Neratinib/Fulvestrant Shows Modest Anti-Tumor Activity in HER2+ Breast Cancer


In the phase 2 MutHER study, the combination of neratinib and fulvestrant demonstrated activity in heavily pretreated patients with estrogen receptor-positive, metastatic breast cancer, but the clinical benefit rate did not meet the predefined efficacy criteria.

Dr Cynthia MA

Cynthia X. Ma, MD, PhD

In part 2 of the phase 2 MutHER study (NCT03289039), the combination of neratinib (Nerlynx) and fulvestrant (Faslodex) demonstrated activity in heavily pretreated patients with estrogen receptor (ER)-positive, metastatic breast cancer (MBC), but the clinical benefit rate (CBR) did not meet the predefined efficacy criteria, according to data presented by Cynthia X. Ma, MD, PhD, during the virtual AACR Annual Meeting 2021.

“Neratinib has shown modest single agent activity for [patients with] HER2-mutant nonamplified MBC,” said Ma, the clinical director of the breast cancer program at Washington University School of Medicine in St. Louis, Missouri. “We hypothesized that neratinib in combination with fulvestrant would improve antitumor activity compared to single agent therapy in this patient population.”

Adult patients with HER2 non-amplified MBC, positive for activating HER2 by CLIA tumor tissue or ctDNA sequencing were eligible for the study. There were no limits on the number of prior lines of therapy. Patients were enrolled to 3 independent cohorts depending on ER status: fulvestrant-treated (FUL-treated; n = 24), fulvestrant-naïve (FUL-naïve; n = 11). Additionally, an exploratory analysis was conducted for a cohort of patients with triple-negative breast cancer (TNBC; n = 5).

The study enrolled a total of 40 patients with a median age of 63 years (range, 35-82). Half of patients with ductal histology and 42.5% were lobular. Patients had received a median of 3 prior lines of therapy. The FUL-treated and FUL-naïve cohorts received neratinib plus fulvestrant and the TNBC cohort received neratinib alone. Neratinib was given at the standard dose of 240 mg orally once daily. Fulvestrant was administered as an intramuscular injection at 500 mg on day 1 and day 15 of the first 28-day cycle, then on the first day of each subsequent cycle.

The primary end point of the study was CBR. Secondary end points included progression-free survival (PFS) and establishing an adverse effects (AEs) profile. The anticipated CBR for the FUL-treated group was 55%, with a null hypothesis of 35%. The anticipated CBR for the FUL-naïve cohort was 65% with a null hypothesis of 40%.

Results from the trial showed that the FUL-treated population had a median PFS of 24 weeks (95% CI, 15.7-31.0) and a CBR of 38% (95% CI, 18%-62%), with 1 patient experiencing a complete response (CR) and 4 patients experiencing a partial response (PR). Patients in the FUL-naïve cohort had a median PFS of 20 weeks (95% CI, 8-not estimable [NE]) and a CBR of 30% (95% CI, 7%-65%) with 3 PRs. Patients in the exploratory TNBC arm had a median PFS of 8.5 weeks (95% CI, 8-NE) and a CBR of 25% (95% CI, 1%-81%) with 1 PR.

Additionally, lobular histology was associated with an increased CBR. The CBR of 13 patients with lobular histology was 61.5% with 1 patient having a CR and 4 having PRs.

Trastuzumab (Herceptin) was added at disease progression on neratinib plus fulvestrant for 4 patients with ER-positive disease and at disease progression for 1 patient with TNBC. Clinical benefit was observed in 4 of these 5 patients (80%; 95% CI, 28%-99%) with a median PFS of 28 weeks (95% CI, 18-NE). Ma noted that improved efficacy observed with the addition of trastuzumab highlights the importance of dual HER2-blockade for this patient population.

The safety profile of the combination was consistent with prior studies. The most common AEs were diarrhea (85%), nausea (53%), and fatigue (50%). The most common grade 3 AE was diarrhea (25%) and there were no grade 4 AEs. No patients discontinued therapy due to an AE. Neratinib was dose reduced in 6 patients to 200 mg daily, 1 of whom had a second dose reduction to 160 mg daily due to diarrhea.


Ma CX, Luo J, Freedman R, et al. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER. Presented at: American Association for Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT026.

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