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Abstract P2-11-03: Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial
Abstract
Background: Neratinib (Puma Biotechnology Inc) is an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2+ BC. Diarrhea, the main toxicity of neratinib, requires active management with loperamide prophylaxis given early in the course of treatment. CONTROL (PUMA-NER-6201) is an international, open-label, phase II study investigating the efficacy of loperamide prophylaxis in the prevention of neratinib-associated diarrhea. CONTROL has recently been expanded to include prophylaxis with loperamide + budesonide, which targets inflammation identified in a preclinical model of neratinib induced diarrhea.
Methods: Pts with HER2+ early-stage BC who had completed trastuzumab-based adjuvant therapy were eligible. All pts were to receive oral neratinib 240 mg/day for 1 year + structured loperamide prophylaxis on d1–56 (2 cycles). Adverse events were graded according to NCI-CTCAE, v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. A protocol defined interim analysis (data cut-off July 2016) was performed when ∼120 pts had completed ≥2 cycles of neratinib + loperamide prophylaxis. A preliminary analysis of the loperamide + budesonide cohort was also performed at this time. Clinicaltrials.gov: NCT02400476.
Results: For the interim analysis, 133 pts received neratinib + loperamide prophylaxis. A further 16 (of 40 planned) pts received neratinib + loperamide prophylaxis (2 cycles) + budesonide (1 cycle). Key results are shown in the table. Incidence of grade ≥3 diarrhea was 27.1% with loperamide prophylaxis and 12.5% with loperamide + budesonide prophylaxis vs 39.9% without protocol-mandated loperamide prophylaxis (ExteNET). Grade 2 diarrhea also decreased (20.3%, 18.8% vs 32.5%, respectively). Grade 3 diarrhea events were uncommon after cycle 1 in all CONTROL cohorts.
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Conclusions: A structured loperamide prophylactic regimen for 2 cycles is associated with a lower incidence and severity of neratinib associated diarrhea, with notably less grade 2/3 diarrhea compared to ExteNET events. There appears to be some adaptation to the effects of neratinib, as higher-grade diarrhea occurs early and does not typically recur. Preliminary data suggest that adding budesonide may further improve outcomes; enrollment into the budesonide cohort continues.
Citation Format: Barcenas C, Olek E, Hunt D, Tripathy D, Ibrahim E, Wilkinson M, Hurvitz S, Iannotti N, Kellum A, Manalo Y, Wong S, Hansen V, Alvarez R, Chan A, Gore I, Kendall D, Wade J, Ruiz R, Fang P, Bryce R, Moran S. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-03.
... Since immunogenicity may be boosted by the action of trastuzumab, many studies investigating the combination of trastuzumab and immunotherapy are currently ongoing • Combinations of anti-HER2 therapy with other agents including CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are possible strategies to overcome some mechanisms of acquired resistance • Many strategies to improve treatment tailoring are currently under investigation, including functional imaging in advanced HER2+ BC and identification of predictive biomarkers of drug efficacy arm, despite no differences in median PFS were observed between HER2+ MBC patients treated with neratinib and paclitaxel compared to trastuzumab and paclitaxel [29]. Since significant gastrointestinal toxicitymostly diarrhea grades 2 and 3 reported in several trialsmay limit the clinical use of this drug, the development of an adequate supportive care therapy for patients receiving neratinib should be a priority; a concomitant treatment with loperamide has been studied in the CONTROL trial with positive preliminary results [30]. A few trials investigating neratinib alone (NCT02673398) or in combination with other therapies, including fulvestrant, capecitabine and T-DM1 (NCT03289039, NCT02236000, NCT03377387) are currently ongoing. ...
Introduction: Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, HER2 positive metastatic breast cancer remains an almost invariably deadly disease, with primary or acquired resistance to HER2 directed agents developing during course treatment. Many efforts are focused on identifying new agents that may more effectively inhibit HER2 signaling and on possible combination strategies.
Areas covered: This review summarizes the landscape of drugs under development for HER2 positive metastatic breast cancer, as antibody-drug conjugates, monoclonal anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors. Moreover, available data for possible combination of anti-HER2 drugs and different agents, as immunotherapy, PI3K/mTOR inhibitors, CDK4/6 inhibitors currently under evaluation are reviewed. These strategies may overcome mechanisms of resistance and further improve patient outcomes.
Expert opinion: Identification of valuable predictive biomarkers is needed to better inform choice of treatment sequence for the individual patient and limit the financial toxicity of these agents.
... Although the mechanism of neratinib-associated diarrhea is not well understood, preliminary investigations suggested an inflammatory component. [23][24][25][26][27] One report suggested that budesonide, an oral, poorly absorbed corticosteroid, decreased grade 3 neratinib-associated diarrhea from 50% to 16% and evaluated the addition of the bile salt-binding agent colestipol in mitigating diarrhea. 28 The median neratinib trough concentration observed was 15 ng/mL (0.09 ng/mL/mg) with a range of 0.9 to 44 ng/mL, which is somewhat lower than that reported previously with 240 mg daily dosing (50 to 60 ng/mL; 0.2 ng/mL/mg). ...
Purpose:
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.
Patients and methods:
In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally.
Results:
Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue.
Conclusion:
We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.
