Unique HER2 Trial Uses New Targeted Drug Therapy

New combination of two effective drugs being tested

In a first-of-its-kind clinical trial led by Cleveland Clinic researchers, women with HER2-positive metastatic breast cancer will receive a treatment regimen of two powerful targeted drugs, one investigational and highly promising, designed to shrink tumors and stabilize the often fatal disease.

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The national trial, “A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) with Neratinib in Women with Metastatic HER2-Positive Breast Cancer,” is sponsored by the NSABP Foundation.

The trial is open to accrual and several patients have been enrolled. The sample size for this Phase Ib/II trial will include about 50 patients.

Lead researcher Jame Abraham, MD, director of the breast oncology program at Cleveland Clinic, says the trial will test the feasibility of a very specific dose-levels that utilize (T-DM1) and Neratinib, agents which have different mechanisms of actions and different toxicity profiles. As monotherapy, both agents have been shown to overcome common resistance in HER2-positive breast cancer patients to trastuzumab alone.

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“These are probably the most exciting drugs to date in targeted therapy and we want to test the mutual effect,” Dr. Abraham says. Based on the proven effectiveness of the drugs when used separately, he expects that combining the two will yield even better results. “We’re hoping this can translate into a virtually non-chemotherapeutic approach, a targeted treatment with fewer side effects and less toxicity.”

“Since this is long-term therapy (in stage four breast cancer), it’s almost like treating a chronic disease. So the goal is to develop an optimum long-term treatment (protocol), but at the same time make sure the side effects are minimal.”

The Phase Ib will focus on the safety and tolerability of the combined drug regimen, as doses are increased, while Phase II will determine the overall response rate in the patients with measurable disease.

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The investigational breast cancer drug, Neratinib, has been shown in a Phase III trial by its developer, Puma Biotechnology, Inc, to have a statistically significant benefit in women with early stage HER2-positive breast cancer when used as an adjuvant treatment after the use of trastuzumab.

New research also shows that T-DM1 promotes tumor cell death and early results on overall patient survival have been promising. It has also been shown to work even in heavily pretreated HER2-positive breast cancer patients and has been labeled as the “preferred” treatment by some leading researchers for progressive HER2 breast cancer.

The response rate to both drugs in patients has been from about 32 percent to 60 percent, Dr. Abraham says, “so it makes sense to combine these two highly effective treatments. We’re hoping their combination will result in a much higher response rate.”