Neratinib Plus Capecitabine Active Against HER2-Positive Breast Cancer Brain Metastases


Key Points

  • Composite CNS objective response rates were 49% in lapatinib-naive patients and 33% in lapatinib-treated patients.
  • Median progression-free survival was 5.5 months in lapatinib-naive patients and 3.1 months in lapatinib-treated patients.

In the phase II TBCRC 022 trial reported in the Journal of Clinical Oncology, Freedman et al found that the combination of neratinib and capecitabine was active against brain metastases in women with HER2-positive breast cancer. Modest activity of neratinib monotherapy had been found in previous cohorts in the study.

Study Details

In the study, 49 patients with measurable, progressive, HER2-positive brain metastases were treated with neratinib at 240 mg orally once daily plus capecitabine at 750 mg/m2 twice daily for 14 days, with 7 days off. Patients were enrolled into a lapatinib-naive cohort (cohort 3A, n = 37) and a lapatinib-treated cohort (cohort 3B, n = 12; closed due to slow accrual). Approximately 92% of enrolled patients had received central nervous system (CNS) surgery or radiotherapy.

The primary trial endpoint was composite CNS objective response rate, defined as a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.

Response Rates

Composite CNS objective response rates were 49% in cohort 3A (partial response in 18 patients) and 33% (partial response in 4 patients) in cohort 3B. Stable disease for at least 6 cycles was observed in an additional 7 patients (19%) in cohort 3A and 3 patients (25%) in cohort 3B.  Median progression-free survival was 5.5 and 3.1 months, respectively, and median overall survival was 13.3 and 15.1 months.

Among 29 patients in cohort 3A with measurable extracranial disease at baseline, 1 had a complete response, 3 had a partial response, and 20 had stable disease. Among 7 patients in cohort 3B with measurable extracranial disease at baseline, 1 had a complete response, 2 had a partial response, and 3 had stable disease.

Adverse Events

Among all patients, the most common grade 3 adverse events considered related to study treatment were diarrhea (29%), hypokalemia (12%), fatigue (10%), and nausea (6%). Adverse events led to neratinib dose reductions in 33% of patients. No grade 4 adverse events were observed.

The investigators concluded, “Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.”

Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Puma Biotechnology, the Translational Breast Cancer Research Consortium’s foundation partners (AVON Foundation, Breast Cancer Research Foundation, Susan G. Komen for the Cure), the American Cancer Society, and others. The study authors' full disclosures can be found at

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