TBCRC 022: A Phase II Trial of Neratinib and Capecitabine 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 to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.

Patients and methods: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m² twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring 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.

Results: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).

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.

Trial registration: ClinicalTrials.gov NCT01494662.

FIG 1.

Waterfall plot for best volumetric response in (A) cohort 3A and (B) cohort 3B. Patients who did not make it to their first reimaging were assigned a zero (six patients in cohort 3A: for toxicity [n = 3], MD discretion [n = 1], and clinical CNS progression [n = 2], and two patients in cohort 3B for clinical CNS progression). Stars represent those patients who also had a CNS response by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

FIG 2.

Progression-free survival (PFS) for (A) cohort 3A and (B) cohort 3B.

FIG A1.

Translational Breast Cancer Research Consortium 022 study cohorts to date. Cohorts 3A and 3B are presented here. HER2, human epidermal growth factor receptor 2.

FIG A2.

Overall Survival for cohorts (A) 3A and (B) 3B.

FIG A3.

Best Response by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) Criteria in (A) Cohorts 3A and (B) 3B Patients who did not make it to their first re-imaging were assigned a zero. Blue bars represent patients who had a CNS response by RANO-BM criteria. Green bars represent patients who did not meet criteria for response by RANO-BM. Red stars represent patients who had a CNS response by composite (volumetric) criteria. On cohort 3A, among the 8 patients who had composite/volumetric responses and not responses by RANO-BM, 6 had stable disease as their best RANO-BM response and 2 had non-sustained partial responses. On Cohort 3B, the 2 patients with composite/volumetric responses met all criteria for RANO-BM response except they were not sustained for at least four weeks.