Neratinib Demonstrates Promising Activity in Patients with HER2-Positive Metastatic Breast Cancer and CNS Metastases

Neratinib demonstrated notable and consistent activity in patients with HER2-positive breast cancer and central nervous system (CNS) metastases in a phase 3 clinical trial and 2 independent phase 2 clinical trials, according to data presented in a poster at the 37th Annual Miami Breast Cancer Conference.

Neratinib is an irreversible small-molecule tyrosine kinase inhibitor of HER1, HER2, and HER4. According to Sara Hurvitz, MD, Director, Breast Cancer Clinical Trials Program, UCLA Health, Los Angeles, and colleagues, patients with baseline CNS lesions who were treated with neratinib demonstrated lesion shrinkage and promising CNS objective response rates (ORRs) in 3 distinct studies and 3 distinct settings—progressive CNS metastases, asymptomatic CNS metastases, and stable CNS metastases.

Although HER2-directed therapies have improved the control of systemic disease and prolonged survival in patients with HER2-positive breast cancer, approximately 50% of patients with advanced disease will eventually develop CNS metastases. Although outcomes for patients with brain metastases from HER2-positive breast cancer have improved over time, recurrent CNS events remain a major cause of morbidity and negatively affect overall survival for many patients. Compounding the problem is the fact that treatment options, particularly systemic approaches, remain limited.

Because data from clinical trials in the advanced breast cancer setting—particularly results from the NALA, the NEfERT-T, and the Translational Breast Cancer Research Consortium (TBCRC) 022 trials—suggest that neratinib-based therapy has activity in patients with CNS metastases from HER2-positive breast cancer, Dr Hurwitz and colleagues reviewed the data with a specific focus on CNS outcomes.

NALA is a phase 3 trial of neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens (N = 621). NEfERT-T is a phase 2 trial of neratinib plus paclitaxel versus trastuzumab plus paclitaxel in previously untreated metastatic HER2-positive patients (N = 479). TBCRC 022 is a phase 2 trial of neratinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases (this analysis includes efficacy data only from patients in TBCRC 022 who received no previous lapatinib [cohort 3A]).

Across all 3 studies, a total of 75 patients had measurable CNS lesions at baseline and were evaluable for CNS ORR: 32 patients in NALA (neratinib plus capecitabine, N = 19; lapatinib plus capecitabine, N = 13); 6 patients in NEfERT-T (neratinib plus paclitaxel, N = 3; trastuzumab plus paclitaxel, N = 3); and 37 patients in TBCRC 022.

In the NALA trial, CNS end points favored the neratinib plus capecitabine arm. Time to interventions for symptomatic CNS disease was significantly lower with neratinib plus capecitabine versus lapatinib plus capecitabine, and fewer patients in the neratinib plus capecitabine group (18%) required interventions for symptomatic CNS disease versus lapatinib plus capecitabine (24%). CNS ORRs were 26.3% with neratinib plus capecitabine (with 1 complete response) versus 15.4% with lapatinib plus capecitabine.

The NEfERT-T trial saw a 100% CNS ORR in patients who received neratinib plus paclitaxel, versus 33.3% in patients who received trastuzumab plus paclitaxel (all partial responses). The risk of CNS progression was also reduced with neratinib plus paclitaxel versus trastuzumab plus paclitaxel (hazard ratio, 0.45; P = .0036).

In TBCRC 022, the composite CNS ORR was 49% in cohort 3A (all were partial responses).

Patients with CNS objective responses also experienced longer progression-free survival and overall survival than those without CNS objective responses. When data for all 3 studies were combined, CNS objective response was associated with improvements in both of these survival end points.

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