Management of Diarrhea in Patients with HER2-Positive Breast Cancer Treated with Neratinib: A Case Series and Summary of the Literature

Breast cancers characterized by human epidermal growth factor receptor 2 (HER2) overexpression represent a common, aggressive subtype, comprising approximately 20% of breast cancers [1]. Although trastuzumab has improved outcomes for patients with HER2-positive (HER2+) breast cancer, long-term follow-up of phase 3 trials has demonstrated that cancer recurs within 10 years in 25–31% of patients treated with adjuvant trastuzumab [1‐4]. Metastatic and recurrent HER2+ breast cancers are often associated with an increased propensity for developing central nervous system (CNS) metastases, which occur in up to 50% of patients with HER2+ metastatic breast cancer (MBC) [1, 5, 6].

In recent years, novel neoadjuvant, adjuvant, and extended adjuvant regimens have reduced the risk of recurrence for patients with HER2+ early-stage breast cancer (ESBC) [1]. The phase 3 NOAH study demonstrated that addition of trastuzumab to neoadjuvant chemotherapy was associated with a greater proportion of patients achieving a pathologic complete response (pCR) and a significant improvement in event-free survival [7]. pCR rate was further improved with the use of neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab based on the results of the phase 2 NeoSphere and TRYPHAENA trials [8, 9]. The combination of trastuzumab and pertuzumab showed efficacy in the phase 3 APHINITY trial, and results of the phase 3 KATHERINE trial have supported adjuvant ado-trastuzumab emtansine (T-DM1) as an option for patients with residual disease [10, 11]. In patients with HER2+ ESBC treated with adjuvant trastuzumab-based therapy, extended adjuvant therapy with the oral, irreversible pan-HER tyrosine kinase inhibitor (TKI) neratinib significantly improved invasive disease-free survival in the phase 3 ExteNET study [12, 13].

HER2-targeted agents, including neratinib, have also improved outcomes for patients with HER2+ MBC. Regimens demonstrating efficacy in this setting include pertuzumab in combination with trastuzumab and docetaxel, T-DM1, trastuzumab deruxtecan, and other trastuzumab plus chemotherapy combinations [1, 14‐17]. Neratinib and other TKIs have shown efficacy in MBC in combination with trastuzumab, capecitabine, and/or other cytotoxic therapies [18‐26]. In addition, TKI-containing combinations, such as neratinib in combination with capecitabine or paclitaxel, lapatinib plus capecitabine, and tucatinib plus trastuzumab and capecitabine, have shown benefit in patients with CNS metastases [18, 27‐30].

Neratinib is approved for use as extended adjuvant therapy for HER2+ ESBC or in combination with capecitabine in the treatment of HER2+ MBC [31]. In the current National Comprehensive Cancer Network Guidelines, neratinib is included as a category 2A recommendation for both HR+, HER2+ ESBC following adjuvant trastuzumab-containing therapy and HER2+ MBC third line and beyond and is also included as a treatment option for recurrent HER2+ breast cancer CNS metastases [32, 33]. Gastrointestinal (GI)-related adverse events, especially diarrhea, are common with neratinib and can lead to early discontinuation. This is likely a class effect for TKIs with broader target profiles. The mechanism is not completely understood, but may involve dysregulated ion transport, inflammation, and mucosal injury [12, 13, 18, 23, 24, 26, 34]. In the ExteNET trial, in which the use of anti-diarrheal prophylaxis was not mandated, 95% of patients on extended adjuvant neratinib experienced diarrhea, including grade 3 diarrhea in 40% of patients. Twenty-eight percent of patients discontinued because of any treatment-emergent adverse event (TEAE) and 17% discontinued because of diarrhea. [12, 35]. Early discontinuation is thought to negatively affect treatment outcomes, as subgroup analyses of ExteNET have shown that remaining on treatment for ≥ 11 of the recommended 12 months is important for neratinib efficacy [36, 37]. In the phase 3 NALA study of capecitabine plus either neratinib or lapatinib in patients with MBC previously treated with ≥ 2 HER2-directed regimens, diarrhea was managed with mandatory loperamide prophylaxis in the neratinib plus capecitabine arm, in which 24.4% of patients experienced grade 3 diarrhea, resulting in discontinuation of neratinib in only 2.6% of patients [26].

The phase 2 CONTROL study was designed to prospectively evaluate strategies for managing neratinib-induced diarrhea in HER2+ ESBC [38]. CONTROL evaluated prophylactic use of various antidiarrheal medications as well as dose escalation (DE) of neratinib from a lower starting dose to the full US Food and Drug Administration (FDA)-approved dose of 240 mg/day [38]. All preventive strategies reduced the incidence, duration, and severity of neratinib-induced diarrhea, lowering neratinib discontinuation rates compared to ExteNET, except in the loperamide-alone arm. Neratinib DE (2-week DE schedule: week 1 = 120 mg/day, week 2 = 160 mg/day, week 3 and onwards: 240 mg/day) was identified as a particularly beneficial strategy for maintaining patients on therapy based on a 13% rate of grade ≥ 3 diarrhea, a 3.3% rate of diarrhea-related discontinuation, and a 13.3% rate of discontinuation due to any TEAE [31, 38, 39]. A 2-week DE schedule also lowered the rate of constipation (all grades) compared with antidiarrheal strategies that mandated loperamide prophylaxis (33% vs. 57–75%) [38].

To better understand clinical management of neratinib-associated diarrhea, this series describes four patients with ESBC and one patient with MBC treated with neratinib. The aim is to discuss strategies for managing neratinib-associated diarrhea in a real-world setting, with the goal of improving the patient experience and maintaining patients on therapy. These cases were identified through the authors’ clinical practice. All identifying details, including the specific institutional settings, have been deidentified to protect the anonymity of the patients.

