Last week, the FDA added a second approval for neratinib (Nerlynx®, Puma Biotechnology, Inc.) in combination with capecitabine for adults with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with at least two anti-HER2–based regimens in the metastatic setting. This adds to the previous approval of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, for the extended adjuvant treatment of early-stage HER2-positive breast cancer following adjuvant trastuzumab-based treatment. In this interview, Adam M. Brufsky, MD, PhD, FACP, principal investigator of the phase 3 NALA trial (NCT01808573) on which the approval was based, spoke with i3 Health about the benefits of neratinib as a treatment option, strategies to handle its adverse events, and the tremendous progress that is being made in the treatment of metastatic HER2-positive breast cancer.
What are the greatest challenges of treating patients with advanced HER2-positive breast cancer?
Adam M. Brufsky, MD, PhD, FACP: One is that most people eventually become resistant to the standard therapies we have. The second, which is probably equally if not more important, is that at least 50% of the people will experience progression to the brain, and a lot of the drugs that we have don't get into the brain. These are probably the two biggest issues.
Can you comment on the significance of the FDA's approval of neratinib in combination with capecitabine for the later-line treatment of advanced HER2-positive breast cancer?
Dr. Brufsky: It is important for a variety of reasons. There are a bunch of treatments coming out, but this is one of the first approvals in the space for many years, and it's the first approval of a tyrosine kinase inhibitor for third-line therapy and beyond. We have lapatinib, but now we have another HER2 tyrosine kinase inhibitor, neratinib, that actually gets into the brain and can slow the progression of metastatic HER2-positive disease in the brain. That it is significant because it gives us yet another tool to be able to use for these women.
What would you advise oncologists to consider in balancing neratinib/capecitabine against other later-line treatments for advanced HER2-positive breast cancer?
Dr. Brufsky: There are a bunch of different treatments. One of the ones that was recently approved was trastuzumab deruxtecan (Enhertu®, Daiichi Sankyo, Inc.), which is a monoclonal antibody with a chemotherapeutic agent bound to it that has a lot of activity. It looks very, very promising, but what we don't know about trastuzumab deruxtecan is whether it gets into the brain. The nice thing about neratinib is that it does get into the brain and can potentially treat the brain metastases that are HER2-positive, and for that reason we think that it is somewhat of an advance. For doctors, that is an important issue.
The biggest problem with this drug is that it does cause substantial diarrhea in the first month or two, but over the last couple of years, we have developed a lot of regimens that can control the diarrhea. In fact, there's a trial called CONTROL (NCT02400476) that has already been submitted for publication, and it will explain more how to do that. You can dose-escalate the drug, starting at a lower dose and escalating up. You can add loperamide. You can add a drug called colestipol. You can add a drug called budesonide. There are many options to control the diarrhea, and it can be made a lot more manageable.
With the control of the diarrhea and the fact that neratinib can get into the brain and can treat brain metastases, this is an advance.
There is another drug called tucatinib, which will likely be approved in the next couple of months, or if not, within half a year. Tucatinib is just as potent as neratinib, but it doesn't cause as much diarrhea, so that may be another advance as well. The bottom line is that we have a lot of new options for patients that we didn't have before.
Are there any other adverse events that clinicians need to be aware of, in addition to the diarrhea?
Dr. Brufsky: There is hand-foot syndrome, there are occasional liver function abnormalities, and there can be occasional rash, but the big one with this drug is diarrhea.
The one thing that I always worry about with HER2-positive patients is heart problems, such as cardiomyopathy with trastuzumab, for example. There does not seem to be a lot of that with neratinib, but it's something where obviously, you need to use echocardiograms and treat it as if it's like trastuzumab. So that is the thing to worry about.
How do you envision the treatment of HER2-positive breast cancer evolving?
Dr. Brufsky: Well, I think what's going to happen is that you're going to have these HER2 tyrosine kinase inhibitors—neratinib and probably tucatinib—you're going to have trastuzumab deruxtecan, and you may have another drug called SYD985. You're going to have a lot of options. There is a drug called margetuximab. There are an enormous number of agents that will prevent HER2 and that hopefully will slow down the progression of brain metastases and slow down the progression of systemic disease.
Right now, the median survival is a little under 60 months, and it is at 54 or 55 months for a patient with HER2-positive metastatic disease. I think these drugs have the potential to make that survival a lot longer, maybe bring it up to six, seven, or eight years. Suddenly, we're now in a space where metastatic HER2-positive breast cancer is being controlled in a substantial fraction of patients, and that's really changing the natural history of what used to be an extremely aggressive disease with few therapies. This is one of the success stories of modern oncology.
Do you have any words of advice for community oncologists treating patients with advanced HER2-positive breast cancer?
Dr. Brufsky: The first thing I would say is that you have a lot of options. The second thing I'd say is don't be afraid of neratinib. Tucatinib is coming out and will be an option, but neratinib has now been FDA approved, and the diarrhea is manageable; it can be controlled. I think that's the big note that can help community oncologists.
About Dr. Brufsky
Adam M. Brufsky, MD, PhD, FACP, a medical oncologist and Professor of Medicine at the University of Pittsburgh School of Medicine, is the Co-Director of the Comprehensive Breast Cancer Center and Medical Director of the Magee-Women's Cancer Program at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. An active member of the American Society of Clinical Oncology and the American Association for Cancer Research, Dr. Brufsky has served as the principal investigator on a number of research projects related to breast cancer. He has authored or co-authored numerous abstracts and research publications in leading journals, including the New England Journal of Medicine, the Journal of Clinical Investigation, the Journal of Clinical Oncology, and The Lancet.
For More Information
Saura C, Oliveira M, Feng YH, et al (2019). Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol (ASCO Annual Meeting Abstracts), 37(suppl_15). Abstract 2002. DOI:10.1200/JCO.2019.37.15_suppl.1002
Clinicaltrials.gov (2019). A study of neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2+ metastatic breast cancer who have received two or more prior HER2 directed regimens in the metastatic setting (NALA). NLM identifier: NCT01808573.
Clinicaltrials.gov (2020). An open-label study to characterize the incidence and severity of diarrhea in patients with early-stage HER2+ breast cancer treated with neratinib and loperamide. NLM identifier: NCT02400476.
Barcenas CH, Hurvitz SA, Di Palma JA, et al (2019). Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial. J Clin Oncol (ASCO Annual Meeting Abstracts), 37(suppl_15). Abstract 548. DOI:10.1200/JCO.2019.37.15_suppl.548Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.