Again, it is important to see a patient through that 1 year of trastuzumab and/or pertuzumab. You will not want to combine pertuzumab with neratinib since they both have a diarrhea-associated risk. I interpret the neratinib data as something you give to women with higher-risk disease after 1 year of trastuzumab.
Can you discuss tucatinib (ONT-380) for the treatment of patients with brain metastases in the HER2-positive population?
All of the second- and third-generation HER2 tyrosine kinase inhibitors (TKIs) have more activity in brain metastases than lapatinib (Tykerb). Lapatinib was not an effective systemic therapy. It had very bad diarrhea that was not as controllable as it is with some of the newer agents.
Neratinib also treats brain metastases. In the NEfERT-T trial, women were treated upfront with neratinib and paclitaxel. The instances of brain metastases fell by 50%. There is clearly activity in the brain with those regimens. Additionally, ONT-380 does have activity and there are many trials investigating it in the metastatic setting.
In lung cancer, poziotinib has been successful for patients who have progressed on neratinib and have HER2-insertion mutations. The second-generation class of HER2 TKIs will likely be effective against brain metastases.
What does the future treatment landscape look like for HER2-positive breast cancer?
The landscape looks exciting. We have taken a disease that was uniformly progressive and fatal within 1 year in the absence of trastuzumab to one that now has a median survival of close to 5 years with trastuzumab, pertuzumab, and chemotherapy as a first-line treatment. We have already made a huge difference.
The second-line therapies are also quite effective. We know that more than 50% of women with HER2-positive metastatic disease relapse in their brain. That is the next big movement. HER2 TKIs are a start, but we will have to see where we take them. There will possibly be an agent that we can combine with them or use in place of TKIs, which will also be important. There is a lot of interest in combining checkpoint inhibitors in HER2-positive breast cancer. Finally, there are new antibody-drug conjugates coming down the pipeline.
Overall, we are at a point where the majority of early-stage HER2 disease is essentially cured. Those women who develop metastatic HER2-positive breast cancer can expect a median survival of 5 years or more.
The next big thing will be, what do we treat the brain with? [We need to] deal with the brain successfully—we are talking 7 to 8 years, if not longer of overall survival for metastatic disease. I am optimistic.
von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). J Clin Oncol. 2017;35(suppl; abstr LBA500).