Neratinib Plus Fulvestrant Appears Active in ER+ HER2-Mutated Metastatic Breast Cancer

Patients with estrogen receptor–positive HER2-mutated metastatic breast cancer experienced promising clinical activity following treatment with neratinib and fulvestrant.

Neratinib (Nerlynx) and fulvestrant appeared active in a population of patients with estrogen receptor (ER)–positive, HER2-mutated metastatic breast cancer, according to a study published in Clinical Cancer Research.

Within the evaluable population, the clinical benefit rate (CBR) was 38% (95% CI, 18%-62%) for the fulvestrant-treated group, 30% (95% CI, 7%-65%) for the fulvestrant-naïve group, and 25% (95% CI, 1%-81%) in the ER-negative group. Three partial responses and 1 case of stable disease were observed at progression with the addition of trastuzumab (Herceptin) at 24 weeks or more.

A total of 40 patients were enrolled into the trial, of whom 24 were in the fulvestrant-treated group, 11 were in the fulvestrant-naïve group, and 5 were in the ER-negative group. The median age was 63 years and patients had a median of 3 prior lines of therapy in the metastatic setting. Moreover, 26 patients had previously received treatment with a CDK4/6 inhibitor and 13 had prior PI3K/AKT/mTOR inhibitors. Additionally, 17 patients had a lobular histology, and 37 had visceral metastases.

The median progression-free survival (PFS) was assessed in all patients in the intent to treat population; the median PFS was 24.0 months (95% CI, 15.7-31.0) in the fulvestrant-treated group, 20.0 (95% CI, 8%.0–not available [NA]) in the fulvestrant-naïve group, and 8.5 (95% CI, 8-NA) in the ER-negative group. The exploratory analysis, which compared durations of prior fulvestrant (<6 months vs >6 months), highlighted no significant differences in median PFS (P = .71) and CBR (P = .65) between groups.

Investigators did note that the presence of exon 20 insertion mutations appear to be associated with significantly higher CBR of 83.3% vs 24.1% following treatment with the experimental regimen.

Among 35 patients evaluable, 22 had prior CDK4/6 inhibitors and 8 were previously with an mTOR inhibitor. Following treatment with these agents, patients a CBR of 45.5%, and 50.0%, respective. Invasive lobular histology was associated with a higher CBR at 61.5% vs 18.2% (P = .02). Additionally, the objective response rate was 38.5% (95% CI, 15.1%-67.7%) in this population.

Most adverse effects (AEs) potentially related to the study included diarrhea (85%), nausea (53%), fatigue (50%), anorexia (35%), and increased aspartate aminotransferase (28%). The most common grade 3 AE was diarrhea in 25% of patients. Dose reductions were necessary in 6 patients who received neratinib plus fulvestrant at 200 mg daily due to of nausea or vomiting (n = 2), diarrhea (n = 3), or elevated liver enzymes (n = 1). A second dose reduction was needed in 1 patient to 160 mg daily because of diarrhea. Treatment was terminated in 5 patients after having received the study treatment for 2 days (n = 1), 7 days (n = 3), or 14 days (n = 1), and went off the trial during cycle 1.


Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res. 2022;28(7):1258-1267. doi:10.1158/1078-0432.CCR-21-3418

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