FDA Update on Nerlynx™ (Neratinib) Tablets

Despite receiving one year of adjuvant treatment with trastuzumab, up to 31% of patients with early-stage HER2+ breast cancer will experience a disease-free survival (DFS) event within 11 years. A DFS event is defined (http://www.nejm.org/doi/full/10.1056/NEJMoa052306) as either:

• Time from randomization to the first occurrence of recurrence of breast cancer at any site
• The development of ipsilateral or contralateral breast cancer, including ductal carcinoma in situ but not lobular carcinoma in situ
• A second, non-breast malignant disease other than basal-cell or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix
• Death from any cause without documentation of a cancer-related event.

The recommended dose of neratinib is 240 mg, taken orally as a single dose of six 40 mg tablets, continuously for one year (see IMAGE). Neratinib should be taken with food (https://nerlynx.com/pdf/full-prescribinginformation.pdf).

Severe diarrhea and sequelae have been reported during treatment (http://www.gotoper.com/publications/ajho/2015/2015nov/effective-management-and-prevention-of-neratinibinduced-diarrhea) with neratinib, and this adverse reaction (AR) is hypothesized to be caused by epidermal growth factor receptor (https://nerlynx.com/pdf/full-prescribinginformation.pdf) (EGFR) inhibition. Because of this, antidiarrheal prophylaxis (loperamide) should be initiated with the first dose of neratinib (https://nerlynx.com/pdf/full-prescribinginformation.pdf) and continued during the first two treatment cycles (56 days) and as needed thereafter.

The FDA approval of neratinib was based on results from the global, multicenter, randomized, double-blind, placebo-controlled ExteNET trial that included 2,840 women (median age = 52 years) with early-stage HER2+ breast cancer. Patients who had completed adjuvant trastuzumab therapy within the past two years were randomized to receive neratinib (https://nerlynx.com/pdf/full-prescribinginformation.pdf) (n = 1,420) or placebo (n = 1,420) for one year.

After two years, invasive DFS (iDFS)—the study’s primary endpoint—was 94.2% in patients treated with neratinib compared to 91.9% in those receiving placebo (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.49–0.90; p = 0.008), representing a 34% reduction in risk of recurrence (https://nerlynx.com/pdf/full-prescribinginformation.pdf) with neratinib.

In a five-year exploratory analysis follow-up cohort that included approximately 75% of the previously noted patient population, iDFS was 90.2% in patients treated with neratinib compared to 87.7% in those receiving placebo (HR = 0.73; 95% CI = 0.57–0.92), representing a 27% reduction in risk of recurrence (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM561722.pdf).

The most common ARs associated with neratinib (https://nerlynx.com/pdf/full-prescribinginformation.pdf) (occurring in at least 5% of patients) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, aspartate/alanine aminotransferase increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection.

Diarrhea occurred in 95% of patients treated with neratinib, with 40% of patients experiencing diarrhea at grade 3 or higher. This was the most common AR leading to treatment discontinuation (https://nerlynx.com/pdf/full-prescribinginformation.pdf): 16.8% of patients receiving neratinib discontinued treatment because of diarrhea, compared to 0.1% of patients receiving placebo.

In addition, in the ExteNET trial, hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients. Healthcare providers should monitor liver function tests at baseline (https://nerlynx.com/pdf/full-prescribinginformation.pdf), monthly for the first three months of treatment, and then every three months thereafter while on treatment and as clinically indicated.

Neratinib can cause fetal harm when administered to pregnant women (https://nerlynx.com/pdf/full-prescribinginformation.pdf), and healthcare providers should advise that females of reproductive potential use effective contraception during treatment and for at least one month after the last dose.

A Conversation With Cynthia Cantril, RN, MPH, OCN®, CBCN

Q: Can you give a brief overview of neratinib?

A: I think it’s an exciting new drug for patients with HER2+ breast cancer. After patients finish trastuzumab, they still have a significant risk of recurrence; consequently, this drug is a new option for patients who want to know what else they can do to prevent a recurrence.

Neratinib is given as six pills, which can be a challenge for many patients. But patients never cease to amaze me in their ability and motivation to be rigorous about doing anything they can to eliminate the risk of recurrence, and they know that HER2+ breast cancer is aggressive.

In terms of the mechanism of action, neratinib binds to the tyrosine kinase signaling domains of EGFR HER1, HER2, and HER4. With HER2 disease, there’s a family of HER2 signaling. What the drug does is inhibit the downstream signaling, reducing tumor cell growth and proliferation of disease.

Q: As you mentioned, HER2+ breast cancer is an aggressive disease, and often patients still need follow-up treatment after receiving trastuzumab. Can you speak to the unmet need in this patient population? How will this treatment fit into a patient’s treatment regimen?

