ESMO 2013-T-DM1 FOR HEAVILY PRETREATED PATIENTS

AMSTERDAM ― The novel twist on HER2-targeted therapy, which combines a monoclonal antibody with a chemotherapy in 1 product, T-DM1 (ado-trastuzumab emtansine, Kadcyla, Roche/Genentech), has now been shown to work even in heavily pretreated patients with advanced HER2-positive breast cancer.

New results from the phase 3 TH3RESA trial, presented for here at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO), show that the new product nearly doubled progression-free survival (PFS) when compared with physician's choice of treatment. The 602 participants had advanced metastatic disease and had already been treated with a variety of chemotherapy and targeted agents that included trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, SmithKline Beecham).

Median PFS was 6.2 months for women on T-DM1, compared with 3.3 months for those on physician's choice of therapy, which was usually chemotherapy plus trastuzumab. This improvement in PFS is both statistically and clinically meaningful, said lead investigator Hans Wildiers, MD, from the University Hospitals Leuven, Belgium.

These new data extend the use of the new product to a larger population of patients from that included in the pivotal registration trial for the drug, known as EMILIA. That study led to the approval in the United States for use of T-DM1 in the treatment of patients with HER2-positive breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. That same indication hasrecently been recommended for approval in Europe, and European Union approval is expected before the end of the year.

The TH3RESA study extends use of T-DM1 into a salvage setting. "Two thirds of the participants had already received 4 or more lines of therapy, and all had received at least 2 targeted agents," noted Dr Wildiers. "In addition, 75% of participants had metastases to internal organs, in addition to skin and bone metastases."

"The main message is that once a woman has received treatment with trastuzumab and a taxane, no matter what follows, T-DM1 should be given in second- or third- or fourth-line," he told Medscape Medical News.

Discussant for the paper, Clifford Hudis, MD, chief of breast cancer at Memorial Sloan-Kettering Cancer Center, New York City, commented that there are not enough data to make the dogmatic statement that T-DM1 should be used in every patient with advanced HER2-positive breast cancer, but it should be considered. "If a woman hasn't received it as second-line, then it should be considered as a third- or fourth-line treatment," he told Medscape Medical News.

"Once HER2-positive breast cancer has recurred and metastasized, there are few treatment options available that show any clear benefit for women who have probably undergone several previous treatments for the disease," commented Cornelis van de Velde, MD, from the Leiden University Medical Center, the Netherlands, and who is current president of the European CanCer Organization (ECCO). These results confirm and extend the usefulness of T-DM1 for the treatment of women with advanced HER2-positive disease, he said in a statement.

Reduced Toxicity

The novelty of T-DM1 is that it transports chemotherapy directly to the tumor, which reduces side effects when compared with systemic chemotherapy. This was seen in the EMILIA study, and it was seen again in the TH3RESA trial. Overall, there were fewer severe adverse reactions in the T-DM1 arm, reported by 32% vs 44% in the control arm. Dr. Wildiers noted that patients receiving T-DM1 had a lower incidence of diarrhea, neutropenia, and febrile neutropenia than those in the control arm, but there was a slight increase in severe thrombocytopenia (4.4% vs 1.8%) and hemorrhage (2.2% vs 0.5%).

There were 2 cases of severe thrombocytopenia with hemorrhage, he noted, 1 a case of subarachnoid hemorrhage and the other tumor-related hemorrhage. "This seems to be a rare side effect of T- DM1, but we did not see a consistent pattern yet," he said in an interview. "The thrombocytopenia is known already, and now there is hemorrhage," he said, although he added that he has not seen any instances among the 30 or so patients he has treated in his own clinical practice.

The results from the TH3RESA trial confirm those from EMILIA and show that T-DM1 provides better disease control and less toxicity than the standard treatment of trastuzumab and a taxane, Dr. Wildiers concluded.

In the EMIL1A study, there was a significant improvement in overall survival, and Dr. Wildiers says this is likely to also be the case for TH3RESA once more time has elapsed. So far, there have been 105 deaths, and there have been fewer deaths in the T-DM1 arm, but for the overall survival analysis to reach statistical significance, 400 deaths must have occurred, he said. He speculated that this is likely to be seen in 2015.

Dr. Wildiers reports that he serves on the advisory board of Roche, and several coauthors are employees of Genentech.

European Cancer Congress 2013 (ECCO-ESMO-ESTRO). Abstract LBA15. Presented September 28, 2013.