Introduction

Neratinib (PB-272; Puma Biotechnology Inc, Los Angeles, CA, USA) is a potent small-molecule kinase inhibitor of human epidermal growth factor receptors HER1 (or EGFR1), HER2, and HER4.^1,2 It binds irreversibly to the intracellular ATP-binding pocket of the HER2 receptor and reduces receptor autophosphorylation.² In vitro studies show that neratinib blocks downstream signal transduction and cell cycle regulatory pathways in cancer cell lines, ultimately leading to decreased cell proliferation.² In animal studies, neratinib inhibits the growth of EGFR– and HER2–dependent tumor xenograft models when given orally on a once-daily schedule.²

Neratinib is currently in late-stage clinical development, with regulatory submission planned in 2016. It has been investigated extensively in the treatment of metastatic HER2–positive breast cancer both as a single agent^3-5 and in combination with chemotherapeutic and targeted agents.^6-11 Overall response rates in phase II studies ranged from 29% to 40% with neratinib monotherapy in women with metastatic HER2–positive breast cancer who had previously been treated with chemotherapy and trastuzumab.^3-5 Considerably higher response rates were observed when neratinib was combined with chemotherapeutic agents, for example, 63% with capecitabine⁸ and 72% to 75% with neratinib plus paclitaxel.^6,10 Of note, neratinib showed clinical activity in women who had been previously treated with trastuzumab,^4,8 suggesting that it may be able to circumvent trastuzumab resistance.

Neratinib is also being investigated in early-stage HER2– positive breast cancer. In a phase III trial of neratinib (ExteNET), a 12-month course of treatment improved invasive disease-free survival after 2 years of follow-up compared with placebo in women with early-stage HER2–positive breast cancer after trastuzumab-containing adjuvant therapy (hazard ratio 0.67, 95% CI 0.50–0.91; 1-sided P = .0046).¹² Diarrhea was the most common adverse event with neratinib (grade 3, 40%; grade 4, <0.1%).¹² As previous efforts to improve outcomes with extended adjuvant therapy with trastuzumab have been unsuccessful,¹³ neratinib is the first agent to significantly prolong disease-free survival in women with trastuzumab-treated early-stage breast cancer. Longer term follow-up and assessment of overall survival in the ExteNET trial is ongoing.

Neratinib is taken orally at a dosage of 240 mg once daily on a continuous schedule.⁴ At this dosage, neratinib is generally well tolerated with a low incidence of grade 3/4 adverse events.⁴ The most commonly reported adverse event and dose-limiting toxicity of neratinib is diarrhea,^3,4 a known class effect of EGFR-directed tyrosine kinase inhibitors.¹⁴

In this article, we will discuss the incidence, severity and patterns of occurrence of diarrhea with neratinib, and how this may be effectively managed with initiation of intensive loperamide prophylaxis at the beginning of treatment.

Cancer Treatment-Related Diarrhea

Grading

The standard tool most commonly used for grading the severity of diarrhea is the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Adverse Events.¹⁵ According to version 4.0 of these criteria, grade 1 (mild) diarrhea is defined as an increase of <4 stools per day from baseline (or mild increase in ostomy output), with asymptomatic or mild symptoms such that intervention is not indicated.¹⁵ Grade 2 (moderate) diarrhea is defined as an increase of four to six stools per day from baseline (or moderate increase in ostomy output), requiring minimal, local, or non-invasive interventions only.¹⁵ Grade 3 (severe or medically significant) diarrhea is defined as an increase of ≥7 stools per day from baseline (or severe increase in ostomy output), incontinence, hospitalization (or prolongation of hospitalization) limiting self-care activities of daily living.¹⁵ Grade 4 events are deemed to be life-threatening requiring urgent intervention.¹⁵ In clinical practice, patient symptom diaries are also generally used as an additional assessment tool in conjunction with the NCI-CTC criteria.

Occurrence

Diarrhea is a common side effect of manyn cancer treatments,including chemotherapeutic agents, molecularly targeted agents and pelvic radiotherapy. EGFR-directed tyrosine kinase inhibitors are associated with high frequencies of clinically important diarrhea, and depending on the agent, up to 95% of patients may experience some grade of diarrhea, although the risk of grade 3/4 events tends to be lower (<15%) (Table 1). Diarrhea is also common with several multi-agent HER2–directed regimens used in the treatment of HER2–positive breast cancer (Table 1). Further, it fluoropyrimidines and irinotecan, carry a high is recognized that regimens used for the treatment of colorectal cancer, particularly those involving risk of diarrhea.⁵⁰ Data from randomized trials suggest that up to 80% of patients treated with regimens involving these agents may experience diarrhea, and 20% will commonly experience grade 3 or 4 diarrhea (Table 1).



