Hurvitz Highlights Advances in HER2+ Breast Cancer Treatment

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.

OncLive: How have HER2-targeted therapies improved outcomes for patients with this breast cancer subtype?

In an interview with OncLive, Hurvitz discussed targeted therapy advancements, the rise of trastuzumab biosimilars, and the future of HER2-positive breast cancer treatment.Hurvitz: 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.

What does a diagnosis of HER2-positive disease mean now versus 5 years ago?

What other novel therapies or regimens on the horizon have promise?

[It is also important to talk about how] to de-escalate therapy—whether or not all patients need fully toxic chemotherapy for 6 rounds and who would require use of a full year of trastuzumab versus a shorter duration. Today, a patient who is diagnosed with HER2-positive disease can expect a DFS or lack of recurrence. That is pretty phenomenal. Ten or 15 years ago, a patient diagnosed with stage I to III HER2-positive breast cancer had the worst outcomes—pretty much on the order of what we see now with triple-negative breast cancer. These drugs have altered the natural history of this disease. There are several new exciting drugs being evaluated for HER2-positive disease. One of them is called DS-8201a and it is showing incredibly promising data in metastatic breast cancer. The data are unlike anything we have ever seen. However, they need to be confirmed and evaluated in phase III clinical trials, which are up and running right now. However, we are seeing response rates of up to 50% in patients with a median of 7 prior lines of therapy in the metastatic setting. The toxicity looks pretty promising, too.

What is the takeaway message that community oncologists should have about the state of HER2-positive breast cancer therapy?

Another drug that I'm excited about is tucatinib, which is an oral HER2-selective drug. It has central nervous system penetration and we're seeing objective responses in brain metastases in HER2-positive disease. For that reason, it's received orphan drug designation from the FDA. There are other drugs as well. It would be wonderful if we saw that ado-trastuzumab emtansine (T-DMI; Kadcyla) did just as well or better than paclitaxel and trastuzumab because this would offer women with low-risk, stage I disease to have a regimen that doesn't cause hair loss. The outlook for patients diagnosed with early-stage HER2-positive breast cancer is quite good now. Right now, we are trying to improve it by adding agents that mainly benefit our high-risk patients. I'm saving neratinib for patients with node-positive, HR-positive expression; that's where the data direct us.

What is your opinion on the impending entrance on trastuzumab biosimilars?

For pertuzumab, the data are compelling. This regimen showed a statistically significant improvement in disease-free survival. But, the benefit will primarily be seen in our patients with node-positive disease, so that's where I'll be using it. Biosimilars are an incredibly important class of drugs that will be coming out shortly. They are important because they're going to increase access to life-saving therapy around the world, where trastuzumab is not available to a lot of patients. The cost of medicine is an issue that we really have to contend with now, especially in the United States, where our drug costs are higher than any place in the world.

Biosimilars will give more access and help us deal with cost issues. Education of clinicians and pharmacists will be important because it's a new type of medication we're not totally sure of. They're not similar to generics because they're not exactly a chemical replica. These are complicated molecules. They don't need to demonstrate superiority, they just need to demonstrate similarity. It's a very different concept.

Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36 (suppl; abstr 506).