CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.
In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.
In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).
"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."
The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.
“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”
“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”
In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”
T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."
The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).
They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.
Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.
The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.
Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.
In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.