De-Escalation Approaches Lead Shift Away From Toxic Standards in HER2+ Breast Cancer

Neil Vasan, MD, PhD

The HER2-positive breast cancer treatment paradigm continues to move away from a one-size-fits-all approach. With the emergence of novel antibody-drug conjugates (ADCs) and anti-HER2 agents, and the exploration of de-escalation approaches, this population is still able to achieve strong outcomes with less toxicity burden, according to Neil Vasan, MD, PhD.

“We have many different treatment options for [patients with] small HER2-positive breast cancers,” Vasan said. “We are at a point now where we, as a field, have designed randomized or single-arm clinical trials to demonstrate that we can safely omit certain therapies that could have [adverse] effects [AEs] and still achieve excellent outcomes for our patient population.”

In an interview with OncLive®, Vasan, oncologist and assistant professor of medicine at Herbert Irving Comprehensive Cancer Center, Columbia University, discussed the emergence of de-escalated treatment strategies for patients with HER2-positive breast cancer, pivotal trials that have shifted standards in clinical practice, and next steps for research.

OncLive®: Could you speak to the shift to exploring opportunities for de-escalated therapy in HER2-positive breast cancer?

Vasan: HER2-positive breast cancer used to be a very difficult disease to treat. Now, with advances made with anti-HER2 therapies, we have seen a large shift in curability—not just in patients with moderate amounts of disease, but even in those with small amounts of disease.

Treatments have gotten so advanced that we are now able to offer de-escalated [approaches], meaning less therapy. [These approaches have] proven to be just as efficacious as the standard [strategies used] in patients with small HER2-positive breast cancers, which are cancers that are less than 2 centimeters or cancers that are lymph-node negative. This has been wonderful for patients [in that it allows] us to tailor treatments.

What are some of the data supporting these de-escalated approaches?

Previously, a one-size-fits-all type of treatment approach [was used] for these tumors, this used to include polychemotherapy and multiple chemotherapy agents with anti-HER2 therapies. Certainly, [we also saw] the development of pertuzumab [Perjeta] in the metastatic setting, [and the agent] made its way into the curable setting, as well. Often, dual anti-HER2 therapy [was leveraged].

De-escalation trials were run several years ago, and these looked at patients with smaller tumors, T1 tumors, tumors that were 2 centimeters or less. Specifically, the phase 2 APT trial [NCT00542451] enrolled about 10% of patients with tumors larger than 2 centimeters, but most patients [had tumors that were smaller] than 2 centimeters and were lymph-node negative.

This was a single-arm, phase 2 trial, and results showed that patients who received just 1 chemotherapy agent, paclitaxel, and 1 anti-HER2 therapy, trastuzumab [Herceptin], had excellent disease-free survival [DFS] rates that persisted even at the 7-year follow-up. This is fantastic news for our patients because it means that we can give less therapy [with] fewer AEs, and patients can still have excellent outcomes and chances of cure.

In this HER2 space, we are now starting to see other drugs like ado-trastuzumab emtansine [T-DM1; Kadcyla]. This is an ADC that is approved for use in the metastatic setting; it has [also] been tested in clinical trials in the adjuvant setting. Moreover, [we also have] drugs that we can offer to patients who have residual disease after having received neoadjuvant therapy; [these patients received] chemotherapy initially to downstage the tumor and then [underwent] surgery.

Making sense of all these therapeutic options is something that we must do every day for our patients. However, [this progress] motivates us because we are always trying to tailor treatment as best as we possibly can.

Could you expand on some of the pivotal trials that have been done in this disease? Have any agents emerged in the paradigm that you are particularly excited about?

The 2 trials that [have made] the most impact [in this area] are the APT trial and the phase 3 KATHERINE trial [NCT01772472]. The latter looked at patients with residual disease after neoadjuvant chemotherapy and anti-HER2 therapy. Normally, for these patients, we would continue the same neoadjuvant anti-HER2 therapy, which [in this case], was trastuzumab and pertuzumab, for 1 year. Instead, investigators took the patients who had residual disease and gave them an ADC, T-DM1. These patients had significantly improved DFS, so that is now the standard of care.

We are in an interesting place right now because many new therapies have been approved for use in the metastatic setting, and these agents are all now being tested in the up-front setting, and in the curable setting, either [as an] adjuvant or neoadjuvant [option]. It will be interesting to see whether these drugs will make it [to the finish line].

One drug that I have my eye on is fam-trastuzumab deruxtecan-nxki [Enhertu]; this is an ADC that is superior to T-DM1 in the metastatic setting. Because it is superior to T-DM1 in this setting, the next question will be: Is it superior to T-DM1 in the neoadjuvant setting for residual disease? That is a trial that everyone in the field is looking forward to seeing.

Where should efforts be focused to move the needle forward?

Even with de-escalation [approaches], other questions remain in the field. One is whether we need 1 year of anti-HER2 therapy. The phase 3 PERSEPHONE trial [NCT00712140] showed that 6 months was not inferior to 1 year [of anti-HER2 therapy]. However, many other trials have tested other durations of less than 1 year and have not found that it is the same. As such, [our decision is made on a] case-to-case [basis, where we need to decide whether] we would invoke this trial to give less trastuzumab [to a patient].

Another trial that has been very important is the phase 3 TRAIN-2 trial [NCT01996267]. This trial looked at the question: Are anthracyclines necessary in the treatment of [patients with] HER2-positive breast cancer? [In this trial,] patients received either chemotherapy with anti-HER2 therapy with an anthracycline-containing regimen, vs an anthracycline-free regimen.

[Results showed that the] DFS rates were similar [between the arms], although there were a few caveats. For example, the anthracyclines were given every 3 weeks [on the trial]; typically, we would give them every 2 weeks. However, because no benefit [was demonstrated with] the addition of an anthracycline, this has changed the way that we treat HER2-positive breast cancers that might be a little bit larger, whether the tumor is larger or there is lymph-node involvement.

The predominant standard of care is a regimen called TCHP, which is 2 chemotherapy drugs, docetaxel and carboplatin, paired with trastuzumab and pertuzumab. Notably, [this regimen] does not contain the anthracycline doxorubicin. That trial was so practice changing that doxorubicin and cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab is not a preferred regimen per National Comprehensive Cancer Network guidelines.

That shows how this has changed the therapeutic landscape for patients [in whom] we need to give a more standard, aggressive therapy—but not too aggressive. We can spare some from the AEs [that come with] anthracyclines, such as cardiotoxicity.