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Treatment options for HER2-positive breast cancer vary by disease stage
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Jame Abraham, MD, is the director of the breast oncology program at Cleveland Clinic. Abraham spoke with Healio about current treatment options for HER2-positive breast cancer, as well as important ongoing and planned trials that may impact management of the disease.
Can you discuss the results of the Short-HER trial that was presented at ESMO in 2018 and what the results mean in regard to the role of trastuzumab in HER2-positive breast cancer?
The Short-HER trial examined whether or not patients with HER2-positive early-stage breast cancer can be treated with a short, 9-week course of trastuzumab (Herceptin, Genentech) compared with 1 year of treatment. The results showed that patients at lower risk, or those with early-stage disease, can potentially be treated with a short course of trastuzumab.
However, it is unclear if this study is going to change the standard of care because it was underpowered to determine the efficacy of 1 year of treatment versus 9 weeks. Additionally, not all the short duration trials are studying the types of regimens currently in use, including taxanes.
The standard of care for HER2-positive early-stage breast cancer will most likely continue to be 1 year of trastuzumab. We don’t have enough data to support using a shorter duration yet.
Where do other available and approved agents, such as kinase inhibitors, fit into the treatment regimen for HER2-positive breast cancer?
The treatment approach for patients with stage 1, HER2-positive breast cancer may be surgery, then 1 year of trastuzumab. Patients with HER2-positive breast cancer that is stage 2 or greater should be seen in the multidisciplinary clinic. They may receive new adjuvant chemotherapy agents before surgery and treatment with trastuzumab and pertuzumab (Perjeta, Genentech).
Based on the KATHERINE trial, if the patient has a complete pathologic response, he or she can continue with trastuzumab plus or minus pertuzumab for 1 year. If the patient does not have a complete response, he or she will receive T-DM1 (trastuzumab emtansine; Immunogen, Genentech) for 14 doses.
This is the new standard of adjuvant treatment for early-stage breast cancer in 2019.
What trials, either ongoing or planned, in HER2-positive breast cancer do you think will have interesting results?
In the early-stage standard adjuvant setting, patients who complete 1 year of trastuzumab, especially those who have ER-positive disease, can be considered for neratinib (Nerlynx, Puma Biotechnology). But we don’t have much data on patients who received T-DM1 in the adjuvant setting and continued neratinib for 1 year.
In the metastatic setting, first-line treatment still involves a taxane, trastuzumab and pertuzumab. CBT Pharmaceuticals is going to open an exciting new trial, NRG 004, soon that will look at the role of immunotherapy in first-line, HER2-positive metastatic breast cancer. It will examine a taxane plus trastuzumab plus pertuzumab plus or minus atezolizumab (Tecentriq, Genentech/Roche). Second-line treatment is going to be T-DM1. Another trial, NSABP-FB10, will examine T-DM1 plus neratinib. We’re really looking forward to the outcomes of these trials.
Another agent that is exciting is the antibody drug conjugate DS-8201 (Daiichi Sankyo). The company is looking at DS-8201 as a second- and third-line treatment. In the second line, the trial is looking at DS-8201 vs. T-DM1. The third line is examining treatment with DS-8201 versus treatment of physician’s choice in patients who progress on T-DM1. DS-8201 is an exciting drug, but we need to see how the trials are going to pan out.
The NALA study examined capecitabine plus neratinib versus capecitabine plus lapatinib in the third-line setting. We’re waiting to learn more about that potential treatment option in metastatic HER2-positive breast cancer.
We have several new drugs for HER2-positive breast cancer, including tucatinib (ONT-380, Cascadian Therapeutics), DS-8201 and neratinib.
What are the greatest unmet needs in the management of HER2-positive breast cancer?
We have made tremendous progress in prolonging DFS and OS in early HER2-positive disease and in metastatic breast cancer, but we still unfortunately lose a large number of patients with HER2-positive metastatic breast cancer.
The most frustrating unmet need is brain metastases. About 25% of patients with HER2-positive disease develop brain metastases. There are several clinical trials that are looking at brain metastases as a primary endpoint. One potentially exciting drug is tucatinib (ONT-380, Cascadian Therapeutics), which is a tyrosine kinase inhibitor. Tucatinib has increased central nervous system penetration and may potentially increase CNS activity. Neratinib has also demonstrated increased CNS penetration and CNS response in clinical trials.
We need to continue to work on finding new and effective agents that can treat brain metastases. It is going to be an ongoing challenge.
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