Oral Adherence With Nerlynx® (Neratinib) Tablets: Introduction

October 26, 2018 by Wendy Vogel MSN, FNP, AOCNP®

This is the first in a series detailing some of the general factors to consider around patient adherence to oral medications, and ways to support patients receiving neratinib.

The cancer treatment landscape has shifted with the emergence of new, targeted therapies. Development and use of oral oncolytics, targeted cancer therapies that can be taken by patients orally in their own homes, has increased in recent years.

This increase is due in part to research in extra- and intracellular signaling pathways. By interfering with or blocking these signals, targeted drugs have become standard agents in cancer therapy (https://doi.org/10.1188/10.CJON.461-466). Oral oncolytics currently account for about 25% of the oncology pipeline of drugs in clinical development, and experts project that oral oncoloytic use will continue to rise (https://www.ajmc.com/journals/supplement/2016/improving-patient-access-to-critical-therapies-in-the-age-of-cost-sharing/in-office-dispensing-of-oral-oncolytics-a-continuity-of-care-and-cost-mitigation-model-for-cancer-patients).

Patients may prefer the convenience of oral therapies because they are taken outside of the office or infusion clinic. However, oral onco­lytics present challenges that can impact their successful use. One issue is that these drugs often have unique side effect profiles that are different from traditional chemotherapy agents. Another key issue, given that patients are taking the therapy on their own without a nurse present, is adherence (https://doi.org/10.1188/13.CJON.629-636).

Oral Oncolytic Adherence

The term “adherence” refers to the extent to which patients follow the medical action plan set out by their healthcare team to achieve a desired therapeutic (https://jamanetwork.com/journals/jama/fullarticle/195606) goal (https://doi.org/10.1002/msc.27). As many as 30%–60% of patients show some degree of nonadherence to prescribed oral medication, even to the point of failing to fill (https://www.ncbi.nlm.nih.gov/pubmed/12078377) their (http://dx.doi.org/10.1136/heart.88.2.203) prescriptions (https://jamanetwork.com/journals/jama/fullarticle/195606).

Oncology nurses have played a large role in patient education as part of cancer care and have helped to identify and address challenges in supporting an increasing number of patients treated with oral agents (https://doi.org/10.1188/10.CJON.41-47). Adherence is an impor­tant topic, because poor adherence to oral cancer medication can negatively affect providers’ abilities to determine treat­ment efficacy and effectiveness, contrib­utes to increased healthcare costs, and can lead to decreased overall patient survival (https://doi.org/10.1188/16.ONF.576-582). Studies have shown that adherence to oral agents, as well as monitoring patients for side effects, dos­ing titration, and psychosocial issues, will impact clinical outcomes. Failure to adhere to oral therapies can result in treatment resistance, disease progression, and even death (https://doi.org/10.1188/10.CJON.41-47).

Patients may not adhere to their health­care regimen as prescribed for a variety of reasons. Recognized barriers to oral treat­ment adherence include:

For example, factors that may hinder the experience for women with estrogen recep­tor–positive (ER+) breast cancer who are initiating oral adjuvant therapy may include feeling overwhelmed and aban­doned despite highly skilled medical care; processing the trauma and putting it in perspective; keeping up the facade while feeling vulnerable; needing to connect cau­tiously; and moving toward healing and being aware. In some cases, such concerns result in women not initiating treatment as prescribed (https://doi.org/10.1188/16.ONF.E143-E152).

Although policies and procedures for IV chemotherapy and biologic therapy administration are in place in most cancer centers, policies and procedures for oral therapy education, support, and patient management may not be as well defined or executed (https://doi.org/10.1188/10.CJON.41-47).


The Role of the Nurse In Oral Oncolytic Adherence

As oral oncolytic use increases, nurses have the challenge of accurately monitor­ing patient medication regimens to help improve outcomes. Currently providers have no standard measure of adherence, but qual­ity of patient-provider communication with increased nursing-centered patient educa­tion could be of great help in improving adherence (https://doi.org/10.1188/16.ONF.576-582).

Side effects of oral cancer therapies may be different from drugs delivered via IV, but they have the same potential for severity. However, patients on oral regimens will generally not visit the clinic as frequently, limiting nurses’ ability to monitor and measure those side effects. “All patients receiving cancer therapy need to know when, who, and how to call for healthcare support during and after clinic hours. Symptoms can quickly escalate at home, resulting in exacerbation of minor side effects into serious acute conditions that require admission to an inpatient unit for management. Good patient teaching and symptom triage prevent this (https://doi.org/10.1188/10.CJON.461-466).”

