Neratinib

An Explosion of Anti-HER2 Therapies

The availability of HER2-directed agents—both antibodies and targeted oral drugs—has transformed a once aggressive, poor-prognosis breast tumor into one that is highly treatable. Agents such as trastuzumab,¹ lapatinib,² and pertuzumab³ play an important role in the treatment of HER2-positive breast cancer (neoadjuvant, adjuvant, and metastatic settings), and the antibody-drug conjugate ado-trastuzumab emtansine⁴ is yet another option thus far reserved for the metastatic setting. The question of extended anti-HER2 treatment in the adjuvant setting is one that emerged shortly after the introduction of trastuzumab in the late 1990s, but data from key clinical trials showed that longer treatment with trastuzumab (2 years vs 1 year) does not yield significantly better outcomes.⁵

Second Year of Adjuvant Treatment: A Highly Specific Niche

Now, however, an oral anti-HER2 tyrosine kinase inhibitor neratinib (Nerlynx)  has been approved for a second year of adjuvant anti-HER2 treatment as a risk-reducing strategy in patients at high risk for recurrence of disease after primary treatment with surgery and/or radiotherapy.⁷ Although the majority of women with early HER2-positive breast cancer will have excellent outcomes with 1 year of adjuvant anti-HER2 therapy, there is a subset for whom consideration of neratinib is reasonable.

According to Beverly Moy, MD, MPH, Associate Professor of Medicine, Harvard Medical School  and Clinical Director, Center for Breast Cancer at Massachusetts General Hospital in Boston, the 5-year update of the ExteNET trial⁸ reported at the European Society for Medical Oncology Congress in September 2017 showed that disease-free survival (DFS) for patients who received neratinib after 1 year of trastuzumab remained significantly better compared with those on placebo.⁹ Patients on neratinib had a DFS of a little greater than 90% vs. 87.5% in those on placebo. “It’s an improvement, albeit a modest one of about 2.5%,” Dr. Moy explained. Subset analyses of the ExteNET trial suggest the “greatest benefit was derived by patients who have both HER2-positive and estrogen receptor–positive (ER-positive) disease and who started neratinib within 1 year of completing their trastuzumab regimen,” Dr. Moy continued.

Based on the findings presented at a meeting of the Oncologic Drugs Advisory Committee (ODAC),¹⁰ Dr. Moy said it seemed those patients (ie, those with high-risk, HER2-positive, hormone receptor–positive breast cancer who recently completed a trastuzumab-based regimen) had about a 5% improvement in DFS,¹¹ “which is better than the 2.5% improvement seen in the overall population. In those patients, it makes sense to consider neratinib.”

Although the benefit associated with neratinib is modest, the toxicity—which is primarily diarrhea—can be significant. According to the findings of a quality of life (QoL) study¹² also presented at the 2017 ESMO Congress, patients who received neratinib experienced significantly diminished QoL during the first month of treatment compared with placebo. However, these differences became clinically insignificant with continued treatment, from months 3 through 9.

Commenting on the QoL study, Dr. Moy said, “Although QoL was negatively affected by neratinib early during the treatment course, it rebounded once the initial severe diarrhea was reduced.”

Dr. Moy pointed out that loperamide prophylaxis was not mandated as part of the pivotal neratinib trials,⁸ which is why there was a significant amount of severe diarrhea. Patients had much better experiences in later (ongoing) studies^13,14 that included antidiarrheal prophylaxis. She also noted that although loperamide is effective and easily available over the counter, other antidiarrheal strategies (eg, diphenoxylate hydrochloride and atropine sulfate) may be considered.

Sometimes the degree of potential risk reduction associated with neratinib must be balanced against other patient factors, such as comorbidities. Madelaine Kuiper, NP, MSN, a nurse practitioner and nurse supervisor in hematology/oncology at the University of California Los Angeles (UCLA), Santa Monica, pointed out that adjuvant treatment with neratinib would probably not be considered for a woman with irritable bowel disease, for example, because of the potential to exacerbate existing gastrointestinal issues.

Different Strategies for Different Patient Subsets

The APHINITY trial¹⁵ and the ExteNET trial⁸ assessed whether pertuzumab or neratinib, respectively, would be of value in the adjuvant setting for patients with early HER2-positive breast cancer. Because the trials were being conducted in parallel, Dr. Moy explained, “We are not able to say that giving neratinib after a chemotherapy/trastuzumab/pertuzumab regimen would be helpful.”

Being Sensitive to Cost of Therapy

Both Dr. Moy and Ms. Kuiper emphasized the need for clinicians to be cognizant of the cost of therapy for the patient. Dr. Moy pointed out that because neratinib is an oral therapy, the “cost of the drug is going to be borne primarily by the patient, depending on what the individual’s prescription benefits cover.”

