Novel Small Molecule Inhibitor Shows Promise in HER2+ Breast Cancer With CNS Metastases

For insight on the potential of ONT-380 in HER2-positive breast cancer, OncLive spoke with the lead author of the primary phase Ib analysis, Erika P. Hamilton, MD.

Erika P. Hamilton, MD

The novel small-molecule HER2 inhibitor ONT-380 showed promise in previously treated HER2-positive metastatic breast cancer, including patients in with CNS metastases, according to two presentations from the 2015 ASCO Annual Meeting.

One discussion focused on an ongoing phase Ib study of ONT-380 combined with capecitabine (Xeloda) and trastuzumab (Herceptin) in patients with HER2-positive breast cancer who had previously received trastuzumab and T-DM1. Four patients have had partial responses, two have had stable disease, and two have had progressive disease. Toxicities have been minimal with a dose-limiting toxicity of reversible cerebral edema with grade 3 dysarthria and visual field deficit seen in one patient with known brain metastases. Most other toxicities have been grade 1 or 2, including nausea, vomiting, and diarrhea.

A separate presentation focusing on patients with CNS metastases included some individuals from the above study, as well as patients from a separate phase Ib trial examining combination therapy with ONT-380 and T-DM1 in HER2-positive patients. According to Oncothyreon Inc, the manufacturer of ONT-380, there was one complete response, four patients had partial responses, and nine patients had stable disease.

Based on the positive phase Ib data, Oncothyreon is planning a blinded, randomized, placebo-controlled phase II trial that will examine the triplet of ONT-380, trastuzumab, and capecitabine in patients who have progressed after both T-DM1 and pertuzumab (Perjeta).

For additional insight on the potential of ONT-380 in HER2-positive breast cancer, OncLive spoke with the lead author of the primary phase Ib analysis, Erika P. Hamilton, MD, associate director, Breast Cancer and Gynecologic Cancer Research Program, Sarah Cannon Research Institute.

OncLive: What is unique about ONT-380?

Dr Hamilton: ONT-380 is only a HER2-specific inhibitor, unlike other oral HER2 inhibitors that are commercially available like lapatinib which block both HER2 and EGFR.

With lapatinib, we sometimes see rash and diarrhea as a problem for patients. Because ONT-380 is just specific against HER2, those side effects are not a problem for patients and the drug has been very well tolerated.

How does the efficacy of ONT-380 compare to other HER2 inhibitors?

It is hard to say at this point, as ONT-380 is still very early in testing. However, it looks very good so far. ONT-380 crosses the blood-brain barrier very well. HER2-positive disease has a predilection to develop brain metastasis, which can be a huge clinical problem for patients. That may make it very effective.

However, to compare it with something like lapatinib at this point would be difficult. In our study, we combined it either with capecitabine, a very common oral therapy used for breast cancer, or trastuzumab, and we also looked at the combination of all three agents.

What have been the findings from this study thus far?

The trial is still ongoing and we are still accepting patients, both in the brain metastasis cohort and the triple combination cohort. However, looking at it overall, the capecitabine combination arms look a little bit better than the trastuzumab arms, so far.

In quarter four of this year, we are planning a phase II trial that would examine the triplet, trastuzumab with ONT-380, and capecitabine with ONT-380, versus just capecitabine and trastuzumab alone. This larger study would really give us an understanding of the efficacy and confirm what we suspect, which is that ONT-380 could really be an attractive option for patients with and without brain metastasis with HER2-positive breast cancer.

What impact could this research have?

This would be another option for these patients. Many of those patients who are HER2-driven do very well for some time. The interesting thing about HER2-positive breast cancer is how frequently it spreads to the brain. We only see brain metastasis in about 10% in all types of breast cancer, but we see it in up to 50% of HER2-positive patients. Therefore, this is a real unmet clinical need.

Why is HER2-positive breast cancer more likely to lead to brain metastasis than other breast cancers?

HER2 is a more aggressive type of breast cancer and expression of that protein has a predilection to move to that site. More importantly, we have several effective treatments for HER2-positive disease that work systemically from the neck down, but because of the blood-brain barrier the brain can often be a sanctuary for the cancer to hide and avoid treatment. That is why a lot of women do well for some time before developing a brain metastasis. Their systemic disease is doing well, but those cancer cells are hiding out in the brain.

What are some of the biggest challenges in HER2-positive breast cancer?

We have had a lot of approvals of new agents recently, which is a win. The challenge is how to sequence them and how to best use them. We have seen the approvals of T-DM1 and pertuzumab in the past couple of years and that adds to the standard medicine we had before trastuzumab. Pertuzumab is being used predominantly in the first-line metastatic setting and is also approved in the neoadjuvant setting, so before surgery and early disease. T-DM1 is also only approved right now for metastatic disease, but both of these drugs are being studied in the adjuvant setting in large clinical trials. The challenge over the next few years is really going to be where to sequence these drugs, where to place them, and how best to use them in combination.

What are some of the most exciting advances in breast cancer on the horizon?

Immunotherapy is very exciting. There has already been buzz about immunotherapy in other tumor types such as lung cancer, melanoma, and kidney cancer. Based on last year’s data from the KEYNOTE-012 [pembrolizumab] study, it looks like triple-negative breast cancer responds to immunotherapy, as well. Therefore, there is now a push to look at immunotherapy more heavily in breast cancer, since it has been so successful in other disease types, and I think that is very encouraging.