AMSTERDAM—In women whose advanced unresectable HER2-positive breast cancer progressed despite multiple prior therapies including trastuzumab, lapatinib, and a taxane, the monoclonal antibody conjugate T-DM1 (combining the anti-HER2 drug trastuzumab linked to the cytotoxic agent emtansine) significantly increased time to progression and had fewer side effects than “treatment of physician's choice” (TPC), according to the results of the international randomized Phase III TH3RESA study reported here at the European Cancer Congress (Abstract 15—accessible via http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Abstract-search.aspx#
The 602 women recruited into the trial, three quarters of whom had metastases, received either single-agent T-DM1 or TPC. Four out of five patients in the control arm then received HER2-directed agents combined with cytotoxic chemotherapy, while the remaining one fifth of patients received single-agent chemotherapy.
Study author Professor Hans Wildiers, MD, PhD, from the University Hospitals Multidisciplinary Breast Centre in Leuven, Belgium, explained in an interview that T-DM1 could pass safely through normal organs on its way to tumor cells: “It's a complex, and is transported through the blood, and in the blood it is not active. When this complex binds to the HER2 receptor of a tumor cell it becomes internalized. Within the cell that linker is cut, and the cytotoxic agent DM1 becomes free.”
Median progression-free survival (PFS) nearly doubled in patients randomized to receive TDM1—6.2 months vs. 3.3 months among those receiving TPC. The interim assessment of median overall survival also showed an improvement, which was short of statistical significance, but which he said did indicate a “strong trend.” The overall response rate to T-DM1 was 31.3 percent vs. only 8.6 percent for TPC.
T-DM1 was also less toxic: “The good thing about T-DM1 is that it's a better drug in terms of tumor control, but it also generally has a better safety profile. There were fewer high-grade adverse events with T-DM1, as well as fewer treatment discontinuations or dose reductions in the T-DM1 arm.”
He said T-DM1 fills an unmet need, since virtually all patients with HER2-positive metastatic breast cancer eventually develop progressive disease and there is presently no clear standard of care for patients whose disease has progressed after two or more treatments.
“The data reaffirm the potential of T-DM1 as a treatment for HER2-positive metastatic breast cancer, demonstrating that T-DM1 has the potential to be a new treatment paradigm for this group of patients who currently have few options,” he said.
Asked whether there might be a subcategory of women in whom the drug is more active, he said there was no biomarker for patients in the study who did or did not respond to T-DM1. But his interpretation was that all women with progressive refractory disease could be candidates for treatment with it: “In all subgroup studies, T-DM1 was better than the control arm, so indeed there is no subgroup where it works less than the control arm,” he noted.
The THER3SA findings add to the earlier EMILIA trial results in which T-DM1 was found to be more effective than capecitabine and lapatinib in patients who had previously been treated with trastuzumab and a taxane. And in the ongoing MARIANNE trial, T-DM1 is being further tested in patients with HER2-positive previously untreated metastatic breast cancer.
Commenting on the study, Cornelis van de Velde, MD, PhD, Professor of Surgery at Leiden University in the Netherlands, called the results important because they confirm and extend the usefulness of T-DM1 for the treatment of women with advanced HER2-positive breast cancer. “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. The fact that T-DM1 extends progression-free survival is good news for these women.”
Cautions about Scope
Still, the commentator at the congress, ASCO President Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, was cautious about the scope of T-DM1's role among all women in this disease category: “We'll need more data. I think what we see here is a hint that it will be positive—the way the second-line data were—and if so those patients who are not afforded the option of getting it earlier maybe should consider it later.”
He noted that the data are entirely consistent with the EMILIA study findings and that this suggests a clinical benefit for this drug compared with the standard options doctors would otherwise choose: “I think it should be considered in the utilization of T-DM1 in the future,” he concluded.
Listen on the iPad edition of this issue as Professor Wildiers elaborates on the study's findings in a video interview with Sarah Maxwell.
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© 2014 by Lippincott Williams & Wilkins, Inc.