Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2019-05-01
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.
Related Questions
How would you treat a patient with HER2 positive CNS only progression on fam-trastuzumab which had previously progressed on tucatinib/capecitabine/trastuzumab, and has failed both SRS and WBRT?
I would present or refer her case to a multidisciplinary tumor board to 1) review her MRI to confirm there is progression vs. therapy changes, 2) see if she is a candidate for resection or irradiation of the progressing lesion (possibly using bevacizumab to reduce risk of radiation necrosis), and 3)...
What systemic treatment would you offer for metastatic HER2+ breast cancer that has progressed through THP and TDM-1 with predominant CNS progression and without localized treatment options?
For patients after 2 standard lines of HER2-targeted therapies with CNS progression who are not candidates for local CNS therapy, my first option would be to use trastuzumab plus tucatinib (with capecitabine if not previously used) if available (e.g. single patient IND). There is demonstrated activi...