The investigational drug trastuzumab-DM1 (T-DM1) outperformed standard therapy in patients with advanced breast cancer, according to results of the first randomized, head-to-head trial of T-DM1 versus trastuzumab plus a taxane in first-line, advanced, HER2-positive breast cancer.
In the Phase II study, presented at the European Society for Medical Oncology Congress, the antibody-drug conjugate produced a better response rate and significantly reduced the rate of side effects among patients with HER2-positive metastatic breast cancer.
T-DM1 is an antibody-drug conjugate, designed for the targeted intracellular delivery of the potent anti-microtubule derivative DM1 via the highly specific monoclonal antibody trastuzumab.
The DM1 molecules form a very stable bond with trastuzumab so that DM1 is not released until trastuzumab finds cells that have HER2 overexpression, explained Ian E. Krop, MD, Assistant Professor of Medicine at Harvard Medical School and a medical oncologist at Dana-Farber Cancer Institute's Breast Oncology Center.
“The cytotoxic drug goes right to the cancer cells so it's not floating around and causing other problems. And trastuzumab still does all the things that trastuzumab does,” said Dr. Krop, who is also studying T-DM1, but was not involved with this work.
T-DM1 Cuts Side Effects
In the trial, which was funded by the drug's manufacturer, Genentech, researchers randomly assigned 137 women to treatment with trastuzumab plus docetaxel, or T-DM1. All participants had HER2-positive metastatic cancer, with no prior chemotherapy for their metastatic disease.
At a median follow-up of six months, the overall response rate was about 48% in the T-DM1 arm, compared with about 41% in the trastuzumab-plus-docetaxel arm, reported Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL.
The rate of clinically meaningful adverse side effects was 37% among patients taking trastuzumab-DM1 compared with 75% among those taking the taxane, she said.
T-DM1 was especially helpful in preventing chemotherapy-related hair loss: Alopecia was observed in only 1.5% of T-DM1 patients, compared with 66.2% of patients in the trastuzumab-taxane arm.
About 7.5% of patients taking T-DM1 experienced neutropenia compared with about 57% of those on the trastuzumab-docetaxel regimen, Dr. Perez said.
Other Trials Also Positive
“This is the first-ever presentation of an anti-HER2 antibody-drug conjugate used as first-line therapy for patients with advanced breast cancer,” Dr. Perez said. “We are encouraged by the results. The study demonstrated that T-DM1 has very good anti-tumor activity as well as much lower toxicity when evaluated side by side with the older standard.”
Other clinical trials have also shown T-DM1 to be effective in patients with advanced cancer that had not responded to as many as seven other treatments, she noted.
Dr. Perez said that other endpoints from this study, including overall survival rates, will be reported in 2011. “Also, a larger Phase III trial known as MARIANNE is now under way. It pits a taxane plus trastuzumab against T-DM1 as administered in this study, with a third option being T-DM1 plus pertuzumab, another novel anti-HER2 agent.”
Much Better Side Effects Profile
Dr. Krop called the results quite encouraging, noting that not only was the side effects profile favorable in the T-DM1 arm, but that the most common adverse effects are those that are usually not that bothersome to patients, such as transient thrombocytopenia.
Taxanes, on the other hand, are associated with side effects such as diarrhea and edema—“things people notice,” he said.
The study is also important as it is the first test of T-DM1 in patients who had not been treated with trastuzumab, he said,
“We hadn't seen any cardiotoxicity with T-DM1, but couldn't really draw any firm conclusions as patients in other trials had done well, with no cardiotoxicity, on trastuzumab. Now we can be more confident that T-DM1 is not associated with cardiac events.”