Neratinib Plus Capecitabine Provides a Glimmer of Hope for a Daunting Disease

Despite major advances in the targeted treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer, the management of CNS metastases in patients with advanced disease is an increasingly common challenge. Large adjuvant trastuzumab trials have demonstrated that 2% to 4% of patients with early-stage HER2-positive breast cancer develop CNS metastases as the first site of relapse.^1-3 Although the risk of relapse is highest in the first 3 years,^2,3 CNS relapses have been observed out to year 10.³ In the metastatic setting, more than 30% of patients diagnosed with stage IV HER2-positive breast cancer develop CNS involvement, most within the first 3 years of their metastatic diagnosis.⁴ It has been well established that patients with breast cancer brain metastases (BCBM) have a worse quality of life, reduced progression-free survival (PFS), and shorter overall survival (OS) compared with those without CNS involvement.^4,5 Identifying regimens to improve outcomes for this poor prognostic subset of patients remains a considerable unmet need in breast cancer.

In the last decade, results from a handful of phase I and II trials evaluating regimens that incorporated orally bioavailable targeted therapy including lapatinib, afatinib, neratinib, and everolimus have been reported for patients with HER2-positive active BCBM.^6-12 The investigational agents being studied in these trials were selected based not only on preclinical and clinical evidence of efficacy in HER2-positive disease but also on the ability to penetrate the blood-brain barrier. Two of these studies were randomized trials,^9,10 one was a report of patients treated through the lapatinib expanded access program in the United Kingdom,¹¹ and the rest were nonrandomized, single-arm trials. With the exception of the LANDSCAPE trial, in which patients were less-heavily pretreated and were excluded if they had prior whole-brain radiation or stereotactic radiosurgery,⁶ as a whole these studies demonstrated a CNS objective response rate (ORR) of less than 40% and a median PFS not exceeding 6 months. Despite their early promise, none of these regimens demonstrated groundbreaking efficacy results, and all were associated with at least some level of moderate to severe toxicity.

The two-cohort, phase II Translational Breast Cancer Research Consortium (TBCRC) 022 study, reported by Freedman et al¹³ in the article that accompanies this editorial, demonstrated arguably some of the most noteworthy efficacy results reported to date for patients with HER2-positive BCBM. In their study, the combination of neratinib plus capecitabine demonstrated a CNS objective response rate of 49% (18 of 37) in patients who were naïve to lapatinib and capecitabine (cohort A) and 33% in the small group of patients (n = 12) who were previously exposed to lapatinib (cohort B). These results are especially impressive in light of the fact that 92% had progressive disease in the brain after receiving local therapy (radiation, surgery, or a combination thereof), although only a third of patients had more than one prior line of chemotherapy in the metastatic setting, and only 27% of patients had ever received ado-trastuzumab emtansine. Importantly, clinical benefit was not short lived, as evidenced by the fact that the majority of patients initiated at least six cycles of therapy. In contrast to the large adjuvant ExteNET study,¹⁴ there did not seem to be any differential activity of neratinib according to hormone receptor status in this trial. Although the primary aim of this study was to evaluate the activity of this regimen in the CNS, four of 29 patients in cohort A and three of seven patients in cohort B with extracranial measurable disease achieved an objective response outside the CNS.

One unique feature of this study was the inclusion of patients with active leptomeningeal disease. Given the poor prognosis associated with leptomeningeal carcinomatosis, the majority of studies have excluded such patients. Although the sample size is quite small (n = 3), one patient reached a partial CNS response and continued to receive treatment for seven cycles, and another patient completed three cycles of therapy with stable disease, providing provocative early hints of the potential activity of this combination for this poor prognostic subcategory of metastatic breast cancer.

Although the activity of this regimen stands out, toxicity remains a concern. Keeping in mind capecitabine was dosed at 750 mg/m² and all patients were prescribed loperamide prophylaxis, 29% of all patients still experienced grade 3 diarrhea. In addition, although patients were eligible for the study if they had an Eastern Cooperative Oncology Group performance status of 2 or better, 90% of study participants had a performance status of 0 or 1, indicating the general overall good health of participants at baseline. In spite of this, a third of all patients had dose reductions of neratinib (dose reductions for capecitabine were not collected), and 22% of patients in cohort A discontinued study early because of toxicity, possibly negatively affecting the clinical efficacy of this regimen. The authors aptly point out that data from ongoing studies evaluating how to best prevent and control this adverse effect will need to be integrated into clinical practice when using this regimen. Moreover, careful patient selection and patient education regarding GI toxicity are warranted. It is unfortunate that patient-reported outcomes were not conveyed in this trial, especially in light of the paramount importance of optimizing quality of life when managing patients with incurable disease.

