There are multiple companies looking at these compounds. We have several in clinical trials at Sarah Cannon Research Institute right now. We have ones in the phase II/III space, as well as some new antibody-drug conjugates and antibodies in our phase I space.
Oncologists are now able to be smarter by targeting these HER2 cells without dumping a lot of poison or “naked chemotherapy” into the body. Some of these new compounds can target HER2 and get more specific by harming just the cancer cells—like T-DM1, which works well in many patients. Many times, that translates to better tolerability and fewer AEs for our patients.
Can you discuss how prevalent brain metastases are and the best way to treat them?
We have always known that HER2-positive patients are getting brain metastases more frequently than other types of breast cancer. Up to 50% of patients with HER2-positive disease will develop brain metastases at some point in their metastatic course. That is much higher than other cancers, such as estrogen receptor–positive breast cancer.
What has become even more obvious is now that we have more HER2 agents that control disease in the rest of the body, such as pertuzumab or T-DM1, women are living longer with this disease, which gives them longer to develop the brain metastases. We are going to continue to see this more frequently.
A lot of our systemic therapies do not cross the blood-brain barrier very well. Although they are great at controlling systemic disease—or disease from the neck down—they do not do a good job of preventing or treating brain metastases.
Neratinib (Nerlynx) is a drug that has some potential for brain metastasis treatment. An FDA-approved drug which we have classically used in the metastatic setting for brain metastases is lapatinib (Tykerb). It is often given in combination with capecitabine.
There are new drugs in development for HER2-positive brain disease. One compound I have been working with for a couple years is tucatinib (ONT-380). It is being developed for all women with HER2-positive metastatic disease, but we have specific interest in the brain metastases space. The trial is very inclusive by allowing patients with brain metastases when, oftentimes, these higher-risk patients are excluded from clinical trials. Tucatinib has shown really encouraging activity in brain metastases.
One of the things that is tough when using drugs such as lapatinib or neratinib is that they not only block HER2, but also block HER1 (or EGFR), which can lead to AEs such as rash and diarrhea. What is unusual about tucatinib is that it is HER2-specific and does not block EGFR. Thus, it does not come with a lot of rash and diarrhea and is very tolerable.
At the 2017 San Antonio Breast Cancer Symposium, it was shown in 2 phase I studies that the population of patients with brain metastases did equally well compared with the people that did not have brain metastases. This is surprising and very encouraging, because we have all known that patients with brain metastases can have a poorer prognosis than their counterparts who do not have brain metastases. A drug that has enough brain activity to even the playing field for women with HER2-positive breast cancer and brain metastases is desperately needed.
Right now, this drug is in a phase III registrational trial with fast-track designation by the FDA. The trial is called HER2CLIMB, which is investigating capecitabine and trastuzumab plus or minus tucatinib.
Looking at the future, what do you hope to see for the treatment of this patient population?
Like we have seen with the recent approval of pertuzumab, I hope we get to the point where we can use these more efficacious compounds earlier in the disease course in the neoadjuvant and adjuvant setting. This will help us prevent patients from developing metastatic, or incurable disease. In the metastatic setting, we need to be smarter when determining sequencing.
I am mostly excited about these new agents, whether it is an antibody-drug conjugate, an antibody, or a tyrosine kinase inhibitor that is specific to HER2 activity. We are getting smarter in treating HER2-positive metastatic disease without causing as many AEs from chemotherapy that we traditionally have. Having new targeted compounds specific for HER2-positive disease will hopefully continue to enable women to do better for longer with an improved quality of life.
Is there anything else you would like to add?
I would encourage patients to seek out their clinical trial options. We are at a point right now in cancer care where we have so many exciting agents coming, and often the best way to gain access to those drugs is through clinical trials. Whether it is neoadjuvant, adjuvant, or metastatic disease, exploring your clinical trial options is a smart thing to do.
von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017; 377:122-131.