FDA Grants Neratinib Orphan Drug Status for Breast Cancer With Brain Metastases

The FDA has granted an orphan drug designation to neratinib (Nerlynx) for the treatment of patients with breast cancer who have brain metastases.

The FDA has granted an orphan drug designation to neratinib (Nerlynx) for the treatment of patients with breast cancer who have 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, chief executive officer and president of Puma Biotechnology, the developer of neratinib, in a press release. “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.”

The FDA grants orphan designation to investigational agents that are designed to treat, prevent, or diagnose rare medical diseases or conditions that affect fewer than 200,000 individuals in the United States.

Approximately 20% to 25% of breast cancer tumors have HER2 overexpression; additionally, this breast cancer subtype is said to be more aggressive than other types, which is associated with an increased risk of disease progression and death.

Prior data have demonstrated the activity of the small-molecule TKI in combination in combination with capecitabine (Xeloda) in patients with HER2-positive breast cancer who also have brain metastases. For example, the international, open-label, phase III NALA study evaluated the combination compared with lapatinib (Tykerb) in patients with HER2-positive disease who have failed ≥2 prior lines of HER2-directed therapies.

In the trial, 621 patients with metastatic breast cancer and centrally confirmed HER2-positive disease were enrolled. Patient characteristics were well balanced at baseline, and nearly 80% of patients in each arm were aged <65 years and about 80% of patients in each arm had visceral disease.

A total 69% of patients had previously received 2 HER2-targeted therapies for metastatic breast cancer, with the remaining 31% having received ≥3. Prior HER2-targeted regimens included single-agent trastuzumab (Herceptin; 38%), trastuzumab plus pertuzumab (Perjeta; 7.5%), trastuzumab plus ado-trastuzumab emtansine (T-DM1; Kadcyla; 20%), and trastuzumab plus pertuzumab plus T-DM1 (35%).

Patients were randomized in a 1:1 ratio to 21-day cycles of either neratinib (n = 307; 240 mg daily) plus capecitabine (1500 mg/m2 on days 1-14) or lapatinib (n = 314; 1250 mg daily) plus capecitabine (2000 mg/m2 on days 1-14). Patients on the neratinib arm also received antidiarrheal prophylaxis with loperamide.

The coprimary endpoints were progression-free survival (PFS) and overall survival (OS). The study was conducted under an FDA Special Protocol Assessment stipulating that the study would be considered positive if either of these coprimary endpoint measures were met: P <.01 for PFS or P <.04 for OS.

Results showed that fewer patients required intervention for central nervous system (CNS) metastases with neratinib versus lapatinib.2 At 54 months, the cumulative incidence for intervention for CNS metastases was 22.8% versus 29.2% for the neratinib and capecitabine arms, respectively (P = .043).

Additional data showed that the combination led to a 24% reduction in the risk of disease progression or death versus lapatinib (HR, 0.76; 95% CI, 0.63-0.93; log-rank P value = .0059). Moreover, it was found that the PFS curves began to separate after 6 months with 6-month PFS rates of 47% versus 38%, 1-year rates of 29% versus 15%, and 18-month rates of 16% versus 7% for the neratinib arm versus the lapatinib arm, respectively.

Based on these data, a supplemental new drug application was submitted to the FDA in July 2019 for neratinib plus capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have failed ≥2 prior lines of HER2-directed treatments.

Moreover, additional study cohorts from the phase II TBCRC 022 trial showcased promising results with the combination of neratinib and capecitabine in patients with HER2-positive breast cancer and CNS metastases.

The phase II study included patients with measurable, progressive, HER2-positive breast cancer and brain metastases who received neratinib 240 mg orally once daily plus capecitabine 750 mg/m2 twice daily for 14 days, followed by 7 days off. The study included both lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients. The investigators had determined that if ≥9 of 35 (cohort 3A) or ≥3 of 25 (cohort 3B) patients had CNS objective response rates (ORR), the combination would be deemed promising.

The primary endpoint was composite CNS ORR in each cohort, which required a reduction of ≥50% in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic symptoms, or non-CNS progression.

Cohort 3A comprised 37 patients; cohort 3B had 12 patients and was later closed due to slow accrual. Results showed that the composite CNS ORR was 49% (95% CI, 32%-66%) in cohort 3A, and the CNS ORR in cohort 3B was 33% (95% CI, 10%-65%).3 The median PFS was 5.5 months and 3.1 months in cohorts 3A and 3B, respectively, and the median OS was 13.3 months and 15.1 months, respectively. The most common grade 3 adverse event was diarrhea, which occurred in 29% of patients in both cohorts.

Neratinib is currently approved by the FDA for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy.


  1. FDA Grants Orphan Drug Designation to Puma Biotechnology’s NERLYNX® for the Treatment of Breast Cancer Patients with Brain Metastases. Puma Biotechnology. Published September 3, 2019. https://bit.ly/2kpQaM9. Accessed September 3, 2019.
  2. Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(suppl; abstr 1002). doi: 10.1200/JCO.2019.37.15_suppl.1002.
  3. Freedman RA, Gelman RS, Anders CK, et al. 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.