Blackwell Hopeful New Agents Will Advance HER2+ Breast Cancer Care

Kimberly L. Blackwell, MD

Although the first- and second-line settings for patients with HER2-positive breast cancer are fairly standardized with pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla) regimens, respectively, ongoing research continues to refine third-line care and beyond, according to Kimberly Blackwell, MD.

The phase III NALA study, for example, is exploring the small molecule inhibitor neratinib in combination with capecitabine compared with capecitabine plus lapatinib (Tykerb) in patients with HER2-positive metastatic breast cancer who have received 2 or more prior HER2-directed regimens (NCT01808573).

The safety and tolerability of another small molecule inhibitor, ONT-380, plus capecitabine, trastuzumab (Herceptin), or both, is being investigated in an ongoing phase Ib study (NCT02025192) in patients with HER2+ metastatic breast cancer who have previously received trastuzumab and T-DM1 (for those eligible).

In an interview during the 2016 OncLive State of the Science Summit on Metastatic Breast Cancer, Kimberly L. Blackwell, MD, a medical oncologist at Duke Cancer Institute, discussed the latest therapeutic developments for patients with HER2-positive breast cancer while providing insight on the hurdles that still remain.

OncLive: What HER2-positive breast cancer advancements did you highlight during this meeting?

Blackwell: In the area of HER2-positive breast cancer, it’s not only exciting but we have a lot of data that help drive decisions for helping our patients facing HER2-positive disease. I reviewed the state of the science in the treatment of patients with HER2-positive breast cancer. We have data now incorporating 3 novel HER2-targeted agents, including pertuzumab, T-DM1, and lapatinib. In each of these, we now have data that drives the orderly fashion: pertuzumab in first-line, T-DM1 in second-line, and small molecular inhibitors—lapatinib being one of them— in combination with capecitabine in third-line.

I also stressed the importance of continuing HER2-targeted agents—to not ever let your foot off of the brake when it comes to treating HER2-positive breast cancer.

Finally, I covered topics about exciting drugs in this area, and they include the novel small molecule inhibitors neratinib and a drug known as ONT-380, which is a pure HER2 small molecule inhibitor. We talked about HER2-directed liposomal chemotherapies, so there are a number of those being studied in clinical trials.

What I am particularly excited about is these super-charged versions of trastuzumab. These are antibodies that not only bind to HER2, but also really rev up the immune system. Those are all promising approaches to the treatment of HER2-positive breast cancer.

The FDA recently accepted a new drug application for neratinib. What potential could that agent have if it is approved?

We are all kind of awaiting the data that we don’t yet have on the use of neratinib in the metastatic arena. The strongest data for the activity of neratinib is in the early-stage setting, which is utilizing it after patients have finished 1 year of adjuvant trastuzumab.

With 5 years of follow-up, data show that it offers a significant improvement in invasive disease-free survival. This is if women complete 1 year of trastuzumab—and they are without evidence of disease—they then take 1 year of the small molecule pill known as neratinib. If it gets approved, the reality is that it will become a new standard of care. Women who are facing early-stage, HER2-positive breast cancer will complete 1 year of trastuzumab and then go on to receive 1 year of neratinib, once the regulatory approvals are made available.

The other data that we are awaiting in this space is the study known as APHINITY, and that is a study looking at adding pertuzumab in the first year on top of trastuzumab. The results of APHINITY and the results of the neratinib study—known as ExteNET—are independent results. If APHINITY is a positive study, I will still be offering patients neratinib after that 1 year of trastuzumab. What do we call that—the year 2, HER2 blockade? We are all very excited about it. The data now, with 5 years of follow-up, really looks like adding a year of neratinib after 1 year of trastuzumab helps prevent disease recurrence. When it becomes available, I will feel obligated to discuss it with my patients.

In your presentation, you discussed the CLEOPATRA and MARIANNE studies. What remains so impactful about these trials?

CLEOPATRA was important because adding pertuzumab really impacted overall survival. However, it didn’t make a significant contribution in terms of toxicity, which we worry about in an incurable metastatic setting.

MARIANNE was an interesting study because it looked at taxane/trastuzumab versus T-DM1 or T-DM1 plus pertuzumab. What it showed was that T-DM1 plus pertuzumab is no better than T-DM1 alone. Additionally, T-DM1 alone has similar efficacy in terms of progression-free survival to taxane/trastuzumab.

I don’t think MARIANNE takes away from the CLEOPATRA results. Adding pertuzumab on top of the taxane/trastuzumab backbone significantly improves survival. It is unfortunate that MARIANNE didn’t yield the positive result for T-DM1 being superior to taxane/trastuzumab, but it doesn’t really change my practice. In order to offer patients the best therapy, you need to offer them pertuzumab/trastuzumab/taxane based on the CLEOPATRA results.

What ongoing studies are exploring the small molecule inhibitors?

There is an ongoing trial with the agent ONT-380, and it’s a clinically savvy, useful study. It takes patients who have received prior pertuzumab as well as T-DM1, and then randomizes them to either trastuzumab/chemotherapy or ONT-380/capecitabine/trastuzumab. As we know, we have familiarity around capecitabine and lapatinib. However, this is really looking at whether we combine a pure HER2-targeted drug—ONT-380—with trastuzumab and capecitabine in the third-line setting. Does that offer us a benefit above what we would give anyway? That’s a priority study.

We also have a study ongoing of capecitabine/neratinib versus capecitabine/lapatinib in a similar patient population, which is accruing. That’s a very clinically useful question. Pertuzumab is a standard of care for the first-line setting, T-DM1 we are utilizing most in the second-line setting, but what do you do after that? For a lot of these patients, they won’t have seen capecitabine, so those 2 studies will help define which small molecule we should be using in combination with capecitabine in the third-line setting.

With the progress being made thus far, what challenges remain?

We have made some exciting progress in the field of treating early-stage and metastatic HER2-positive breast cancer. What I would like to see is that we would no longer have to give chemotherapy to achieve the benefits of trastuzumab or trastuzumab/pertuzumab combinations. How do we either alter trastuzumab or add immune stimulation to trastuzumab, and get the chemotherapy out of the treatment paradigm?

We will get some very good data around immunotherapy in combination with HER2-targeted agents, and there is a lot of good progress that can be made. The progress I would ultimately like to see is to no longer have to give chemotherapy to patients facing HER2-positive breast cancer.