Management

Diarrhea caused by cancer treatments requires early intervention to prevent complications such s dehydration, electrolyte imbalances, and renal insufficiency.⁵¹ If left unmanaged, persistent diarrhea can require additional resources beyond oral antidiarrheal agents (fluid replacement, octreotide, antibiotics, unplanned clinic visits, hospitalization) and can be costly to manage.^52,53 Severe diarrhea can also lead to changes in treatment, including dose reductions and treatment discontinuation.^52-54 These alterations may have a negative effect on tumor control, although the consequences of diarrhea-driven treatment modifications and discontinuations on clinical outcomes have never been formally investigated.

Effective management should involve a continuous process of assessment, reassessment, and appropriate dietetic and pharmacological interventions, with an increase in aggressive stepwise management as needed. There are several sets of guidelines for the management of cancer treatment-related diarrhea,^50,51,55-59 although there is little consensus between them on the details of care. Treatment is often empirical and the guidelines have served to highlight that there are few clinically relevant studies on which to base decisions relating to the management of cancer treatment-related diarrhea.⁵

Pharmacological treatment of cancer treatment-related diarrhea is based primarily on the empirical use of opioids. Loperamide, a synthetic opiate, is the standard first-line treatment for chemotherapy-induced diarrhea.^50,59 It acts as an agonist on opioid receptors in the gastrointestinal tract to decrease gut motility.⁵¹ Systemic absorption of loperamide and systemic adverse events are minimal, although high-dose therapy can lead to paralytic ileus.⁵⁵ Alternative opioids recommended for cancer treatment-related diarrhea include deodorized tincture of opium^50,59 and diphenoxylate plus atropine (Lomotil^®).⁵⁹ Octreotide is the other main pharmacologic intervention for cancer treatment-related diarrhea. It is generally reserved for use in complicated cases or as a second-line treatment for persistent diarrhea after loperamide.⁵⁰ Octreotide is a somatostatin analogue that decreases hormone secretion to prolong intestinal transit time, promote intestinal absorption of electrolytes, and decrease mesenteric blood flow.⁵¹ It is well tolerated, with the most common adverse events being mild abdominal pain and injection site pain.⁶⁰

Other than the use of atropine for early cholinergic diarrhea associated with irinotecan infusion,⁶¹ prophylactic anti-diarrheal therapy is not standard for any cancer treatment. Several small studies have investigated the utility of different prophylactic anti-diarrheal regimens to reduce the frequency and severity of cancer treatment-related diarrhea. Activated charcoal⁶² and oral alkalinization⁶³ may be beneficial for irinotecan-associated diarrhea, and probiotics may have a role in preventing 5-fluorouracil (5-FU)-related diarrhea.⁶⁴ However, studies of prophylactic octreotide^65-67 and an intestinal adsorbent⁶⁸ did not show benefit.

Many studies have investigated potential risk factors for the development of cancer treatment-related diarrhea (ie, genotype, clinical characteristics), although prospective studies are lacking and no predictors are used in clinical practice. Readers are referred to Andreyev et al⁵⁵ for a more detailed discussion of this subject.

Occurrence of Diarrhea with Neratinib

Studies with No or Suboptimal Antidiarrheal Prophylaxis

Diarrhea management in initial trials of neratinib involved treatment with antidiarrheal agents and/or dose modifications only after diarrheal symptoms became apparent. A few studies included antidiarrheal prophylaxis, but the doses of loperamide used were proven to be suboptimal (ie, 2 or 4 mg/day).^7,69,70 For example, in the Translational Breast Cancer Research Consortium 022 phase II study, the incidence of grade 3 diarrhea was 33% before the introduction of prophylaxis compared with 21% with low-dose loperamide prophylaxis (2 mg/day).⁶⁹

Practical Application Diarrhea is a common side effect of many cancer treatments and can lead to severe complications and treatment modifications if left unmanaged. Diarrhea is the most common adverse event of neratinib, a novel irreversible pan-HER tyrosine kinase inhibitor. Most higher-grade diarrhea with neratinib occurs during the first cycle of treatment. For effective management, neratinib should be used in conjunction with an intensive regimen of loperamide prophylaxis for the first cycle of treatment.

