Combination demonstrates activity in brain metastases from HER-2–positive breast cancer

CHICAGO — The combination of neratinib and capecitabine conferred benefit to patients with HER-2–positive breast cancer whose disease metastasized to the brain, according to results of a phase 2 study presented at the ASCO Annual Meeting.

“Brain metastases from HER-2–positive breast cancer remains an important clinical challenge for patients and providers, particularly if cancer in the brain returns after initial treatment with surgery and / or radiation,” Rachel A. Freedman, MD, MPH, an associate clinical director of the Breast Oncology Center at Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, told HemOnc Today. “There are no FDA-approved medical treatments for this clinical problem and finding new ways to treat brain metastases effectively is a priority.”

Freedman and colleagues conducted a single arm, open-label study of 39 patients (median age, 51 years) with HER-2–positive breast cancer whose disease metastasized to the brain and who did not receive prior lapatinib (Tykerb, Novartis) or capecitabine therapy.

Sixty-five percent of patients had received prior whole brain radiation therapy.

All patients had measurable brain metastases of 1 cm or greater and all but three developed central nervous system progression after receiving local treatment.

All study participants received neratinib (PB272, Puma Biotechnology) in combination with capecitabine.

However, two patients withdrew prior to receiving therapy.

During 21-day cycles, patients received capecitabine 750 mg/m² twice daily for 14 days followed by 7 days off, plus neratinib 240 mg administered orally once daily.

The researchers recommended 16 mg loperamide prophylaxis daily during cycle 1. Brain MRI and non-central nervous system imaging were repeated every two cycles for the first 18 weeks, and then every three cycles thereafter.

Composite central nervous system objective response rate served as the primary endpoint. Secondary endpoints included 12-month overall survival and safety.

The researchers noted to reach the primary endpoint, patients had to meet multiple requirements. Patients must have had a 50% or greater reduction in volumetric sum of target CNS lesions, no progression of non-target or non-CNS lesions, no new lesions, no escalation of steroids, and no progressive neurologic signs or symptoms.

Forty-nine percent of the patient population experienced a volumetric response to therapy without progression in other sites, Freedman said.

Overall 12-month survival was 63%, and according to Freedman, median PFS was 5.5 months.

Diarrhea was the most common reported toxicity, with approximately 32% reporting grade 3 events despite mandatory prophylaxis with loperamide during cycle 1. No patients reported any grade 4 adverse events.

“[These] results provide further support for the efficacy of HER-2-directed systemic therapy for the treatment of breast cancer brain metastases,” Freedman said. “Future studies could examine local therapy versus systemic therapy in CNS disease and further explore the role of neratinib-based combination regimens. Further efforts to optimize toxicity management with neratinib-based regimens will be required to reduce the impact on quality-of-life.” – by Ryan McDonald

Reference:

Freedman RA, et al. Abstract 1005. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosures: Freedman reports receiving research funding to her institution from Eisai, Genentech and Puma Biotechnology.