... The main toxicity concern related to neratinib is clinically significant diarrhea, that might be better managed with primary prophylactic loperamide, reducing the incidence of grade 3 events [63,64,67]. The CONTROL trial is designed specially to establish an adequate regimen of diarrhea management during the use of neratinib [68]. ...
Introduction: Despite improvements in the management of HER2+ breast cancer, metastatic disease is still fatal. Usually, these patients receive several lines of chemotherapy associated with HER2 targeted treatments. Most of the trials using innovative approaches are positioning themselves in disease that is resistant to pertuzumab and trastuzumab emtansine (TDM1).
Areas covered: We describe the recent advances in clinical development of anti-HER2 treatments. To this aim, we used literature search via Pubmed and made an inventory of abstracts published during the last two years in major oncology conferences.
Expert opinion: Further changes will probably occur during the next decade in the management of metastatic HER2-positive breast cancer. This is mainly driven by the fact that the two mainstay drugs (pertuzumab and TDM-1) that confer prolonged survival (56 months) to these patients are currently being used in the treatment of early-stage disease in a subset of patients. Thus, there is an urgent need to develop new, innovative approaches in those patients whose disease has become resistant to these highly potent drugs. Several new antibody-drug conjugates, bispecific antibodies or new generation tyrosine kinase inhibitor (TKIs) hold promise and should be assessed and compared with drugs currently used.
... prn = as needed. Information from Barcenas et al. (2016). a Noncompliance with loperamide prophylaxis in patients with grade 3 diarrhea was 71% with the original loperamide schedule, 35% with the modified loperamide schedule, and 0% with loperamide prophylaxis plus budesonide. ...
Neratinib following the completion of trastuzumab has been shown to reduce the risk of disease recurrence for patients with HER2-positive early breast cancer in whom extended adjuvant therapy seems advisable. In clinical trials, the most common side effect of neratinib and other anti-HER2 therapies was diarrhea. Presenters at JADPRO Live clarified the findings of trials studying the benefit of differing prophylactic regimens with loperamide, budesonide, and colestipol.
Approximately 6% of breast cancer diagnosis occurs in women under 40 years of age, accounting for more than 40% of all cancers in women in this age group. Indeed, according to WHO report on women and health, breast cancer represents the leading cause of death among women under the age of 45 years in high-income countries, following car and domestic accidents [1].
Introduction: Breast cancer (BC) is the most common cancer in women. Human epidermal growth factor receptor 2-positive (HER2-positive) BC represents up to 15% of all BC cases and is associated with a poor prognosis. Despite the substantial improvement obtained with the addition to the treatment of trastuzumab in this subtype of BC, disease recurrence can still occur.
Areas covered: Anti-HER2 targeting drugs such as trastuzumab, pertuzumab, and T-DM1 have shown significant results in (neo)adjuvant setting. In this article, we will focus on available data for neratinib to reduce BC recurrence based mainly on the results of the ExteNET trial. This trial aimed to investigate whether neratinib can further reduce the risk of recurrence of patients diagnosed with HER2-positive BC. This trial demonstrated a significant reduction in the risk of invasive disease-free survival, particularly in hormone receptor-positive population. In addition, this review provides an expert opinion and analysis of the current situation in the adjuvant HER2-positive BC setting and in particular the escalation strategy of HER2 targeting.
Expert opinion: The treatment landscape of HER2 positive BC in this setting will evolve in the coming years with a need for clinical and molecular perspective tools to guide therapy.
Background
Neratinib is a novel pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor that has shown promising activity against several types of malignancies, especially HER2-overexpressing breast cancer.
Objective
The objective of the current study was to provide a comprehensive insight into the efficacy and safety profiles of neratinib-based therapies.
Methods
Comprehensive literature searches of the PubMed, EMBASE, and Web of Science electronic databases were performed for all relevant clinical trials. Adverse events (AEs) of any grade and of grade 3 or higher were summarized and event rates were calculated. For controlled trials, odds ratios (ORs) were calculated to determine the role of neratinib in AEs. A random-effects model was applied if heterogeneity was observed (I² ≥ 50%), otherwise a fixed-effects model was used. Kaplan–Meier survival curves were extracted for hazard ratio (HR) calculation, and survival outcomes were measured by progression-free survival (PFS) and overall survival (OS).
Results
Twenty-three studies and 4896 patients were included in the analysis. The most frequently occurring all-grade AEs in neratinib monotherapy were diarrhea (83.9%), nausea (37.9%), and abdominal pain (28.4%). The most common AEs for grades 3 or 4 were diarrhea (25.1%), dyspnea (5.6%), and abnormalities in liver enzyme levels (4.2%). Diarrhea, the most common AE, can be mitigated by prophylactic loperamide. Neratinib demonstrated promising clinical activity as monotherapy in HER2-positive breast cancer; however, in contrast, the effect became much less significant among HER2-mutated breast cancer patients. Notably, neratinib-based combination therapy achieved a higher response rate than neratinib monotherapy.
Conclusions
Neratinib-based therapies led to a higher frequency of some AEs, although these were mostly tolerable. Most studies demonstrated that neratinib provides a benefit in survival outcome. When combined with other anticancer agents, neratinib may hold promise for treating breast cancer with central nervous system metastases.
In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer - HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including the "real-life" benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new imaging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER antibodies, which may, in coming years further push the boundaries of what we can do for our patients.
Introduction: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer.
Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review.
Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.
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