From the studies with no or suboptimal prophylaxis, it was evident that most diarrhea events with neratinib occurred in the first month of treatment. For example, in the ExteNET trial, the overall incidence of grade 3 or higher diarrhea was 40%; however, 73% of these patients experienced grade 3 events during the first month of treatment. After the third month of treatment, grade 3 diarrhea was relatively infrequent with approximately 6% of patients on treatment or fewer experiencing grade 3 diarrhea after month 3. The rate of grade 2 diarrhea also declined from about 30% in the first month to 18% to 19% in months 2 and 3, and to 12% in month 12 (data on file, Puma Biotechnology Inc.).

In studies with no or suboptimal prophylaxis, treatment-emergent diarrhea with neratinib was generally of mild-to-moderate severity; grade 1/2 events occurred in 56% to 67% of patients (Table 2).^4,12,61 The incidence of grade 3 diarrhea ranged from 30% to 53% (Table 2),^4,9,12,70 with an incidence of 40% in the largest study performed to date (ExteNET).¹² Where details of grade 4 events were available, these events were rare (0% to 3% of patients).^{3,4,6,7,9,10,12,69} The median duration of all grade events was 7 to 14 days per episode as reported in two studies (Table 2).



Diarrhea resolved in most patients either spontaneously or with standard management involving antidiarrheal medications and/or dose modifications.⁵ Neratinib dose reductions because of diarrhea were documented in 10% to 15% of patients.^5,8,10 Most patients continued treatment despite the occurrence of diarrhea, and treatment discontinuation as a result of diarrhea was uncommon (0% to 14% of patients).^{3-6,8,10,12,71}

Studies with Intensive Loperamide Prophylaxis

The mainstay of management for neratinib-associated diarrhea is intensive prophylaxis with loperamide. An intensive prophylactic regimen was first instigated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) FB-8 study after the investigators noted a high occurrence of diarrhea in the first week of neratinib therapy despite early treatment with loperamide.⁹ Prophylaxis was initiated with the first dose of neratinib and given for the first cycle of treatment. Although the patient numbers in the NSABP FB-8 study were small, the introduction of intensive loperamide prophylaxis reduced the occurrence of grade 3 diarrhea from 53% (8 of 15 patients) before its introduction to 0% (0 of 6 patients).⁹

Based on the early success of this regimen, intensive antidiarrheal prophylaxis with loperamide for the first cycle of treatment has been introduced as a mandatory measure in new and ongoing trials of neratinib. The precise loperamide regimen used in these studies has evolved over the past 2 years to improve patient compliance. However, the initial dose of loperamide has remained constant (ie, 4 mg with the first dose of neratinib), and all regimens have tapered to a lower dose of loperamide over the course of the first cycle. The recommended loperamide prophylactic regimen for use with neratinib is shown in Figure 1.



Safety data from trials that included intensive loperamide prophylaxis show a marked reduction in the incidence of grade 3 diarrhea to 0% to 17%, even though many of the patients who experienced grade 3 diarrhea did not receive the full prophylactic regimen due to compliance issues (Table 2).^9,70,72 This compares with rates of 30% to 53% in studies with no or suboptimal prophylaxis (Table 2). The median duration of all-grade treatment-emergent diarrheal events was also reduced from 7 to 14 days to 2 days with loperamide prophylaxis (Table 2).



A detailed management algorithm for treatment-emergent diarrhea during neratinib therapy is shown in Figure 2. Any new-onset diarrhea may be managed with the maximum dose of loperamide (ie, 16 mg/day), with the addition of diphenoxylate plus atropine (Lomotil^®) or octreotide according to severity. Dietetic changes, such as the BRAT diet (ie, low-fat diet enriched with bananas, rice, applesauce, and toast), increased fluid intake, stopping all lactose-containing products, and frequent small meals, should also be encouraged. Treatment interruptions or dose reductions are recommended only if patients have significant persistent diarrhea and are unresponsive to the above-mentioned interventions.

