Ado-trastuzumab emtansine received FDA approval in February, and a number of ongoing trials now seek to determine whether the antibody-drug conjugate can be combined with other agents.
Mark Pegram, MD
Ado-trastuzumab emtansine (Kadcyla, or T-DM1 in clinical trials) received FDA approval in February, and a number of ongoing trials now seek to determine whether the antibody-drug conjugate (ADC) can be combined with other agents.
Mark Pegram, MD, director of the Breast Cancer Program at the Stanford Women’s Cancer Center in California, discussed the promise of ADCs and ongoing research with T-DM1 at the Annual Miami Breast Cancer Conference in March.
Although targeted antibodies in cancer have been promising, with a few exceptions, most have only marginal activity in their targeted cancer and must be paired with a chemotherapeutic agent to maximize their efficacy. Researchers who worked on monoclonal antibodies during their early development had hoped that the new drugs would serve as a “magic bullet” in cancer, something that would prove to be effective in treating the disease without the side effects frequently caused by chemotherapy, Pegram said.
His research in the 1990s included work on trastuzumab, a monoclonal antibody that targets HER2 on tumor cells, and he found the drug to be somewhat disappointing because it had to be combined with cytotoxic agents in order to provide patients with any substantial benefit.
However, even just a few years ago, the thought of combining trastuzumab with the cytotoxic agent emtansine (DM1) would have been unthinkable, Pegram said. Following early research in the 1980s, emtansine sat on the shelf for many years after being developed because it was deemed too toxic to be given to patients parenterally.
“Now, we have the opportunity to recapture the promise of targeted antibody therapeutics because these antibody- drug conjugates, at least in the case of T-DM1, are very well tolerated,” Pegram said.
When emtansine is conjugated to trastuzumab, the total amount of the cytotoxic agent is trivial when compared to the traditional delivery method for chemotherapy drugs, Pegram said. Additionally, trastuzumab has a tight binding affinity to HER2-overexpressing tumor target cells, so emtansine ends up in the tumor bed and not scattered in normal tissues, where it is prohibitively toxic.
“The therapeutic index, which is efficacy divided by toxicity, is exceptionally wide and really lives up to the promise of the ‘magic bullet’ finally in the case of T-DM1 because you get so much therapeutic response with so little toxicity,” Pegram said.
The phase III EMILIA trial confirmed the efficacy of T-DM1. In that trial, 991 patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized in a 1:1 ratio to receive T-DM1 or the combination of lapatinib and capecitabine.
In results presented at the European Society for Medical Oncology (ESMO) 2012 Congress, and concurrently published in The New England Journal of Medicine, T-DM1 was shown to reduce the mortality risk in women with HER2- positive, unresectable, locally advanced or metastatic breast cancer by 32% when compared with lapatinib and capecitabine (hazard ratio [HR] = 0.68; 95% CI, 0.55-0.85; P <.001), with a 6-month difference favoring T-DM1.1 Median overall survival was 30.9 months for T-DM1 versus 25.1 months for lapatinib and capecitabine.
The survival benefit comes with an excellent safety profile, according to Pegram. The only toxicities that have been observed in clinical trials are transient transaminase elevation and thrombocytopenia, which Pegram said are both reversible. Pegram highlighted the fact that patients did not experience common side effects, including alopecia and neutropenia, and very little gastrointestinal toxicity was observed.
Stanford is one site for a phase I trial that is currently enrolling patients. Pegram and his colleagues are studying whether T-DM1 can be given in combination with paclitaxel with or without pertuzumab, another monoclonal antibody.
Results are expected to be presented at the 2013 San Antonio Breast Cancer Symposium in December. Results from the phase III MARIANNE trial should also be presented sometime within the coming year. In that trial, patients were randomized to T-DM1 plus pertuzumab, T-DM1 plus placebo, or trastuzumab plus a taxane (either paclitaxel or docetaxel).