Hurvitz Evaluates De-Escalation Strategies in Early-Stage HER2+ Breast Cancer

Sara A. Hurvitz, MD

Several studies have evaluated and confirmed the benefit of de-escalating therapy for patients with early-stage HER2-positive breast cancer, but whether these therapies should replace more traditional cytotoxic regimens has yet to be determined, explained Sara A. Hurvitz, MD.

“It takes clinical judgment to determine whether to use one of these regimens or a more traditional regimen that has been evaluated in a phase III randomized trial,” said Hurvitz, an associate professor in the Department of Medicine at the University of California, Los Angeles.

Seven-year follow-up data from the APT trial, for example, suggest that patients with small HER2-positive lesions and negative lymph nodes may not require additional HER2-targeted therapy. Data from the analysis showed a 93.3% rate of disease-free survival (DFS) with the use of adjuvant paclitaxel and trastuzumab (Herceptin) for 12 weeks, followed by 39 weeks of weekly trastuzumab.

Moreover, Hurvitz noted that a short course of docetaxel and cyclophosphamide with trastuzumab is a well-tolerated regimen for lower-risk patients with HER2-positive disease.

Novel HER2-targeted therapies, such as the tyrosine kinase inhibitor (TKI) tucatinib, and more recently, the investigational antibody-drug conjugate (ADC) DS-8201a are showing potential in the paradigm.

OncLive: Can you elaborate on de-escalation strategies that are being explored in early-stage HER2-positive breast cancer?

In an interview with OncLive, Hurvitz discussed these de-escalation strategies in early-stage HER2-positive breast cancer and novel HER2-targeted therapies in development.Hurvitz: Our approach to early-stage HER2-positive breast cancer has changed in recent years. When trastuzumab was first FDA approved for the treatment of patients with HER2-positive early-stage disease, it was primarily for patients with tumors >2 cm or those with lymph node-positive disease.

Data have come out suggesting that patients with stage I tumors—small tumors that are <1 cm in size—still have a worse 5-year DFS than those with the same size tumor who are HER2 negative. For this reason, a number of studies have begun to assess and address whether or not these tumors should be treated as higher-risk tumors with HER2-targeted approaches.

One study that looked at this was the APT trial. This was Dr Sara Tolaney's single-arm phase II study that evaluated weekly paclitaxel with weekly trastuzumab. Trastuzumab was continued for 1 full year. In this study, patients were lymph node-negative and had to have tumors that were <3 centimeters in size. The DFS was above 95% at 3 years and above 90% at 7 years.

The outcome for patients is quite good with this regimen. It wasn't a comparative study, but it does give us a good regimen to use in a patient with smaller-volume disease and has a lower risk for recurrence. Also, [it is an option] for patients who might not be able to tolerate a full chemotherapy regimen like docetaxel, carboplatin, and trastuzumab (TCH) or doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH), elderly women, and those with comorbidities.

Another de-escalation strategy in lower-risk tumors involves 4 cycles of docetaxel and cyclophosphamide with trastuzumab, which is the other TCH regimen. This study was initiated based on Dr Stephen E. Jones’s docetaxel/cyclophosphamide (TC) regimen. The trial looked at patients who were lower risk with lymph node-negative tumors. The study showed an excellent DFS exceeding 98% in patients with stage I node-negative breast cancer. These 2 regimens are both appropriate to consider in a patient with very early-stage HER2-positive breast cancer.

What do these regimens look like from a tolerability standpoint?

What are the remaining questions we still have for these early-stage patients?

I might consider trying a traditional regimen in a patient with a higher-grade tumor, a lymph avascular invasion, and/or estrogen receptor (ER)-/progesterone receptor (PR)-negative tumors, even if they are stage I or IIa. One could always support using a de-escalation strategy in other situations [in which the patient is] lower risk.Patients do quite well with the weekly paclitaxel/trastuzumab regimen. It's only 12 doses, so the risk of cardiac toxicity is quite low with the omission of an anthracycline. The risk of leukemia and myelodysplasias is omitted without anthracycline-based therapy. Neuropathy rates are fairly low because we're just using 12 weeks of paclitaxel. Rates of neutropenia and febrile neutropenia are also lower. Overall, the safety profile is certainly better than a full ACTH regimen and also probably easier on patients than TCH in terms of risk of neutropenia and gastrointestinal side effects.At this point, it's really hard for us to distinguish between who requires a more traditional regimen versus a de-escalation strategy. As an example, I would recommend that a 32-year-old woman with a very high-grade 1.2-cm HER2-positive and ER/PR—negative tumor with lymph avascular invasion go with a more traditional approach that's based on phase III evidence. It is this type of patient who concerns me, in terms of relapse.

On the other hand, somebody who has hormone receptor co-expression in the tumor will probably do better [with a de-escalation strategy]—–[someone with] a lower-grade tumor, [or even] an intermediate-grade tumor with a lack of lymph avascular invasion. However, this isn't an exact science at this point.

How have novel HER2-targeted therapies impacted patients with early-stage disease?

What are some of the trials showcasing these agents?

We're looking for biomarkers from the ongoing clinical trials looking at de-escalation strategies that may help us understand who needs more a traditional cytotoxic approach and who could do quite well on something like ado-trastuzumab emtansine (T-DM1; Kadcyla) or a HER2-targeted therapy and endocrine therapy.This is a very exciting time. There are a number of agents, both monoclonal antibody—based therapies, as well as TKIs or oral therapies, that hit HER2. Several agents are very close to phase III development. I wouldn't be surprised if in the next few years, we have a few more approvals.One of the drugs that I am really excited to see how it does is tucatinib. Tucatinib is a selective HER2 TKI that shows good evidence that it penetrates the blood-brain barrier. It has orphan drug status from the FDA based on the phase I data showing activity in central nervous system (CNS) tumors that are HER2 positive. I'm very excited to see the results of the HER2CLIMB trial, which is a randomized phase II study looking at tucatinib plus trastuzumab and capecitabine versus trastuzumab and capecitabine. I'm hopeful that this is going to be not only an active drug for patients without CNS metastases, but in particular patients with progressive CNS metastases.

Another agent that is very exciting is DS-8201a. This agent, which is an ADC, is showing incredibly promising activity in early-phase clinical trials. The agent has shown objective response rates of over 60% in very heavily pretreated HER2-positive metastatic breast cancer. Interestingly, there's also activity being noted in HER2-low expressing tumors—–not HER2-amplified, but 1+ or 2+ breast cancers. This is going to be a very interesting agent to watch as we go forward.

Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) followup of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017;35(suppl 15):511. doi: 10.1200/JCO.2017.35.15_suppl.511.