Future Research With Neratinib

A comprehensive clinical development program of neratinib is currently ongoing (Table 3). In a recently reported phase III trial (ExteNET), treatment with neratinib demonstrated a statistically significant improvement in invasive disease-free survival compared with placebo in patients with early-stage HER2– positive breast cancer who had previously received adjuvant trastuzumab. However, because no antidiarrheal prophylaxis was given in ExteNET, the rate of grade 3 (or higher) diarrhea was high (40%).¹² To better understand the ability of high-dose loperamide prophylaxis to reduce neratinib-related diarrhea, a phase II study (PUMA-NER 6201) has been initiated to formally investigate the effectiveness of this loperamide prophylaxis regimen. Similar to ExteNET, the study is enrolling women with early-stage HER2–positive breast cancer following trastuzumab-based adjuvant therapy. All patients are receiving neratinib 240 mg/day plus intensive loperamide prophylaxis (ie, 4 mg with the first dose of neratinib, 4 mg 3-times daily for 2 weeks, then 4 mg twice daily). The primary outcome of the study is the incidence and severity of diarrhea, and secondary outcomes include the incidence and severity of diarrhea by loperamide exposure.


The precise molecular mechanism of neratinib-induced diarrhea is unknown, but is postulated to be due to EGFR inhibition and resultant secretory diarrhea.⁵⁵ Preclinical studies are ongoing to better characterize the histopathology, clinical symptoms, and blood biochemistry of neratinib-induced diarrhea, and to understand the on-target effects of neratinib on the gastrointestinal system and the specific mechanisms of the neratinib-related diarrhea.

Conclusions

Diarrhea is a recognized adverse event of many cancer treatments and a side effect well understood by most oncologists. Once diarrhea occurs, it should be managed promptly and aggressively to prevent an escalation in severity and patient morbidity, and to maintain full-dose therapy. Diarrhea is a class effect of EGFR-directed tyrosine kinase inhibitors, and the most common toxicity of neratinib, a novel irreversible pan-HER tyrosine kinase inhibitor. For patients receiving neratinib, preventive management with intensive loperamide prophylaxis is required to reduce the severity and duration of diarrhea. Loperamide prophylaxis should be started with the first dose of treatment and continued until the end of the first cycle, regardless of the presence or absence of diarrhea. Any treatment-emergent diarrhea should be managed according to standard guidelines.

Initial trials with neratinib were all performed without the support of effective antidiarrheal prophylaxis. Intensive loperamide prophylaxis has been implemented and refined in ongoing and new trials of the drug. Preliminary safety data from these trials suggest that active management with intensive loperamide prophylaxis reduces the incidence, severity, and duration of neratinib-associated diarrhea. The frequency of grade 3 diarrhea when neratinib is given with intensive loperamide prophylaxis (0% to 17%) is similar to rates observed with other EGFR-directed tyrosine kinase inhibitors (1% to 14%), and considerably lower than rates observed with many chemotherapy regimens used in routine oncology practice (Table 1).

Intensive loperamide prophylaxis provides an effective means of reducing the incidence, severity and duration of neratinib-associated diarrhea. It should be given for the first cycle of treatment in all patients receiving neratinib. Current diarrhea prophylaxis recommendations are 4 mg with the first dose of neratinib, then 4 mg 3 times on day 1 (for a total of 16 mg on day 1), 4 mg 3-times daily (for a total of 12 mg/day) on days 2 and 3, reducing to 2 mg 3- or 4-times daily (for a total of 6-8 mg/day) for the remainder of the first cycle. Nonpharmacologic interventions, including dietetic changes and increased fluid intake, are recommended for new-onset uncomplicated diarrhea.

Affiliations: Federico Ustaris, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD, are from Puma Biotechnology Inc, Los Angeles, CA, USA. Cristina Saura, MD, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Jack Di Palma, MD, Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama, USA.

Disclosures: Dr Saura declares consultancy work and involvement in paid advisory boards. Dr Di Palma is involved in an independent data management committee. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnology Inc, and Drs Bryce and Neuman also declare stock ownership in the company.

Source of Funding: Puma Biotechnology Inc was involved in the collection, analysis, and interpretation of safety data, and provided funding for editorial assistance. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnology Inc. All authors revised the manuscript for intellectual content and approved the final version.

Address Correspondence to: Dr Federico Ustaris; Phone: 424-248-6500; fax: 424-248-6501; email: RUstaris@ pumabiotechnology.com

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