T-DM1 Now Preferred for Progressive HER2 Breast Cancer

Veronica Hackethal, MD

June 27, 2014

Trastuzumab emtansine (T-DM1) should be the new standard of care for women with HER2-positive advanced breast cancer that has progressed despite multiple lines of treatment, new research shows.

"T-DM1 was clearly superior to the physician's choice of therapy in terms of efficacy and tolerability," said first author Ian Krop, MD, PhD, assistant professor in the Department of Medicine at Harvard Medical School and director of breast cancer research at the Dana-Farber Cancer Institute in Boston. "These data suggest that T-DM1 should be considered a standard of care for patients with metastatic breast cancer who have progressed on trastuzumab and lapatinib."

Interim results from the phase 3 TH3RESA trial were published in the June issue of the Lancet Oncology. Results were previously presented at the 2013 European Cancer Congress, as reported at the time by Medscape Medical News.

T-DM1 is an antibody–drug conjugate. When it binds HER2 receptors, the tumor cells internalize the drug along with the antigen–antibody complex. Inside the cells, trastuzumab is degraded, releasing the cytotoxic agent emtansine, which promotes tumor cell death.

TH3RESA is the first study of T-DM1 in women with HER2-positive breast cancer who have progressed on trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, SmithKline Beecham). This group has not been well studied, and there has not been a true standard of care for this population until now, according to Dr. Krop.

Data from TH3RESA are consistent with results from the EMILIA trial, which compared T-DM1 with capecitabine and lapatinib in patients who progressed on trastuzumab and taxane. Improvements in progression-free and overall survival in EMILIA led to the approval of T-DM1 in this setting in parts of Europe and in the United States.

When the results from TH3RESA and EMILIA are considered together, "essentially any patient who has progressed on trastuzumab and a taxane could consider T-DM1 as a standard of care," Dr. Krop explained. "HER2 remains a valid target even after many lines of HER2-directed therapy."

TH3RESA Details

Dr. Krop and colleagues conducted their randomized open-label study from September 2011 to November 2012 in 22 countries in Asia-Pacific, Europe, North America, and South America. All participants had HER2-positive breast cancer that had progressed despite at least 2 HER2-directed treatments.

The researchers randomly assigned 404 participants to T-DM1 and 198 to physician's choice of treatment, which mostly consisted of trastuzumab-containing regimens. After the publication of the EMILIA results, participants with progressive disease could switch to T-DM1 therapy, which 44 participants did.

Follow-up was a little over 7 months in the T-DM1 group and 6.5 months in the physician's choice group.

Median progression-free survival was significantly better in the T-DM1 group than in the physician's choice group (6.2 vs 3.3 months; P < .0001).

It is probably too soon to say whether T-DM1 improves overall survival, Dr. Krop explained, but he added that the early results look promising.

"There's a strong trend favoring T-DM1 in terms of overall survival, but it wasn't technically significant because this was such an early look at the data," he reported.

And because patients take T-DM1 every 3 weeks, fewer clinic visits are required, he pointed out.

In addition, T-DM1 seems to be well tolerated.

Adverse effects that can be particularly troubling to patients, like gastrointestinal toxicity and hair loss, were less frequent in the T-DM1 group than in the physician's choice group.

Adverse events of grade 3 or higher, such as fever with low neutrophil counts, were less common in the T-DM1 group than in the physician's choice group (32% vs 43%). There were also fewer dose reductions in the T-DM1 group than in the physician's choice group (9% vs 20%), and fewer discontinuations related to toxicity (7% vs 11%).

However, rates of severe thrombocytopenia were higher in the T-DM1 group than in the physician's choice group (5% vs 2%). In addition, there were 3 treatment-related deaths in the T-DM1 group, 1 of which was caused by subarachnoid hemorrhage in a patient with thrombocytopenia who was on anticoagulant therapy.

You do have to follow patients for thrombocytopenia," Dr. Krop emphasized. This is particularly true for "patients who start with low platelet counts or who are on anticoagulation."

Another trial of T-DM1 is currently in progress, write Michael Gnant, MD, and colleagues from the Comprehensive Cancer Center at the Medical University of Vienna in Austria, in an accompanying comment.

The MARIANNE trial is evaluating the combination of T-DM1 and pertuzumab as first-line treatment.

Those results could again change the standard of care for HER2-positive breast cancer, Dr. Gnant told Medscape Medical News. Currently, T-DM1 is not considered first-line therapy, he noted.

"For now, T-DM1 should be considered standard after trastuzumab failure." Dr. Gnant said. "The median progression-free survival in the trastuzumab emtansine group was nearly double that of patients in the control group, in which 80% of patients received trastuzumab, suggesting that T-DM1 is superior to trastuzumab continuation."

This study was designed and funded by Genentech. Dr. Krop reports that his institution received a grant from Genentech. His coauthors report relationships with a number of companies, as detailed in the publication. Dr. Gnant reports financial relationships with sanofi-aventis, Novartis, Roche, GlaxoSmithKline, Pfizer, Smith Medical, AstraZeneca, Accelsiors, Amgen, Eisai, and Nanostring Technologies. His coauthors report relationships with a number of companies, as detailed in the publication.

Lancet Oncol. 2014;15:668-669, 689-699. Comment, Abstract

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