaluate an antibody–drug conjugate for HER2-positive metastatic breast cancer, compared with standard therapy," she said.
"These results validate the hypothesis that the unique targeted delivery of chemotherapy through T-DM1 may lead to an improved therapeutic index," Dr. Hurvitz concluded.
She added that the drug is currently being evaluated in phase 3 clinical trials; the first results will be available in 2012.
Martine Piccart-Gebhart, MD, PhD, the discussant of the paper, noted that these results are exciting. Perhaps this is the "magic drug, the one we have been waiting for," she said, cautioning that this is an open-label study and the data are still early.
"This is an important study with exciting results, but we need validation in the phase 3 setting," said Dr. Piccart-Gebhart, who is from the Jules Bordet Institute in Brussels, Belgium.
She pointed out that there is a very comprehensive phase 3 program ongoing, so the drug might soon be available to patients.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 5001. Presented September 25, 2011.
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Cite this: Targeted Chemo Shows Promise in Metastatic Breast Cancer - Medscape - Sep 26, 2011.