Expert Discusses Toxicity Management With Neratinib for HER2-Positive Breast Cancer

Wolfgang Janni, MD, PhD

Wolfgang Janni, MD, PhD

As the FDA Oncologic Drugs Advisory Committee's review of neratinib for patients with HER2-positive breast cancer following adjuvant trastuzumab (Herceptin) is upcoming, the breast cancer community is focused on the side effects associated with this agent.

In the latest available data from the pivotal ExteNET study, the 2-year invasive disease-free survival rates were 94.2% and 91.9% for neratinib and placebo, respectively. This represented a 34% reduction in the risk of disease recurrence or death (HR, 0.66; CI, 0.49-0.90;P= .004).

However, 95.4% of patients treated with neratinib experienced diarrhea of all grades, with 39.9% experiencing grade 3/4. The subsequent phase II CONTROL study demonstrated that prophylactic loperamide significantly reduced the incidence of neratinib-associated diarrhea.

In an interview withTargeted Oncology, Wolfgang Janni, MD, PhD, professor and chair of the Department of Obstetrics and Gynecology, University of Ulm, Germany, discussed toxicity management with neratinib and other agents for HER2-positive breast cancer, as well as emerging treatments and impactful trials in the field.

TARGETED ONCOLOGY:Can you discuss your work in the management of toxicities associated with HER2-targeted therapies?

Janni:

In my opinion, there is no doubt that the benefit of HER2/neu targeted treatment in breast cancer, both in early and advanced breast cancer, outweighs, by far, the adverse effects. In this setting, though, we have to carefully look out for adverse effects of whatever we do, especially the drugs associated with HER2/neu targeted treatment.

The main toxicities which derive from HER2/neu targets agents are cardiotoxicity associated with usage of monoclonal antibodies and diarrhea associated with the use of TKIs. So that is what I have been focusing on, cardiotoxicity in association with trastuzumab (Herceptin) and pertuzumab (Perjeta). We can reduce the risk associated with cardiomyopathy induced by combinations of pertuzumab and trastuzumab and anthracyclines. We do a thorough history of the patient, a physical examination, we monitor the patient’s heart rate, cardiac symptoms and signs, we monitor body weight, and we do LVF studies at the beginning of therapy and every 12 weeks after. 

Neratinib, which is going up for approval in the adjuvant setting, would be the first TKI used in this setting for early breast cancer. As for diarrhea associated with TKIs, we need thorough measures to reduce the incidence of grade 3/4 diarrhea. Loperamide, a synthetic opioid frequently used in the treatment of diarrhea, can be used to treat TKI-associated diarrhea, but also as a prophylactic measure. Very early on, we give a dose of loperamide then titrate it down a little bit, but keep the prophylaxis for 2 cycles of neratinib. With that, we can lower the grade 3 diarrhea toxicity from 40% down to approximately 10% to 15%, so it was quite significant. 

Cardiotoxicities are a dangerous risk, but by doing what I just summarized, it can be lowered substantially. The same is true about diarrhea, and even though it is not as life-threatening, it influences the quality of life of the patient. Using agents like loperamide can significantly lower the incidence of diarrhea—it is an acute, but manageable side effect of neratinib therapy.

TARGETED ONCOLOGY:What are the letting developments in the adjuvant setting for HER2-positive breast cancer?

Janni:

In the adjuvant setting, we already have the positive data from the ExteNET study with extended adjuvant treatment of trastuzumab followed by neratinib. And this year at ASCO we will have the results of the APHINITY study, which is dual-targeted treatment of trastuzumab and pertuzumab for 1 year. We already know this is a positive study as per a press release by Roche; we are all looking forward to seeing the data and weighing the strategy of extended adjuvant treatment versus dual targeted treatment for 1 year in these patients.

Right now, the focus is on the APHINITY study, and then everything will then be focused on dealing with the data and weighing them against other strategies. Both coming from neoadjuvant to extended adjuvant treatment.

In terms of new agents, it will be very interesting to see data from other targeted agents, such as CDK 4/6 inhibitors in the HER2/neu-positive setting—some very interesting data suggesting that this might be a way to go. The same might be true for PI3 kinase inhibitors; also, other TKIs are under investigation. There are a lot of treatment options that will be studied in the future.

TARGETED ONCOLOGY:What do you feel is the most pressing challenge in this landscape?

Janni: