Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

Abstract

Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

“…With this regimen, the rate of grade 3 diarrhoea was 22% (Extended Data Table 2), consistent with previous experience 19 . Among patients who developed grade 3 diarrhoea, the median time to onset was 10 days and the median duration of the diarrhoea episode 2 days.…”

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

“…The efficacy of neratinib in patients with heavily pretreated progressive CNS metastases from HER2-positive breast cancer is also being investigated in a phase II study (Translational Breast Cancer Research Consortium 022). A CNS objective response rate of 8% was reported with single-agent neratinib 240 mg/day, which did not meet the study threshold for success [74]; however, the study is continuing and will test neratinib in combination with capecitabine in this patient population.…”

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…86 A single arm phase II trial on neratinib (HER2 TKI) in patients with brain metastases previously treated with either WBRT or SRS has shown a response rate of 8% with an OS of 8.7 months (class IIb). 87 Due to a lack of prospective trials, it is not clear whether trastuzumab, which probably can cross a more permeable BBB within established brain metastases, can be active as well. 88 Several case reports and small patient series indicate that the antibody-drug conjugate T-DM1 (trastuzumab emtansine) may be active against brain metastases of HER2+ breast cancer (class IV).…”