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

TLDR

Evidence‑based treatments for metastatic HER2‑positive breast cancer to the CNS are limited, and prior studies have shown only modest activity of neratinib monotherapy for brain metastases. The study aimed to evaluate the efficacy and tolerability of neratinib 240 mg daily plus capecitabine 750 mg/m² twice daily for 14 days with a 7‑day break in patients with measurable, progressive HER2‑positive brain metastases. Patients were enrolled in two cohorts—lapatinib‑naïve and lapatinib‑treated—and the primary endpoint was composite CNS objective response rate, defined as a ≥50 % reduction in target lesion volume without progression of non‑target lesions or new CNS disease. The combination achieved composite CNS ORRs of 49 % in cohort 3A and 33 % in cohort 3B, with median progression‑free survival of 5.5 and 3.1 months and median overall survival of 13.3 and 15.1 months, respectively, and was associated with grade 3 diarrhea in 29 % of patients, demonstrating activity against refractory HER2‑positive brain metastases and supporting enhanced efficacy of HER2‑directed therapy when combined with chemotherapy.

Abstract

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 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.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.