Sara A. Hurvitz, MD
Historically, a diagnosis of HER2-positive breast cancer left a patient with a grim outlook, but therapeutic advances over the past 10 to 15 years have dramatically altered the landscape, explained Sara A. Hurvitz, MD.
These breakthroughs, including 2 recent FDA approvals in the adjuvant setting—single-agent neratinib (Nerlynx) and pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy—have “literally altered the natural history of this disease,” she said.
Neratinib was approved in July 2017 for the extended adjuvant therapy of patients with early- stage, HER2-positive breast cancer following adjuvant trastuzumab. In October 2017, pertuzumab was approved for use in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive disease and a high risk of recurrence.
The combination of tucatinib (ONT-380), an oral HER2-selective tyrosine kinase inhibitor, with capecitabine and trastuzumab has shown objective responses in patients with HER2-positive breast cancer who have brain metastases. This regimen was granted an orphan drug designation in June 2017.
Research is also ongoing in de-escalation strategies. Phase III findings from the PERSEPHONE trial indicated that a shorter 6-month adjuvant course of trastuzumab as noninferior with disease-free survival (DFS) compared with the standard 1-year schedule for patients with HER2-positive early breast cancer. After 5 years of follow-up, median DFS was 89.8% with 12 months of trastuzumab versus 89.4% under the 6-month regimen.
“As long as a patient receives HER2-targeted therapy, in any stage, they can expect an outcome that's as good or better than a patient with HER2-negative disease,” said Hurvitz, the director of the Breast Oncology Program and medical director of the Clinical Research Unit, University of California, Los Angeles Jonsson Comprehensive Cancer Center. Improvements can still be made for patients with a high-risk of recurrence, she added.
In an interview with OncLive
, Hurvitz discussed targeted therapy advancements, the rise of trastuzumab biosimilars, and the future of HER2-positive breast cancer treatment.
OncLive: How have HER2-targeted therapies improved outcomes for patients with this breast cancer subtype?
: It has literally altered the natural history of this disease; without HER2-targeted therapies, it has among the worst prognoses. There are new therapies that have been FDA approved over the last 1.5 years or so. Neratinib is approved for 1 year after completing trastuzumab and chemotherapy. Pertuzumab is approved for 1 year given concurrently with trastuzumab. Figuring out who to use these agents for is a bit tricky.
Neratinib is associated with significant gastrointestinal (GI) toxicity; it causes a lot of diarrhea. Therefore, patients need to be premedicated with antidiarrheals and carefully educated on how to get in touch with the doctor. This toxicity needs to be taken into consideration. I wouldn't give neratinib to a patient who had preexisting GI issues or a patient with really low-risk disease who is unlikely to derive benefit from it.
Similarly, pertuzumab adds a little bit of toxicity. It causes an increase in diarrhea and possibly an increase in the rates of febrile neutropenia. Again, patients must be watched closely and advised about these side effects. In terms of the risk reduction we see by adding neratinib to patients, we see that patients expect their risk of recurrence will improve on the order of 20% or more, maybe even higher. Patients who have hormone receptor (HR)–positive, HER2-positive disease tend to derive even more benefit.
The use of neratinib in patients who received pertuzumab in the neoadjuvant or adjuvant setting has not been studied, so we don't know what kind of benefit can be expected in this setting. Pertuzumab tends to benefit patients who have node-positive disease. It's a bit of a tricky situation.