Novel Approaches Push the Envelope in HER2+ Breast Cancer

Douglas K. Marks, MD

Developments in antibody-drug conjugates (ADCs), TKIs, and neoadjuvant interventions are improving outcomes for patients with early- and advanced-stage HER2-positive breast cancer, said Douglas K. Marks, MD, adding that investigational approaches could expand the treatment armamentarium even further.

“For the treating oncologists, the options to offer patients who previously had a very poor prognosis are becoming better and better,” said Marks, a medical oncologist at NYU Winthrop Hospital. “We will have to be cognizant that as we work with all of these new therapies, we pay attention to the sequence in which they are offered. Patients with HER2-positive metastatic breast cancer can live for many, many years.”

In an interview during the 2019 Onclive^® State of the Science Summit™ on Breast Cancer, Marks, who is also a clinical instructor in the Department of Medicine at NYU Langone Health, discussed key developments in the HER2-positive breast cancer space and shed light on novel approaches under investigation.

OncLive: There has been a lot of excitement regarding ADCs in this space. Could you speak to some of the key updates with these agents?

Marks: Ado-trastuzumab emtansine (T-DM1; Kadcyla), the prototype ADC, is approved for use in HER2-positive breast cancer. T-DM1 has provided incredible clinical benefit to our patients and is now being followed by several ADCs that all look very promising. These agents differ slightly in terms of the chemotherapy agent that they are partnered with as well as the drug-to-antibody ratio. Several frontline contenders are now in phase III trials.

One of them is a compound made by Daiichi Sankyo, which is trastuzumab (Herceptin) with a HER2-targeted antibody with a novel irinotecan-based payload. This drug has a very high drug-to-antibody ratio, of, I believe, 8:1. It is interesting because this drug appears to have activity not only in HER2-positive breast cancer, but also in HER2-expressing but not amplified breast cancer, such as HER2-low breast cancers. The drug has an interesting toxicity profile in that it does have some chemotherapy-related adverse events but to a much lesser degree than would be expected if it was not a targeted chemotherapy drug. These events include neutropenia and other cytopenias, as well as nausea. However, generally, the drug appears to be well tolerated. The DESTINY trials are currently looking at this drug in the phase III setting.

Another ADC that I highlighted was [vic-]trastuzumab duocarmazine (SYD985), which is a similar compound with a HER2-directed antibody and another payload. This drug also looks promising and is being investigated in the TULIP trials.

Moving on from ADCs, what research is being done with TKIs?

TKIs have taken the backseat to HER2-directed antibody therapies over the past few years, partly due to the fact that lapatinib (Tykerb) and neratinib (Nerlynx) were inferior to the other agents that came about at the same time, such as pertuzumab (Perjeta) and T-DM1. However, TKIs are now gaining attention again with multiple agents demonstrating central nervous system (CNS) activity.

For example, a drug called pyrotinib was recently profiled at the 2019 ASCO Annual Meeting. [Pyrotinib] is a drug that still needs to be better understood in terms of where it will fall into the landscape of treatment; however, it has demonstrated strong CNS penetrance and looks promising. The other TKI that also looks promising is tucatinib and that’s being investigated in the ongoing HER2CLIMB trial.

Could you expand on the data seen with pyrotinib?

The PHENIX trial was presented at the 2019 ASCO Annual Meeting, and data from a small subset of about 20 of 270 patients enrolled on the trial were published. In this study, investigators looked at pyrotinib in combination with capecitabine (Xeloda) versus capecitabine alone. There was a significant improvement in progression-free survival as well as response rate with pyrotinib. The only caveat is that this is not exactly the type of study we would currently design. These patients had to have progressed on trastuzumab [and taxanes]. The comparator-arm did not include a HER2-directed therapy; it explored capecitabine alone, which is atypical. However, the data are still compelling—especially in patients with brain metastases, where they found this drug to be significant effective when used [in combination with] capecitabine.

What work is being done in the adjuvant setting?

The data for pertuzumab (Perjeta) in the adjuvant setting from the APHINITY trial were not quite as exciting as some of us would have hoped. It appears that there is a small benefit associated with completing 1 year of pertuzumab in the adjuvant setting; this is mostly seen in patients with node-positive disease and hormone receptor (HR)—negative, HER2-positive breast cancer. Certainly, that is currently what is offered by most oncologists in the United States.

Neratinib (Nerlynx) is very interesting; there is a benefit for offering this drug in the highest-risk patients in the adjuvant setting. The issue is that the patients on ExteNET, the trial which gained neratinib's approval in the adjuvant setting, did not receive this common sequence that we would currently treat patients with; they did not receive pertuzumab. Now [that we have data from] KATHERINE, which looked at a modified adjuvant regimen for patients that are treated with neoadjuvant therapy and have residual carcinoma. None of these patients will have also been treated with that approach.

As such, it is hard to extrapolate the role for neratinib in the setting of pertuzumab and T-DM1. However, I would say it is still [an option] I would consider, particularly for patients with HR—positive HER2-positive breast cancer who had a very high burden of nodal disease or are very high-risk otherwise.

Could you expand on the data seen in the KATHERINE trial?

The KATHERINE trial was the most interesting data that came out of the 2018 San Antonio Breast Cancer Symposium. [KATHERINE explored] this idea of adapted change of therapy based on treatment response. For HER2-positive breast cancer tumors that are >2 cm, most will elect to at least consider neoadjuvant therapy. The KATHERINE trial makes a strong case for doing that now, particularly with the demonstrated disease-free survival [benefit]. This is selecting a highest-risk population who have residual carcinoma and modifying their therapy. This will become a new standard of care for the treatment of patients with HER2-positive breast cancer who are believed to need neoadjuvant therapy, which is the majority of patients.

What would you say are the key challenges that still need to be addressed in this space with future research?

One major challenge will be adequately treating patients with brain metastases. While there has been some activity seen with T-DM1, monoclonal antibodies are limited in CNS penetrance. My hope is that TKIs will fill that space. As patients live longer with HER2-positive breast cancer, there will be more patients with brain metastases; they will need superior treatments. [We need to offer] these patients who would otherwise just receive surgery, radiation, and subpar therapeutic systemic therapy active agents for the CNS.

What is your take-home message to your colleagues treating these patients?

HER2-positive breast cancer has completely changed with the advent of HER2-directed therapy. That is something we have already known, but it is still an extremely exciting area in that we are pushing the boundaries of what patients can be offered. I believe that with these multiple promising ADCs for patients with progressive disease through T-DM1 and heavily pretreated patients, as well as these TKIs [that have emerged], the space will continue to be highly [promising] for patients, and they will continue to be offered better therapies [as time goes on].