Hurvitz Highlights Emerging Agents for Heavily Pretreated HER2+ Breast Cancer

Sara A. Hurvitz, MD

While there are well-established standard therapies for first- and second-line settings in patients with HER2-positive metastatic breast cancer, Sara A. Hurvitz, MD, said that a number of novel agents and combinations are poised to shape later lines of treatment.

“The number of therapies in development right now is quite phenomenal, but it is a brave company to take these emerging therapies on head-to-head in the frontline setting or second-line setting and challenge the current standards,” said Hurvitz, director of the Breast Oncology Program and medical director of the Clinical Research Unit at the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

For example, the selective oral TKI tucatinib is being combined with trastuzumab (Herceptin) and capecitabine in the hopes of tackling the challenge of central nervous system (CNS) metastases. In an open-label, nonrandomized phase Ib study, 61% of patients with measurable disease treated with this 3-drug combination had an objective response. In an exploratory analysis, a brain-specific response was observed in 5 of 12 patients (42%) with CNS metastases who were treated with the recommended phase II dose of 300 mg twice daily of tucatinib.

Other agents, such as margetuximab, trastuzumab deruxtecan (DS-8201), neratinib (Nerlynx), and checkpoint inhibitors have also shown promise in early studies and are being evaluated in larger phase II/III trials.

OncLive: What is the current treatment landscape for patients with HER2-positive metastatic breast cancer?

In an interview with OncLive, Hurvitz discussed recent updates in the paradigm and promising therapeutic strategies on the horizon for patients with HER2-positive metastatic breast cancer.Hurvitz: It's a really exciting time to be treating patients with HER2-positive metastatic breast cancer because of the many therapeutic options we now have available. The standard of care is to treat patients in the frontline setting with trastuzumab, pertuzumab (Perjeta), and a taxane. The taxane is given for 4 to 6 cycles, and then the patients go on to maintenance trastuzumab and pertuzumab. That is the gold standard based on findings from the CLEOPATRA study, which showed a significant improvement in overall survival (OS) with that triplet strategy. The second gold standard is second-line ado-trastuzumab emtansine (T-DM1; Kadcyla), which is an antibody-drug conjugate (ADC) that targets HER2. This is the gold standard based on data from the EMILIA study.

What are some of these agents that are on the horizon?

Therefore, there aren't a whole lot of questions about what you should treat your newly diagnosed patients with or what you should use as second-line therapy. After that, we have multiple different therapeutic options we can utilize, including lapatinib-based therapy, trastuzumab plus chemotherapy, or trastuzumab plus lapatinib. While we have several treatment options available including lapatinib, trastuzumab, pertuzumab, and T-DM1, there are myriad therapies in clinical trials right now.There are a number of agents that are really exciting right now. One of them is neratinib, which is already FDA approved in the adjuvant setting, after completion of 1 year of adjuvant trastuzumab. Neratinib is being combined with capecitabine and being compared with lapatinib (Tykerb) plus capecitabine in the phase III NALA study. There was a press release indicating that NALA met its primary endpoint; neratinib plus capecitabine did demonstrate superior progression-free survival (PFS). Those results are going to be presented at an upcoming meeting, and we are all eagerly anticipating them.

Another drug that has been given a lot of press and excitement recently is another oral TKI called tucatinib. This is a selective HER2 inhibitor, and because it is selective, it may [be associated with] less gastrointestinal (GI) toxicity. In phase I studies, tucatinib showed very good response rates combined with trastuzumab, capecitabine, or both.

The ongoing phase II randomized HER2CLIMB trial is comparing tucatinib plus trastuzumab/capecitabine to placebo plus trastuzumab/capecitabine. The interesting aspect of this study is that they are allowing patients to enroll who have actively progressing CNS metastases. Most studies exclude these patients. This drug does penetrate the blood-brain barrier, and objective responses in the CNS have been noted in the phase I study. That is particularly exciting for our patients given that one-third to one-half of patients with HER2-positive metastatic breast cancer will develop brain metastases during the course of their disease.

Another drug that garnered a lot of attention is DS-8201, which is an ADC that is fairly novel because the cytotoxic payload is a different form of chemotherapy. It is along the lines of irinotecan. The antibody to drug ratio is quite high with this drug, and the overall response rate seen in a very heavily pretreated patient population was in excess of 50%. Moreover, this drug does show some activity in HER2-low expressing breast cancers, such as 1+ and 2+. There are phase III trials ongoing in both of those areas, and DS-8201 is actually going head-to-head with T-DM1 in a study that recently started. These data are incredibly exciting and we will have to watch closely.

Have we reached a point where we are comfortable with the toxicity profile of neratinib?