This article is based on previously conducted studies and anonymized case descriptions and does not contain any new studies with human participants or animals performed by any of the authors.

The patient cases presented in this series provide examples of proactive management of diarrhea in patients with HER2+ ESBC and MBC treated with neratinib. In four of five cases, diarrhea was managed with neratinib DE, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy, although two patients were unable to reach or maintain the full approved dose, in one case because of diarrhea and the other because of PPE.

Management of diarrhea with neratinib DE and antidiarrheal prophylaxis in this series is consistent with results from the CONTROL trial [38]. Neratinib DE was effective for managing and possibly reducing neratinib-associated early-onset diarrhea in cases 1, 2, 3, and 5, allowing therapy continuation. Three patients reached the full dose, and one patient was able to titrate to her maximum tolerable dose. DE was more effective for diarrhea management than loperamide prophylaxis in case 5, consistent with results from CONTROL [38], in which antidiarrheal prophylaxis with loperamide alone was not as successful as neratinib DE. Results from CONTROL showed that 2-week neratinib DE with loperamide PRN was associated with the lowest rate of both diarrhea-associated discontinuation (3.3% vs. 4–20%) and all-grade constipation (33% vs. 57–75% in prophylaxis cohorts with mandatory loperamide and 38% with mandatory colestipol/loperamide PRN) [38] as well as a higher mean cumulative dose of neratinib compared to ExteNET (67,364.0 mg vs. 54,193.9 mg) [31, 38, 39]. Notably, neratinib DE was effective for managing neratinib-induced diarrhea in the patient with MBC described in case 5, consistent with the FDA-approved dosing strategy for MBC in addition to ESBC [31]. Because early-onset diarrhea may lead to neratinib discontinuation, proactive management of diarrhea with neratinib DE may allow for continuation of therapy across neratinib treatment settings.

Antidiarrheal prophylaxis with loperamide and colestipol was effective for managing diarrhea during the early course of treatment in case 4, although neratinib dose reduction was eventually required because of subsequent PPE. Prophylactic loperamide and colestipol reduced the incidence and severity of diarrhea in CONTROL, resulting in a diarrhea-related discontinuation rate of 4%; however, as described above, prophylactic strategies were associated with a higher rate of GI adverse events compared to DE [38]. In addition, these regimens may be more inconvenient for patients because of the number of pills/tablets required per day.

Although neratinib DE was used in most of the cases described here, some escalation schedules differed from the DE schedules evaluated in CONTROL (Fig. 1) [38]. Several patients in this series initiated neratinib on longer or slower DE intervals as a precaution due to comorbidities or other considerations that could increase the likelihood of discontinuation, suggesting that extended DE strategies may be an option. As described in case 3, for patients with slower DE or other interruptions, oncologists may consider prolonging the course of therapy to make up for missed doses.

The patient cases described in this series suggest that neratinib-associated diarrhea is generally manageable, even in patients with potentially complicating comorbidities. In the extended adjuvant setting, neratinib has been shown to offer greater benefit in patients with hormone receptor–positive, lymph node–positive disease who were ≤ 1 year from completion of trastuzumab, but patients with clinically significant GI comorbidities were excluded from ExteNET [12]. However, results reported in case 4 of this series demonstrate that a patient with well-managed Crohn’s disease was able to complete the entire course of neratinib with implementation of prophylactic antidiarrheal treatment. Similarly, patients with HER2+ MBC who had previously been treated with an anti-HER2 TKI were excluded from NALA [26]. The patient described in case 5 achieved disease response to neratinib plus capecitabine immediately following treatment with lapatinib plus capecitabine by managing neratinib-induced diarrhea and maintaining adherence to therapy using DE. These results suggest that some patients excluded from previous trials may be able to tolerate neratinib and thereby experience potential clinical benefit, meriting additional evaluation in an expanded patient population.

This case series highlights the importance of provider-patient communication in establishing patient expectations and managing adverse effects of neratinib. Early conversations may help identify patient concerns and manage expectations about long-term therapy [41, 42]. As described in case 5, some patients may prefer the convenience of oral therapy, which is also a consideration during the COVID-19 pandemic to minimize in-person visits [43]. Likewise, reducing the incidence of severe diarrhea may decrease inpatient admissions or reduce the need for administering additional supportive care measures in a clinical setting, thereby decreasing contact with the health care system. Providing patients with a written plan during early consultations may alleviate anxiety and establish expectations for treatment [41], although the plan may change based on clinical factors. The patient described in case 2 was enrolled in a patient management program through a specialty pharmacy, which augmented educational counseling at neratinib initiation and provided additional support for managing adverse effects. As described in this case and in case 1, frequent contact at initiation of neratinib may be beneficial, and pharmacists and advanced practice providers can play an important role in treatment optimization [44].

As described above, results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or DE of neratinib from a lower starting dose can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer [38]. The 2-week DE schedule (week 1 = 120 mg/day, week 2 = 160 mg/day, week 3 and onwards: 240 mg/day) has been included in the FDA label for both HER2+ ESBC and MBC since June 2021 [31]. An alternative DE schedule with a panel recommendation to start neratinib at a dose of 120 mg/day with PRN loperamide and escalate the dose by 40 mg/day each week until patients reach the recommended dose of 240 mg/day of neratinib has also been published [45].

In summary, this case series shows that neratinib-associated diarrhea can be effectively managed with neratinib DE from a lower initial starting dose or prophylactic antidiarrheal medications in a real-world clinical setting. Widespread adoption of the strategies described here may allow more patients to adhere to neratinib therapy and thereby improve clinical outcomes for patients with HER2+ breast cancer treated with neratinib.