Blackwell Discusses Emerging HER2-Positive Breast Cancer Agents

Kimberly L. Blackwell, MD

Emerging therapies are advancing through the pipeline in HER2-positive breast cancer, potentially giving oncologists options beyond some of the current treatments, such as pertuzumab (Perjeta), trastuzumab (Herceptin), and ado-trastuzumab emtansine (T-DM1; Kadcyla).

Excitement is building from a phase I study that looked at margetuximab (MGAH22-01), a HER2-targeting monoclonal antibody engineered for increased Fc-domain binding. The agent demonstrated significant response rates among patients with heavily pretreated breast cancers, including four patients with confirmed partial responses still ongoing at the time of the analysis and lasting from >10 weeks to >100 weeks.¹

In a recent phase III study, the tyrosine kinase inhibitor neratinib administered to patients immediately following adjuvant trastuzumab plus chemotherapy improved invasive disease-free survival (DFS) against placebo at the cost of low-grade diarrhea in nearly all patients with HER2-positive early-stage breast cancer. The 2-year invasive DFS rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (HR, 0.67; 95% CI, 0.50-0.91; P = .009).²

Additionally, researchers are also hopeful with the small-molecular HER2 inhibitor ONT-380, shown to have promise in previously treated metastatic patients with CNS metastases.

Moreover, long-term follow-up results from the phase III CLEOPATRA trial, which examined the safety and efficacy of pertuzumab, trastuzumab, and chemotherapy in patients with previously untreated HER2-positive metastatic breast cancer, showed a 16-month survival benefit³ compared to those who received trastuzumab and chemotherapy alone, demonstrating the efficacy with pertuzumab and validating it as a standard of care, explains Kimberly L. Blackwell, MD.

OncLive: What are the some of the up-and-coming, novel therapies for HER2-positive breast cancer?

Can you go into greater detail about margetuximab and its potential?

In an interview with OncLive, Blackwell, professor of Medicine, assistant professor of Radiation Oncology, Duke Cancer Institute, discusses the potential for these emerging therapies, as well as the benefits of current treatments for patients with HER2-positive breast cancer.Blackwell: There is a new way in how we target HER2, including new antibodies, margetuximab, which is a high-affinity HER2-antibody that we think stimulates the immune system even better than trastuzumab does. There is updated pertuzumab data, as well as data showing promise with small-molecule inhibitors. There has been a lot of talk about the ExteNET study looking at adjuvant neratinib. Also, there is ONT-380, which is another small-molecule inhibitor in development. Bringing it all home, there is talk about antibody-drug conjugates, including T-DM1, and another compound, which has encapsulated doxorubicin.It is actually a very cool antibody. The constant domain of the antibody which, if you think of the fork of the antibody and then the tail, the constant domain has been changed by approximately 5 amino acids. It stimulates natural killer cells and tumor-associated macrophages more, and inhibits the inhibitory immune cells less. Therefore, the net effect is more stimulation of the anticancer immune effector cells, and less inhibition of the immune inhibitory cells. Hypothetically, it should offer a more vigorous immune response against HER2.

What can you share regarding updated data on pertuzumab in HER2-positive disease?

We just received the phase I/II data at the 2015 ASCO Annual Meeting, but that is moving into a fairly interesting go/no-go clinical trial that is currently available. The way that the trial is being designed is that it is not actually for classically defined HER2-positive breast cancer. It is actually for what we call equivocal or borderline HER2. These are tumors that are HER2+ positive and are not amplified. There is this idea that if you have a higher affinity antibody against HER2 that stimulates the immune system, margetuximab might benefit those patients who have some HER2 overexpression, but are not necessarily eligible in any classic way for trastuzumab.To give a presentation in 2015 without presenting the 16-month survival benefit from pertuzumab, I would be leaving out a major advancement in the field.

I think most of us are at a point where adding pertuzumab in first-line metastatic breast cancer is now a, if not the, standard of care. It is pretty exciting to see that we are helping women live longer with the addition of a monoclonal antibody.

A recent article published in the Journal of Clinical Oncology concluded that pertuzumab was found to not be a cost-effective drug. Do you agree or disagree with the authors’ findings?

Results from the ExteNET study recently showed that neratinib reduces HER2-positive breast cancer recurrences. What role do you envision neratinib having in the treatment of this disease?

I am not a cost-effective expert, so I will leave that to the experts. For me, I am a practicing clinician, as well as a clinical trialist, and my approach is that of, “What can I do to help the patient sitting in front of me?” I think, at this point, the cost-effectiveness is probably going to need to be dealt with on a more global, industrial, political, and societal level. For me, in my day-to-day practice, I will still be offering it to the patients who are facing metastatic breast cancer.This confirmatory data with this centrally confirmed HER2 testing suggests that we are really just starting to understand the implications of the ExteNET study. What we saw presented at the 2015 ASCO Breast Cancer Symposium was findings from about 60% of the patients who were enrolled in this study. I anxiously wait to see the full data set with centrally confirmed HER2 testing.

What steps need to still be taken regarding ONT-380 for HER2-positive breast cancer and its role in CNS metastases?

Even with the subset, two-thirds of the patients, we still see the benefit for adding neratinib after a year of trastuzumab. We will see. We have the 2-year results, and the study has been amended so that we can see the 5-year disease-free survival and overall survival, and I think we will just have to let the data mature a little bit before we can make definitive conclusions about how to apply it to our day-to-day practice.Data presented at the Breast Cancer Symposium suggests that, in patients who were very heavily pretreated, the small-molecule inhibitor might have CNS activity, which is very much supported by the preclinical models of the drug. That drug is moving forward, looking at both progressive and untreated brain metastases.

What can community oncologists take away from these recent data on the therapies you mentioned?

The other thing that is interesting about the drug is it is going to be fairly easy to develop. It is a pure HER2 inhibitor. It has no HER1 activity and no HER4 activity so, in many ways, it will be developed almost like a monoclonal antibody, and we will not see the diarrhea or skin toxicities that we see with the pan-HER inhibitors. It will be interesting to see what this drug does. If it continues to show activity in CNS metastases, it will certainly have a use in clinical practice.There is life beyond pertuzumab, trastuzumab, and T-DM1. There are also vaccines in the early-stage settings. There is a clinical trial accruing of a peptide vaccine for HER2-positive breast cancer, so I am hoping this will encourage clinicians for patients who have done well but need new treatment options for their HER2-positive breast cancer. There are trials out there that are worth either referring their patients to or looking into.

References

1. Burris HA, Giaccone G, Im SA, et al. Updated findings of a first-in-human, phase I study of margetuximab (M), an FC-optimized chimeric monoclonal antibody (Mab) in patients (pts) with HER2-positiveadvanced solid tumors. J Clin Oncol. 2015;33(suppl; abstr 523).
2. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). J Clin Oncol. 2015;33 (suppl; abstr 508).
3. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-734.