A: A significant challenge in breast cancer treatment is that patients are going to have a recurrence. This treatment allows a patient to have one more possible regimen that will extend their DFS. Anything that comes on our formularies that helps patients delay or eliminate the possibility of recurrence will be very welcome in the patient community. I’m excited for the medical community to have this additional opportunity. It’s one thing to give patients a breast cancer diagnosis; it’s another to help patients understand how often recurrence happens. Anything that we can do to prolong that disease-free interval is critically important.

Q: Can you speak to the outcomes from the ExteNET trial?

A: This trial clearly demonstrated a significant reduction in recurrence. Patients who received neratinib for two years had a 34% reduction in risk of recurrence versus placebo. Also, neratinib seems to be fairly well tolerated, with the exception of diarrhea, which is manageable.

Q: What are your recommendations for nurses handling patients who experience diarrhea while taking this drug? What about dietary management related to the potential for diarrhea?

A: For dietary management of patients with gastrointestinal toxicities, we would suggest taking probiotics and eliminating certain foods. I always tell patients to be aware of anti-inflammatory foods. A lot of it is balancing a good, nutritious diet and antidiarrheal medications. And obviously hydration. We also have to help patients manage their antidiarrheal medications; it’s a matter of adjusting the dose.

Q: What are your suggestions for potential dose interruptions or modifications?

A: I think by the time patients reach this line of therapy, they know a lot about managing side effects. Neratinib is indicated for patients who have been through a pretty rigorous course of therapy already, so my hope would be that these patients are educated properly and know that there are certain side effects that happen, but there’s a way to manage them (see TABLE).

Q: What is the impact of an oral treatment at this stage in the disease?

A: Oral administration is so important for patients who are finishing treatment, because they spend so much time in infusion with previous lines of therapy. The fact that neratinib is given orally is a great benefit. I also think the fact that neratinib is administered for a limit of one year is also a huge benefit to patients.

However, there’s a difference when patients are coming in to get an infusion: they’re getting a lot of education and support. When they’re on an oral therapy, they’re not coming in as frequently, so I think it’s important to figure out what resources are available, like a mobile application or website.

My experience is that previously treated patients are established veterans of care and treatment. They will look forward to it being an oral medication. They will look forward to having an extended treatment opportunity that isn’t an infusion. However, we know that these patients still need a great deal of support for symptom management, compliance, and education.

Q: From a nursing perspective, how does a drug like this impact your management and treatment of patients with cancer?

A: A significant shift occurs when patients finish treatment; it’s one of the most anxiety-producing times in their cancer trajectory, because while they were on prior treatment, they were actively doing something to prevent a recurrence. What happens then is they think, “Now what do I do?”

This drug gives patients an additional resource. When we do survivorship care plans, patients are constantly asking, “Now what?” After they finish trastuzumab, this is an opportune time to tell patients about neratinib and reinforce that an additional therapy is available. I think psychologically that’s going to be important to patients.

Q: As someone who spends a lot of time with patients, can you speak to how this drug could impact their treatment and outcomes?

A: I’ve been in oncology nursing for 45 years, and I tell patients every day that we are coming closer to being able to control disease for very long periods of time. When I inform patients of their diagnosis, I tell them that this is a journey of care, and I discuss what I see their course of treatment being over the next six months, a year, and beyond.

So neratinib is just one more piece of information we can give patients. We would say, “We have something that’s an extended adjuvant treatment beyond trastuzumab.” I think patients will be very interested and energized, or hopeful, about a subsequent treatment after trastuzumab.

Q: How would you introduce this extended adjuvant as a new step in treatment planning?

A: When patients are finishing trastuzumab and we are working on a survivorship care plan, that is an opportune time to do a nursing intervention and say, “We are going to transition you to a new medication.” That’s the time when you go over how to reduce side effects with an antidiarrheal prophylaxis.

When you weigh the benefits and toxicity of the drug, I think patients are more than willing to accept some of these side effects, particularly those seen with oral drugs, because they’re easier to manage and patients don’t have to come back in for an infusion regimen.

Cynthia Cantril, RN, MPH, OCN^®, CBCN, is the director of cancer support services and patient navigation at Sutter Pacific Medical Foundation in Santa Rosa, CA, and was a founding board member of ONS. Cantril received her nursing degree from Meramec Community College, a bachelor’s degree in psychology from Lindenwood College, and a masters of public health from the University of California, Berkeley. She has received a number of oncology nursing awards, including ONS’s Distinguished Service Award in 2010 for novel work in patient navigation and ONS’s Lifetime Achievement award in April 2016. She has published more 12 articles and authored several book chapters.

Cantril received compensation for her contribution to this initiative.

Disclosure: This material was sponsored by Puma Biotechnology, Inc.