Neratinib Combo Improves Outcomes in Patients With HER2+ Metastatic Breast Cancer With CNS Disease


The addition of neratinib to capecitabine improved progression-free survival and central nervous system outcomes in patients with HER2-positive metastatic breast cancer with central nervous system disease.

Patients with HER2-positive metastatic breast cancer with central nervous system (CNS) disease at baseline demonstrated improved outcomes following treatment with neratinib (Nerlynx) plus capecitabine, compared with lapatinib (Tykerb) plus capecitabine, according to study findings presented at the 38th Annual Miami Breast Cancer Conference®.

In particular, neratinib plus capecitabine improved progression-free survival (PFS) and CNS outcomes, which was consistent with findings from 3 other prospective studies – NEfERT-T, TBCRC-022, and ExteNET.

“Our findings support 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,” the investigators concluded in a poster presentation of their findings.

CNS metastases from HER2-positive breast cancer have presented as a clinical challenge given the limited availability of evidence-based treatments, investigators noted, adding that there is a need for multiple lines of safe and effective CNS-directed treatments.

In the international, randomized, open-label, active-controlled phase 3 NALA trial (NCT01808573), investigators compared the addition of neratinib – an irreversible small-molecule pan-HER tyrosine kinase inhibitor – versus lapatinib to capecitabine in patients with HER2-positive metastatic breast cancer who previously received 2 or more lines of HER2-directed therapy in the metastatic setting. In their poster presentation, investigators aimed to report efficacy and safety outcomes in the subgroup of patients from the trial who had CNS metastases at baseline, with a particular focus on CNS-specific end points.

Patients were eligible for the trial if they had asymptomatic metastatic brain disease managed with stable doses of corticosteroids for 14 or more days prior to randomization; patients were excluded if they had symptomatic or unstable brain metastases.

Investigators randomized patients 1:1 to receive either 240 mg neratinib once daily plus 750 mg/m2 capecitabine twice daily or 1250 mg lapatinib once daily plus 1000 mg/m2 capecitabine twice daily.

Centrally-assessed PFS and overall survival (OS) served as the co-primary end points. Intervention for symptomatic metastatic CNS disease was a secondary end point.

In the NALA trial, treatment with neratinib plus capecitabine showed a significant improvement in PFS, compared with lapatinib plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). In addition, fewer interventions for CNS disease were required with the neratinib combination, compared with lapatinib (P = .043). Lastly, intracranial overall response rate (ORR) among patients with 1 or more target CNS lesion (n = 32) was 26.3% with neratinib, compared with 15.4% with lapatinib.

Of the 621 patients enrolled in the NALA trial, 101 (16%) had documented baseline CNS disease and 520 (84%) had no CNS disease at baseline. Of the 101 patients with documented baseline CNS disease, 51 received the neratinib combination and 50 received the lapatinib combination.

Mean age in the CNS subgroup was 54 years (range, 25-75 years). Overall, patients had an ECOG performance status of 1, and 51 (50.5%) patients had hormone receptor-positive disease. Among patients with CNS disease, 81 (80.2%) previously received CNS radiation and/or surgery (whole brain, n = 59 [58%]; stereotactic, n = 17 [17%]; unknown, n = 2 [2%]) and 5 (5%) underwent CNS surgery.

Median duration of study treatment was 5.7 months (range, 0.4–28.6 months) for neratinib and 3.5 months (range, 0.5-20.8 months) for lapatinib. The study cut-off date was September 28, 2018.

The neratinib combination demonstrated superior PFS (7.8 vs 5.5 months; HR, 0.66; 95% CI, 0.41-1.05; P = .0741) and OS (16.4 vs 15.4 months; HR, 0.90; 95% CI, 0.59-1.38; P = .6352), compared with lapatinib.

Time to intervention was 25.5 months and 36.0 months with neratinib and lapatinib, respectively (P = .430), with neratinib demonstrating superior CNS PFS (12.4 vs 8.3 months; HR, 0.62; 95% CI, 0.32-1.18; P = .143).

Three patients reported leptomeningeal disease (LMD), of which 2 treated with neratinib had disease progression after 5.6 and 9.8 months, respectively, and OS times of 17.4 and 19.8 months. The 1 patient who received lapatinib had disease progression after 4.3 months and an OS of 6.5 months.

The safety profile appeared consistent with adverse events (AEs) previously observed. The most common AEs included diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia syndrome. The most common CNS AEs associated with neratinib and lapatinib included headache (18% vs 29%, respectively), dizziness (18% vs 16%), hemiparesis (4% vs 4%), seizure (4% vs 4%), and gait disturbance (0% vs 8%). Of note, CNS AEs were slightly more common in the CNS subgroup of patients, compared with the overall patient population in the NALA trial.

“The data suggest an association between (neratinib plus capecitabine) and improved PFS and CNS outcomes in patients with CNS metastases from HER2-positive metastatic breast cancer compared with (lapatinib plus capecitabine) in the phase 3 NALA trial,” investigators concluded. “A unique feature of NALA was the inclusion of patients with LMD, 2 of whom were treated with (neratinib plus capecitabine) with good outcomes.”


Saura C, Ryvo L, Hurvitz S, et al. Impact of Neratinib 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: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual. Poster 10.

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