FDA Grants Neratinib Orphan Drug Designation for Breast Cancer Brain Metastases

The FDA has granted neratinib with an orphan drug designation for the treatment of patients with breast cancer–related brain metastases.

The FDA has granted neratinib (Nerlynx) with an orphan drug designation for the treatment of patients with breast cancer—related brain metastases.1

“Receiving orphan drug designation from the FDA signifies our continued progress and commitment to developing treatments for patients with HER2-positive breast cancer,” Alan H. Auerbach, chairman, CEO, and president of Puma, the company developing the kinase inhibitor, said in a statement. “Despite expanded treatment options for HER2-positive breast cancer, brain metastases in these patients represent a significant clinical challenge, as well as sources of morbidity and mortality for most of these patients. The blood-tumor penetrability of Nerlynx represents a potential treatment option for these underserved patients.”

In the phase II TBCRC 022 trial, neratinib in combination with capecitabine demonstrated a significant benefit in patients with HER2-positive breast cancer and brain metastases.2

The trial enrolled 49 patients across 2 cohorts, one with patients who had been pretreated with lapatinib (Tykerb; n = 12) and another with patients who were not previously treated with lapatinib (n = 37). The lapatinib-treated cohort was closed for slow accrual, however.

Patients with progressive HER2-positive brain metastases, most of which had already undergone central nervous system (CNS) surgery and/or radiotherapy, received 240 mg neratinib once daily plus 750 mg/m2capecitabine twice daily for 14 days followed by 7 days off. Patients also received 16 mg loperamide once per day during cycle 1 for mandatory diarrhea prophylaxis. The primary endpoint was composite CNS objective response rate (ORR).

In the lapatinib-naïve cohort, the composite CNS ORR was 49% (95% CI, 32%-66%) and the CNS ORR was 33% (95% CI, 10%-65%) among the lapatinib-pretreated patients, which consisted of all partial responses in each cohort. The median progression-free survival for the lapatinib-naïve and -pretreated patients was 5.5 and 3.1 months, respectively, and the median overall survival was 13.3 and 15.1 months.

The extracranial ORR was 14% (95% CI, 4%-32%) in the lapatinib-naïve group and was 43% (95% CI, 10%-82%) in the lapatinib-pretreated group.

The most common adverse event observed with the combination was diarrhea, which was reported at grade 3 in 33% of the lapatinib-naïve group and in 29% of the lapatinib-pretreated group. There were no grade ≥4 events observed. Dose reductions were required in 33% of patients.

Neratinib has been approved by the FDA for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed or HER2-amplified breast cancer following adjuvant trastuzumab (Herceptin)—based therapy. The agent is also being reviewed for a potential approval in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have progressed on ≥2 prior HER2-targeted treatments.


  1. FDA Grants Orphan Drug Designation to Puma Biotechnology’s NERLYNX for the Treatment of Breast Cancer Patients with Brain Metastases [press release]. Los Angeles, CA: Puma Biotechnology, Inc; September 3, 2019. https://bit.ly/2kgFK1u. Accessed September 4, 2019.
  2. Freedman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. 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.J Clin Oncol.2019;37(13):1081-1089. doi: 10.1200/JCO.18.01511.