Nursing interventions, including patient and caregiver education and side effect and medication management, can increase adherence to oral cancer therapies. Nurses can track a patient’s oral adherence of medication in numerous ways, including pill counts, a microelectronic monitoring system (MEMS), prescription refill monitoring, or a medication diary. Because tracking methods can be manipulated by patients, they must be closely monitored by oncology nurses or clinicians (https://doi.org/10.1188/10.CJON.461-466).

About Neratinib

Nerlynx® (neratinib) tablets, an oral kinase inhibitor, is approved by the U.S. Food and Drug Administration for the extended adjuvant treatment of adult patients with early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer, following adjuvant trastuzumab-based therapy.

The recommended dose of neratinib is 240 mg daily, taken orally as a single dose of six 40 mg tablets, continuously for one year.

In clinical trials, the most common adverse reactions associated with neratinib (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 decrease, and urinary tract infection (https://nerlynx.com/pdf/full-prescribing-information.pdf).

Mechanism of Action

Neratinib is an irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is a potent inhibitor of HER2, is highly active against HER2-overexpressing human breast cancer cell lines in vitro, and also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. It behaves as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor, and results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation (https://doi.org/10.1158/0008-5472.CAN-03-2868). In brief, neratinib inhibits the proliferation and the growth of breast cancer cells by stopping downstream signaling from the overexpression of HER2 receptors.

The ExteNET Study

The ExteNET study, an ongoing, interna­tional, randomized, placebo‑controlled phase III trial, investigated the efficacy and safety of 12 months of neratinib after trastu­zumab-based adjuvant therapy in 2,840 women with early-stage HER2-positive breast cancer (https://doi.org/10.1016/S1470-2045(15)00551-3).

Patients were randomized to receive nera­tinib (n = 1,420) or placebo (n = 1,420) for one year. After a one-year course of nera­tinib 240 mg/day after trastuzumab‑based adjuvant therapy in women with early-stage HER2-positive breast cancer significantly improved invasive disease‑free survival (iDFS) after a median follow-up of 2 years (https://doi.org/10.1016/S1470-2045(15)00551-3) (hazard ratio = 0.67; 95% confidence inter­vals [CI] = 0.50–0.91; p = 0.009).

Efficacy and safety of neratinib among patients who ended treatment early (i.e., ≤ 3 months) as well as among those who remained on treatment longer (i.e., ≥ 11 months) after five years of follow-up was analyzed in post hoc data. At the five-year follow-up, one year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significant­ly reduced the proportion of clinically rel­evant breast cancer relapses, including those that might lead to death, such as distant and locoregional relapses outside the preserved breast, without increasing the risk of long-term (https://doi.org/10.1188/16.ONF.E143-E152) toxicity (https://doi.org/10.1016/S1470-2045(17)30717-9).

In the ExteNET clinical trial, the HR+ patient population saw a 51% reduction in risk of recurrence with one year of neratinib verses placebo at two years’ follow-up and a 40% reduction in the risk of recurrence at five years (https://doi.org/10.1016/S1470-2045(17)30717-9).

Key Points

ONS Oral Adherence Toolkit

The increased use of oral oncolytics affects the infrastructure of targeted therapies such as neratinib, because the site of care has increas­ingly moved from an infusion center to con­tinuous oral dosing taken in a patient’s home. Patient nonadherence can be caused by a vari­ety of reasons and may take the form of missed doses, accidental additional doses, doses taken in the wrong quantity or at the wrong time, or even the choice not to fill the prescription (http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.8621) at (https://www.ncbi.nlm.nih.gov/pubmed/11983753) all (https://www.ncbi.nlm.nih.gov/pubmed/18377852). The World Health Organization (WHO) projects that only about 50% of patients worldwide typically take their medicines as pre­scribed (https://doi.org/10.1188/10.CJON.41-47).

Medication adherence is not a new issue. It happens with various illnesses, from short-term colds to long-term conditions such as diabetes. Because of the severity of cancer, healthcare professionals may assume that patients would be more inclined to adhere to medication. However, reports have demonstrated adher­ence levels as low as (http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.8621) 20% in (https://www.ncbi.nlm.nih.gov/pubmed/2293862) some (https://www.ncbi.nlm.nih.gov/pubmed/11983753) cancers.

To help nurses improve their practice in terms of assisting with patient adherence, ONS created the Oral Adherence Toolkit (http://www.ons.org/sites/default/files/ONS_Toolkit_ONLINE.pdf). The toolkit provides information, strategies, and resources for nurses who care for patients receiving oral oncolytic therapy. The goal is to help nurses facilitate adherence among patients with cancer, with sections devoted to safety concerns and adverse events, financial resources and help, adher­ence monitoring, and information on helping patients go from nonadherent to (https://doi.org/10.1188/14.CJON.E88-E92) adherent (https://www.ons.org/practice-resources/toolkits/oral-adherence).

Read the other articles in this series:

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