A new study published on Clinical Cancer Research shows that a combination of the irreversible pan-HER inhibitor neratinib with the anti-HER2 fulvestrant is active in metastatic estrogen receptor-positive and HER-2 mutated, non amplified breast cancer, regardless of prior treatment with a CDK4/6 inhibitor.
MutHER study, a single-arm multi-cohort phase II trial, enrolled 40 patients with a stage IV breast cancer and a median of three prior treatments. It comprised three cohorts: estrogen receptor positive and fulvestrsant naïve (11), estrogen receptors positive and fulvestrant treated (24), estrogen receptor negative (5). The median progression free survival after neratinib in combination with fulvestrant was 24 months in the fulvestrant-treated group, 20 in the fulvestrant-naïve group, and 8.5 in the estrogen receptor-negative group; the clinical benefit rate was 38%, 30% and 25% in the three cohorts, respectively, and the most common grade 3 adverse event was diarrhea in 25% of patients. Sensitivity to neratinib may be influenced by breast cancer histology and HER2 mutation location: lobular histology was particularly responsive to the treatment, while HER2 L755 alterations were associated with less efficacy; moreover, response to therapy was accompanied by early decreases in HER2 mutation variant allele frequency and progression was associated with acquired HER2 mutations, demonstrating the value of serial circulating tumor DNA monitoring. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease, suggesting dual HER2 blockade may be important in targeting HER2 mutation. «Further investigation of trastuzumab in combination with neratinib is therefore warranted», authors conclude.