De-Escalated Approaches Continue to Show Benefit in HER2+ Breast Cancer

Deborah L. Toppmeyer, MD

The shift away from chemotherapy as a standard treatment for patients with HER2-positive breast has continued with the incorporation of de-escalated therapies into the treatment paradigm, according to Deborah L. Toppmeyer, MD.

Allowing patients to avoid potential adverse events associated with chemotherapy has been a key benefit of expanded treatment options, Toppmeyer said. She added that there are multiple ongoing clinical trials aiming to make further strides for patients with either HER2-positive or triple negative breast cancer (TNBC).

“Everything we do is really evidence based. We always like to have clinical trials available to us where we can slot our patients into. We've made incredible progress, but we can still do better,” Toppmeyer said. “Patient participation in clinical trials is critical in this effort to affect change and to make progress.”

In an interview with OncLive^®, Toppmeyer, professor of medicine at Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, discussed clinical trials involving treatments for HER2-positive and TNBC, as well as the importance of making these trials accessible to all patient populations in an attempt to address disparities.

OncLive: Could you highlight some recent clinical trials of note in this space?

Toppmeyer: One of the directions we have moved in the treatment of breast cancer is de-escalating therapy. The phase 3 TAILORx trial [NCT00310180] was a good example of that. Women with estrogen receptor [ER]-positive disease, even with 1 to 3 positive lymph nodes, don't necessarily require chemotherapy. That was an excellent example of de-escalation, saving more than 70% of women the toxicity of chemotherapy.

Similarly, we have learned over the years that a certain subclass of breast cancer, the HER2-positive population, does extremely well with our HER2-targeted therapies and chemotherapy. The question came about if clinicians can de-escalate the therapy. The phase 2 APT trial [NCT00542451] conducted at Dana-Farber Cancer Institute showed in more than 400 patients that the 7-year overall disease-free survival was outstanding.

This led to the design of the phase 2 CompassHER2-pCR trial [NCT04266249], which is now looking at higher risk disease to examine dual-targeted therapies, trastuzumab [Herceptin] and pertuzumab [Perjeta], with single-agent paclitaxel or taxane. This is a critically important trial because more chemotherapy [means] more toxicity. The ability to give less [chemotherapy] is more [treatment] in the long run. That is a very important trial that we are actively accruing to in the space of deescalation.

What are investigators exploring for patients with TNBC?

We know that is a very aggressive subtype of breast cancer. Clinicians are always looking for different [treatment] strategies. The advent of checkpoint inhibitors has changed the landscape, certainly in the neoadjuvant setting and even in the metastatic setting. The phase 2 I-SPY trial [NCT01042379], which is a multi-institutional trial, is a critically important study that allows clinicians to use an approach where we look at several different investigational agents on a backbone of taxane and now checkpoint inhibitor in the TNBC population. Based on response, we can then start the phase 3 trials to examine if this is a new weapon in the treatment of triple-negative disease.

Similarly, as part of that trial, there is a low-risk, ER-positive population that can go on a clinical trial as part of that larger trial. These are patients who typically would not benefit from the addition of chemotherapy, but it allows clinicians to look at a neoadjuvant hormonal therapy approach to this lower-risk population based on the biology of the disease, as determined by MammaPrint. The COVID-19 pandemic opened clinicians’ eyes to the notion that we don’t always have to approach treatments the same way. We can give neoadjuvant hormonal therapy because we may have to wait for surgery.

When thinking about biology of disease, it really is the trump card in forming treatment decisions. We need to tailor our treatment not to the extent of disease, but rather the biology of the disease. We have dragged our heels with ER-positive disease, thinking we should give chemotherapy, but it is important to consider different options. This trial will really help answer that question.

What are you hoping to see reported from the phase 2 I-SPY trial (NCT01042379)?

The ability to test new investigational agents in a different way, where we can rapidly determine if an agent is effective, then moving that forward very quickly if it is potentially showing the kind of activity we anticipate. The underperformers are dismissed, and then those that are very active graduate to a potential phase 3 trial.

In your practice, how do you address sequencing in patients with HER2-postive disease?

The sequencing of therapies in the HER2-positive metastatic patient population is determined by many different clinical trials that show activity. For example, the phase 3 CLEOPATRA trial [NCT00567190], which evaluated a taxane with pertuzumab and trastuzumab, showed an overall survival advantage. Typically, everything depends on a discussion, an assessment of the patient, and the extent of disease, but typically we would consider that as first-line therapy, given the data.

This is why we are incredibly grateful to our patients who do participate, because they play such an important role in shaping the future of treatment for patients with other diseases, and [for] other women like them.

How I sequence on my treatment in the metastatic setting is evidence-based, stemming from the clinical trial data. But unlike in the adjuvant or the neoadjuvant setting, the metastatic disease provides more opportunity to not necessarily follow strict guidelines. There is more of an art than direct science sometimes in the treatment of certain patients with metastatic disease.

What are some continued challenges in the HER2-positive and TNBC spaces? How will some ongoing clinical trials seek to address those needs?

It is very important that our trials reflect the general population. There is typically an over representation of Caucasians in clinical trials, and it is important that there is inclusion of minorities; particularly African Americans, Hispanics, Asians, and South Asians; who may respond differently to treatment, as the biology of their disease may be slightly different. It's important that clinicians provide access to participation in these clinical trials and education about participation in these clinical trials to the minority population, the underserved, the underinsured, or the uninsured.

That is a barrier many times [for treatment], and it's important to educate providers of what trials are available, what is appropriate for their patients, and when [to] refer for a clinical trial. Typically, we get referrals when patients have received multiple regimens and they have end-stage disease. However, for many of our trials, they're no longer eligible because [the patient] needs to be [undergoing] first- or second-line therapy for participation. The eligibilities for these trials are informing the type of patient that needs to be assessed, because the disease is different when it's highly refractory [compared with] a patient who has received only 1 or 2 lines of chemotherapy.

Our community outreach and engagement program at Rutgers Cancer Institute strives to engage minorities in participation in clinical trials. This work will help build a base so we can help, not just Caucasians with cancer, but also understand how our treatments work in other populations.

What does the future hold for this patient population?

We have made incredible progress, but we have a long way to go before we cure this disease. Clinicians can't do it without the participation of our willing patients and providers who educate our patients about participation. Every patient should be offered participation in clinical trial, if eligible.