Finally—although there are many other agents—is margetuximab. This is a HER2-targeted antibody that is engineered to enhance the immune response to tumor cells. It enhances the FC binding to the FC receptors, which may allow the antibody-dependent cellular cytotoxicity to occur more readily. This was studied in a phase III trial called SOPHIA, in which margetuximab was combined with chemotherapy compared with trastuzumab plus chemotherapy. A press release has indicated that their primary endpoint was met, so we expect to see these data presented in the short term.The diarrhea that we see with neratinib is certainly a concern. In the ExteNET study—the adjuvant trial where patients were healthier in general—there was about a 40% rate of grade 3 diarrhea. Grade 3 diarrhea is relatively crippling; just to keep in mind, this is about 7 bowel movements over 1 on any given day. Incontinence, intravenous fluid hydration, and hospitalization should be considered.

This is difficult diarrhea. Having said that, clinicians are pretty good at controlling diarrhea. We have a lot of experience as oncologists in dealing with GI toxicity. As long as patients are educated, and we use upfront loperamide for all patients when they initiate therapy with very close clinical follow-up, we can manage it.

Are any of these emerging agents creating sequencing challenges, and do they have the potential to move upfront?

A study that we participated in called CONTROL was aimed just at looking at how we can control diarrhea associated with neratinib. In this study, we utilized combinations of loperamide and budesonide or colestipol. The grade 3 diarrhea rates came down to about 10% based on the most recent data. Therefore, we are getting better at this, but a lot of attention is warranted.We need to keep in mind that in the frontline setting with trastuzumab, pertuzumab, and taxane, the OS achieved is greater than 56 months. That is over 5 years—quite a big threshold to beat—and the PFS is 18 months. Again, to show a substantial improvement in those numbers is going to take a pretty remarkable agent.

Were there additional data in the HER2-positive space from the 2018 San Antonio Breast Cancer Symposium that you found intriguing?

Similarly, when you are looking at T-DM1 in the second-line setting, the results are quite good in terms of OS and PFS when compared with lapatinib plus capecitabine. It is going to take a very active agent to beat those 2 standards. With that being said, there are drugs such as DS-8201 that are up to the challenge based on their early data. There are trials opening up that are comparing these agents with one another, so we may have a new standard in 4 or 5 years.There were a couple of posters of interest that were discussed in HER2-positive disease. One is a study evaluating palbociclib (Ibrance) in combination with trastuzumab in HER2-positive breast cancer. This was a phase I study, and the way the study was designed was allowing patients [to enroll] with both hormone receptor (HR)¬—positive, HER2-positive disease and be treated with combined palbociclib and trastuzumab with letrozole. [Patients with] HR-negative disease were also enrolled, and they were just treated with palbociclib and trastuzumab. There are good preclinical data [indicating] that CDK4/6 inhibitors should have activity in HER2-positive disease [that is HR-negative]—not just in HR-positive, HER2-positive breast cancer.

This study met the threshold for evaluation in a phase II trial for HR-positive, HER2-positive disease. It barely didn't pass the threshold for HR-negative patients. Out of 15 patients who had received the palbociclib plus trastuzumab for HR-negative, HER2-positive breast cancer, 5 patients were progression free at 6 months. They required 6 out of 15 patients in order to pass into phase II studies.

Unfortunately, that combination is not going to be looked at further in that clinical trial, although there was activity in heavily pretreated patients. We need to continue looking at CDK4/6 inhibitors in HR-negative, HER2-positive disease. However, they did meet the threshold to pass for patients with HR-positive, HER2-positive breast cancer. That phase II trial is ongoing.

What are your thoughts on the recent FDA approval of subcutaneous trastuzumab for HER2-positive breast cancer?

Another area of interest is combining immuno-oncology with HER2-targeted therapy. There is a fair amount of data that HER2-positive breast cancer does on occasion have immune infiltrates—suggesting that the immune response might be able to be augmented to improve outcomes for patients. In the KATE2 study, atezolizumab (Tecentriq) was combined with trastuzumab. In that study, especially in the patients who had tumor PD-L1 expression, there was promising activity.The approval of subcutaneous trastuzumab is great for patients. It will minimize their time in the infusion room. This is especially important in terms of quality of life for patients dealing with metastatic breast cancer, where the visits to the doctor can be become quite overwhelming and time consuming.

Also, patients need lifelong therapy. However, [this approval] does not address patients getting pertuzumab combined with trastuzumab because they have to be in the clinic for pertuzumab infusion. However, it does help for the many patients who are using trastuzumab combined with oral endocrine therapy, oral chemotherapy, or single-agent maintenance trastuzumab.

Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(7):880-888. doi: 10.1016/S1470-2045(18)30256-0.