Promising New Combination Therapy for Advanced, HER2+ Breast Cancer Shown Safe and Effective

Neratinib and trastuzumab emtansine (T-DM1) combination potent and well tolerated

Women with advanced HER2-positive breast cancer have several treatment options, but a large number of patients still die from this aggressive form of breast cancer.

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A combination therapy of two promising drugs, however, offers hope of stopping disease progression in some, while slowing it for others.

Preliminary results of NSABP FB-10, the dose-escalation trial of neratinib with trastuzumab emtansine (T-DM1) combination therapy, show response from more than half of women with advanced, HER2-positive breast cancer that has developed resistance to trastuzumab and pertuzumab. Some experienced complete response for nearly a year and a half.

“Our hope is this combination will provide another highly active regimen for women with metastatic, HER2-positive breast cancer that could increase the chances of response and extend survival,” says Jame Abraham, MD, Director of the Breast Oncology Program at Cleveland Clinic’s Taussig Cancer Institute. Alberto Montero, MD, staff in the Department of Solid Tumor Oncology, was a coauthor. Dr. Abraham presented the findings at the 2017 American Association for Cancer Research meeting in Washington, D.C.

A total of 22 patients were enrolled in this phase 1B dose-escalation trial. For the 16 patients who were evaluable for efficacy, the objective response rate was 56 percent. Efficacy results showed that three patients had a complete response, which lasted 17.1 months, 11.9 months and 12 months; six patients had a partial response; three patients had stable disease; and four patients had progressive disease.

New drugs, new hope

Both drugs have differing mechanisms of action that appear to have synergistic effects in cases of advanced HER2-positive breast cancer.

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T-DM1 is a conjugated antibody that targets the extracellular domain of HER2. With T-DM1, trastuzumab is armed to deliver the potent cytotoxic payload of DM1, a maytansinoid antimicrotubule agent, selectively to antigen-expressing HER2-positive cells.

Neratinib, on the other hand, targets tumors from within the cell. It is an irreversible tyrosine kinase inhibitor (TKI) that interrupts signaling across the ErbB family by inhibiting phosphorylation and activity of HER2, in addition to epidermal growth factor, HER1 and HER4.

Potent and well-tolerated

Major side effects of the combination included diarrhea, which Abraham and his collaborators intend to treat prophylactically during a now-ongoing phase 2 trial, and nausea.

“Side effects from this therapy appear to be manageable with antidiarrheal and antinausea medications, which is something we consider promising for the future of this regimen,” says Dr. Abraham.

Patients in the study all had metastatic HER2-positive breast cancer with prior trastuzumab and pertuzumab treatment. None of the participants had previous therapy with T-DM1 or any HER2 tyrosine-kinase inhibitors, persistent grade 3 or higher diarrhea, symptomatic brain metastases, active hepatitis or other conditions significantly affecting gastrointestinal function.

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Abraham and collaborators will soon move into a phase 2 trial of an estimated 63 women to demonstrate efficacy. Participating sites include Cleveland Clinic, University of Oklahoma Health Services Center, Magee Women’s Hospital of UPMC, Women & Infants Hospital of Rhode Island and West Virginia University. All sites are currently enrolling patients.

Photo Credit: ©Russell Lee