Ms. Kuiper often guides patients as they explore their responsibilities in terms of a co-payment for neratinib. “We are fortunate to have a pharmacy department we can work with, but I always assist my patients with these important questions. We talk with the pharmacy about whether the drug can be added to our formulary. We find out whether we can we obtain co-pay assistance if it does go on formulary. Does the manufacturer offer any support to help patients who have exorbitant co-pays?”

Preventing and Managing the Big D

If the cost hurdle doesn’t present a major obstacle, Dr. Moy said, the next issue is the toxicity, primarily diarrhea, which can be severe.

According to Ms. Kuiper, “One of the first things we need to do is define what diarrhea is: ‘a liquid, watery stool.’ A soft bowel movement, on the other hand, is normal. If the patient is having more than two bowel movements in one day or the diarrhea is not easing or improving, or if she is unable to take in adequate fluids to compensate for the fluids lost, I urge her to contact me.”

It is extremely important for patients to adhere carefully with the loperamide prophylaxis regimen. Dr. Moy said, “My clinical experience has been that loperamide prophylaxis is very effective in reducing neratinib-related diarrhea. The diarrhea usually occurs early in the neratinib course, so we caution patients not to start it just before they go on vacation or before important events, eg, weddings, etc. [Editor’s Note: The Hematology/Oncology Pharmacy Association recommends¹⁶ giving 4 mg of loperamide prophylactically three times a day for the first 2 weeks of neratinib treatment. For weeks 3 through 8, 4 mg of loperamide should be taken twice a day. Thereafter, 4 mg of loperamide may be taken, as needed.] Cancer care teams would be well advised to check in with patients during the first 2 days of neratinib treatment to determine whether they are managing the diarrhea adequately at home.

“After reviewing the definition of diarrhea, my first step,” Ms. Kuiper explained, “would be to sit down with my patient and give instructions for the use of loperamide, starting with the guideline-recommended dosing. However, I also ask the patient to contact me daily (by phone, e-mail, or text message) about how she’s doing so we can adjust in real time and perhaps prevent constipation from becoming an issue. In general, the diarrhea is most pronounced when the patient first starts on the regimen and diminishes with time. There are patients, however, for whom it is a persistent challenge.”

Of note, Ms. Kuiper pointed out, “When we participated in the neratinib clinical trial, antidiarrheal prophylaxis was part of the protocol. Ironically, the biggest problem we had was constipation. The key in everyday practice is going to be fine-tuning the antidiarrheal: We want to prevent severe diarrhea, but we don’t want to cause constipation in the process.”

The key in everyday practice is going to be fine-tuning the antidiarrheal: We want to prevent severe diarrhea, but we don’t want to cause constipation in the process.

For patients who are comfortable with obtaining information online, Ms. Kuiper said, “I like to look at the manufacturer’s website—if it is clear and well done—to review key points together with the patient. For instance, the website for neratinib¹⁷ warns patients not to take an antacid within 3 hours of having taken their dose. The good thing is the patient can easily go back to the website when she’s at home, if she has questions, or if she doesn’t remember certain details.” Ms. Kuiper also noted downloadable handouts and other information may be printed for patients.

Oncologists and cancer care teams are accustomed to managing diarrhea, but patients being treated in the adjuvant setting may have a harder time, Ms. Kuiper said. “We try to help patients persist with the regimen, but it is very much an individual thing.” [Editor’s Note: The combination of neratinib plus capecitabine has been studied in the metastatic setting for the management of brain metastases from advanced breast cancer. Results, which were promising, were reported at the 2017 ASCO Annual Meeting.¹⁸]

With regard to other potential gastrointestinal issues (ie, aside from diarrhea), Ms. Kuiper said, “By the time we are discussing neratinib with a patient, she has usually already received neoadjuvant and/or adjuvant regimens that include chemotherapy, trastuzumab, and pertuzumab. So, she is usually aware of the dietary (eating small, frequent meals; avoiding dairy products; avoiding acidic or spicy foods) and other recommendations for preventing or reducing other gastrointestinal symptoms, such as nausea and vomiting.” Ms. Kuiper recommended briefly reviewing those suggestions.  

Red Flags

Clinicians should also discuss what to watch for, the red flags, if the patient develops diarrhea (eg, loss of fluids and dehydration). Some of those red flags include changes in urination—such as output of urine that is significantly diminished and/or urine that is very dark. Feeling thirsty, a dry mouth, and a headache are other signs of dehydration. “We discuss management of diarrhea and dehydration, perhaps by drinking coconut water, as well as other recommendations for replacing fluids,” Ms. Kuiper said. “We tell patients they should normally be consuming 2 L of fluid a day, by drinking liquids and consuming foods such as fruits and vegetables, gelatin desserts, etc. When they have diarrhea, they should increase fluid intake to more than 2 L. If the patient finds she cannot take in that amount of fluid, then I want her to call me.”