Although the data from TBCRC 022 are arguably some of the most promising seen to date for HER2-positive BCBM, the decision to use neratinib plus capecitabine in place of standard first- or second-line systemic treatment is not yet supported by phase III evidence. Current ASCO Clinical Practice Guidelines¹⁵ recommend patients receive first-line treatment with trastuzumab plus pertuzumab and a taxane (THP), given the significant PFS and OS benefits demonstrated with this regimen in the CLEOPATRA trial.¹⁶ Moreover, ASCO guidelines specific to patients with HER2-positive BCBM¹⁷ recommend that systemic therapy be chosen based on algorithms for HER2-positive breast cancer rather than selecting a regimen on the basis of the presence or absence of brain metastases. Granted that patients with active, untreated brain metastases were excluded from CLEOPATRA, the median OS associated with the THP regimen was close to 5 years, the longest reported to date in a phase III trial for HER2-positive advanced disease, thus making this regimen the gold standard in the United States. Head-to-head studies comparing lapatinib to trastuzumab in the hopes that lapatinib would reduce CNS metastases demonstrated inferior outcomes with the tyrosine kinase inhibitor. The first-line MA.31 study comparing taxane plus either lapatinib or trastuzumab demonstrated a worse PFS associated with lapatinib-based therapy,¹⁸ and the phase III CEREBEL trial demonstrated a worse PFS and OS with lapatinib plus capecitabine compared with trastuzumab plus capecitabine, with similar rates of CNS metastases as first site of relapse.¹⁹ Although the NEfERT-T study²⁰ demonstrated that first-line neratinib plus paclitaxel was associated with a reduced rate of CNS progression events, this regimen failed to demonstrate superior PFS compared with trastuzumab plus paclitaxel and thus cannot be recommended to replace the standard first-line THP regimen.

Despite this, emerging real-world data indicate that the ASCO guidelines are not being universally followed. Results from the US-based SystHERs observational registry, in which approximately 1,000 patients with newly diagnosed HER2-positive metastatic breast cancer were followed for treatment patterns and outcomes, demonstrated that patients with brain metastases were less commonly treated with standard-of-care first-line trastuzumab-based therapy than those without brain metastases.⁴ Almost a quarter of patients with brain metastases were treated with lapatinib-based therapy first line compared with less than 3% of patients who did not have brain metastases. This indicates that the presence of CNS metastases is influencing the selection of systemic therapy by some clinicians, even though there is no randomized evidence to support this practice.

Numerous questions are left unanswered when it comes to optimal management of HER2-positive BCBM. For example, there is still a lack of prospective randomized data to indicate whether patient outcome is improved by aggressive local therapy (surgery/radiation) followed by tailored systemic therapy versus a systemic therapy approach from the outset. This question will become more pressing as active brain-penetrating targeted therapies are made available. Moreover, assuming new small-molecule HER2-targeted agents such as neratinib and the promising HER2-selective tyrosine kinase inhibitor tucatinib²¹ receive regulatory approval for BCBM, studies will be needed to specifically define their activity in lapatinib-pretreated disease, given the widespread use of lapatinib in this setting. Interestingly, four of 12 patients in cohort B of TBCRC 022 had a CNS response despite receiving prior lapatinib, although these data need confirmation in a larger sample. Randomized studies are also needed to determine optimal first- and second-line treatment of patients with CNS-only metastases as the current standard of care (THP followed by ado-trastuzumab emtansine) may not be the most effective way to provide long-term disease control for those without extracranial metastases.

Although the adverse effects need to be carefully managed, the efficacy data from the TBCRC 022 study provide evidence that neratinib plus capecitabine can achieve meaningful responses for our patients with CNS metastases and gives hope that this regimen may have activity even in leptomeningeal disease and an early indication of activity even in lapatinib-pretreated disease. Despite the fact these phase II data do not address many critical outstanding questions, they do provide a glimmer of hope that we are getting closer to successfully managing a formidable disease.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Neratinib Plus Capecitabine Provides a Glimmer of Hope for a Daunting Disease

The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Sara A. Hurvitz

Research Funding: Genentech (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Boehringer Ingelheim (Inst), Sanofi (Inst), Pfizer (Inst), Amgen (Inst), OBI Pharma (Inst), Puma Biotechnology (Inst), Dignitana (Inst), Bayer (Inst), BioMarin Pharmaceutical (Inst), Eli Lilly (Inst), Merrimack (Inst), Medivation (Inst), Cascadian Therapeutics (Inst), Seattle Genetics (Inst), Daiichi Sankyo (Inst), Macrogenics (Inst), Ambryx (Inst),

Travel, Accommodations, Expenses: Novartis, Eli Lilly, OBI Pharma