Neratinib Plus Capecitabine Improved PFS in Patients With HER2+ Breast Cancer With Brain Mets


Neratinib in combination with capecitabine induced a 34% reduction in the risk of disease progression or death as treatment of patients with HER2-positive breast cancer who had central nervous system metastases at baseline compared with lapatinib and capecitabine.

Cristina Saura, MD, PhD

Cristina Saura, MD, PhD

Neratinib (Nerlynx) in combination with capecitabine (Xeloda) induced a 34% reduction in the risk of disease progression or death as treatment of patients with HER2-positive breast cancer who had central nervous system (CNS) metastases at baseline compared with lapatinib (Tykerb) and capecitabine, according to an analysis of the NALA trial (NCT01808573) that were presented during the 2020 San Antonio Breast Cancer Symposium.1,2

Within the CNS at baseline subgroup (n = 101; 16.3%), the data suggested an improved PFS between those who received the neratinib combination (n = 51) compared with the lapatinib regimen (n = 50), with a median PFS of 7.8 months and 5.5 months, respectively (HR 0.66; 95% CI, 0.41-1.05).

“The data suggest an association between neratinib and improved PFS and CNS outcomes in patients with CNS metastases from HER2-positive metastatic breast cancer,” said lead study author Cristina Saura, MD, PhD, head of Breast Cancer Unit, Vall d’Hebrón University Hospital. “These findings are consistent with three other prospective studies.”

In February 2020, the FDA approved a supplemental new drug application for neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting, based on earlier findings of the NALA trial.

Data showed that the combination of neratinib and capecitabine reduced the risk of disease progression or death by 24% compared with lapatinib/capecitabine (HR, 0.76; 95% CI, 0.63-0.93; log-rank P value = .0059).3 The median PFS was 8.8 months vs 6.6 months for neratinib/capecitabine and lapatinib, respectively. However, there was no statistical difference in overall survival (OS) between arms (HR, 0.88; 95% CI, 0.72-1.07; P = .2098). 

The international, open-label, phase III NALA trial enrolled 621 patients with metastatic breast cancer and centrally confirmed HER2-positive disease. Patient characteristics were well balanced at baseline. Nearly 80% of patients in each arm were aged <65 years and about 80% of patients in each arm had visceral disease.

Sixty-nine percent of patients had 2 prior HER2-targeted treatments for metastatic breast cancer, with the remaining 31% having received 3 or more. 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 1:1 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 PFS and 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 <.04 for OS.

A predefined secondary end point was time to intervention for symptomatic CNS disease. In the ITT population, significantly fewer interventions for CNS disease occurred with the combination compared with lapatinib/capecitabine, with cumulative incidence of 22.8% vs. 29.2% (P = .043).

Additional data from this subgroup analysis showed that, similar to the overall population, there were no differences in OS between the 2 arms.

Specific to CNS-specific outcomes, the 12-month incidence of interventions for CNS metastases was 25.5% in the neratinib arm and 36.0% with lapatinib.

Moreover, data suggest an association between neratinib and improved CNS-PFS, which was an ad hoc composite endpoint assessing disease progression in the brain or death from any cause. Here, the median CNS-PFS was 12.4 months in the neratinib arm compared with 8.3 months with lapatinib (HR, 0.62; 95% CI, 0.32-1.18).

Patients with leptomeningeal disease (LMD) were also included in the NALA trial. Updated findings showed that 2 of these patients who were treated with neratinib/capecitabine had disease progression after 5.6 and 9.8 months, and OS times of 17.4 and 19.8 months, respectively. One patient with LMD who received the lapatinib regimen had disease progression after 4.3 months and an OS of 6.5 months.

Regarding safety in patients with CNS metastases at baseline was consistent with the overall NALA safety population. The most common adverse events were diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia syndrome. Moreover, common CNS adverse events that were of grades 1-4 included headache (18% with neratinib vs 29% with lapatinib), dizziness (18% vs 16%, respectively), hemiparesis (4% vs 4%), seizure (4% vs 4%), and gait disturbance (0% vs 8%).

“CNS metastases from HER2-positive breast cancer present a clinical challenge due to the limited availability of effective treatments,” said Alan H. Auerbach, chief executive officer and president of Puma, the developer of neratinib. “These findings from the NALA trial add to the growing body of data on the efficacy of neratinib in patients with HER2 positive metastatic breast cancer that has metastasized to the brain and may suggest a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.”

Neratinib is also approved for use as a single agent for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy.


  1. Saura C, Ryvo L, Hurvitz S, et al. Impact of neratinib plus capecitabine on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: findings from the phase 3 NALA trial. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD13-09.
  2. Puma Biotechnology presents efficacy and safety outcomes from the phase III NALA trial at the 2020 SABCS. News release. Puma Biotechnology. December 11, 2020. Accessed December 14, 2020.
  3. 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
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