Other Neratinib Toxicities

Another rare but important adverse effect of neratinib is liver toxicity, Dr. Moy said. Clinicians should therefore monitor liver function monthly in patients who are taking neratinib during the first 3 months of treatment and every 3 months thereafter. Neratinib-related liver abnormalities are rare, Dr. Moy said, but if they occur, they are almost always reversible by discontinuing the treatment.

Cardiac toxicities are rare and roughly comparable to those seen with adjuvant trastuzumab. “Nevertheless, we recommend performing serial echocardiograms,” Dr. Moy said, “in the same way they are done when patients are on trastuzumab—about every 3 months.”

Adherence: A Challenge With Any Oral Therapy

Adherence is a critical issue with all the oral targeted therapies. “We provide calendars and written tools and reminders,” Ms. Kuiper said, “but I also like to understand how patients learn and remember. Some of the older patients do very well with check boxes. In other words, every time they take their dose, they manually check the box for that date with a pencil or pen. Other patients may use their smart phones to keep themselves on track.” Some manufacturers provide useful “starter” kits or bags that contain clearly written information and instructions, as well as handy tools.

Bottom Line: Patient Selection

The take-home message about neratinib, according to Dr. Moy, is to be critical about which patient populations might be appropriate for this approach. “Even though the ExteNET trial was positive, meaning there was a statistical advantage for those in the group who were treated with neratinib, the benefit was modest. For the overall population of patients with early HER2-positive disease, I don’t think the toxicity or the cost of neratinib warrants an extra year of adjuvant therapy. However, subsets of patients may derive more benefit. Those patients are the ones with high-risk, HER2-positive, ER-positive disease who have recently completed their year of adjuvant trastuzumab treatment.”

As an illustration, Dr. Moy described a patient with whom she has been discussing neratinib as a consideration. The patient is a young woman who presented with node-positive, HER2-positive, ER-positive breast cancer. She initially received neoadjuvant treatment with trastuzumab and chemotherapy but had significant residual disease at the time of surgery. “There were still positive nodes when she had surgery, so we would regard this patient as high risk. The patient is finishing up her year of trastuzumab, but I’m concerned. This represents the type of case that might be ideal for consideration of neratinib.”

DISCLOSURES

Beverly Moy, MD, MPH, disclosed no relevant relationships.

Madelaine Kuiper, NP, MSN, has served as a speaker for Novartis.

REFERENCES

1. Trastuzumab (Herceptin^R). U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Accessed January 22, 2018.
2. Lapatinib (Tykerb^R). U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Accessed January 22, 2018. 
3. Pertuzumab (Perjeta^TM). U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Accessed January 22, 2018.          
4. Ado-trastuzumab emtansine (Kadcyla^TM). U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Accessed January 22, 2018.
5. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 Years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analyses of the        HERceptin Adjuvant (HERA) trial. Lancet 2017;389:1195–1205.            
6. Neratinib (Nerlynx^R). U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Accessed January 22, 2018.  
7. U.S. Food & Drug Administration. U.S. Department of Health and Human Services. FDA          approves neratinib for extended adjuvant treatment of early stage HER2-positive breast          cancer. Accessed January 22, 2018.
8. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:367–377.
9. Jimenez MM, Holmes F, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 5-year analysis of the phase III ExteNET trial. ESMO 2017 Congress, Madrid, Spain. Abstract 1490. Presented September 8, 2017.
10. U.S. Food & Drug Administration. NDA 208051 Neratinib. Accessed January 22, 2018.
11. U.S. Food & Drug Administration. FDA Briefing Document Oncologic Drugs Advisory Committee Meeting, May 24, 2017. NDA 208051. Accessed January 22, 2018.
12. Delaloge S, Cella D, Buyse M, et al. Effects of neratinib on health-related quality of life in early-stage HER2+ breast cancer: longitudinal analyses from the phase III ExteNET trial. ESMO 2017 Congress, Madrid, Spain. Abstract 177P. Presented September 11, 2017.
13. Barcenas C, Olek E, Hunt D, et al. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients with HER2+ early-stage breast cancer: interim analysis from the multicenter, open-label, phase II control trial. 2016 San Antonio Breast Cancer Symposium. Abstract P2-11-03.
14. ClinicalTrials.gov. A Study Looking at the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide. NCT02400476. Available at https://clinicaltrials.gov/ct2/show/NCT02400476. Accessed January 22, 2018.
15. von Minckwitz G, Proctor M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017;377:122–131.
16. Hematology/Oncology Pharmacy Association. Neratinib (Nerlynx, Puma Biotechnology, Inc) with PAP. Accessed January 22, 2018.
17. 2017 Puma Biotechnology. Neralynx. Available at https://nerlynx.com. Accessed January 22, 2018.
18. Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases. 2017 ASCO Annual Meeting. Abstract 1005.