Breast cancer is the second leading cause of cancer-related deaths in women in the United States. An estimated 252,710 new cases of invasive breast cancer will occur in US women in 2017, and 40,610 women in the United States are expected to die from breast cancer in 2017.
Breast cancer is classified into clinical subtypes based on the expression of HER2, the estrogen receptor (ER), and the progesterone receptor. ER and HER2 are interrelated, are expressed in most breast cancer tumors, and are the dominant drivers of tumor growth and progression. Therapeutic interventions targeting ER and HER2 pathways are effective in selected patients; however, endocrine and treatment resistance remain problematic. Studies show that bidirectional crosstalk between HER2 and ER pathways occurs when targeted therapies are used individually. Blockade of the HER2 pathway results in endocrine resistance while ER modulates response to HER2-targeted agents, resulting in tumor escape and anti-HER2 resistance. Based on this, a promising strategy to overcome HER2/ER crosstalk is combination endocrine therapy with anti-HER2 treatment in patients with ER-positive and HER2-positive tumors.
Neratinib (HKI-272) is an irreversible, pan-HER tyrosine kinase inhibitor (TKI) being developed for the treatment of HER2-positive early-stage breast cancer, metastatic breast cancer (MBC), and HER2-mutant MBC. The relevance of HER2/ER crosstalk as it relates to neratinib is currently being investigated in SUMMIT, a phase 2, international, multicenter, multihistology study of patients with solid tumors harboring HER2 mutations, HER3 mutations, or epithelial growth factor receptor amplification.
Inclusion criteria for this study included MBC and documented HER2 mutation. Patients previously treated with any pan-HER TKI—including lapatinib, afatinib, dacomitinib, and neratinib—were excluded. Patients receiving any other anticancer agents, patients with symptomatic or unstable brain metastases, and women who were pregnant or breastfeeding were also excluded. As of September 2016, a total of 35 patients had received neratinib.
Patients with MBC, documented HER2 mutation, and ER-positive or ER-negative tumors received 240 mg daily of oral neratinib monotherapy, and patients with ER-positive and HER2-mutant MBC received combination therapy with oral neratinib 240 mg daily and 500 mg of fulvestrant, a selective ER degrader, on days 1 and 15 of the first month, and then on day 1 of every 4-week cycle. Patients also received high-dose loperamide prophylaxis during cycle 1. The primary objective of this study was to determine the objective response rate (ORR) at 8 weeks. Secondary outcome measures included clinical benefit rate (CBR), progression-free survival (PFS), and safety.
Twenty-four patients received neratinib monotherapy, and 11 patients received neratinib in combination with fulvestrant. Patients in both treatment arms were heavily pretreated and had received a median of 4 prior cancer therapies in the metastatic setting. The ORR at 8 weeks was 33% in the neratinib monotherapy arm, and 42% in patients receiving neratinib in combination with fulvestrant. The CBR was 42% in the monotherapy arm and 58% in patients receiving neratinib in combination with fulvestrant. The median PFS was 3.5 months in the neratinib monotherapy arm and 3.7 months in patients receiving neratinib in combination with fulvestrant.
Diarrhea was the most common adverse event, with grade 3 events occurring in 24% of patients receiving neratinib monotherapy and in 12% of patients receiving neratinib in combination with fulvestrant. Diarrhea was short-lived, and lasted a median of 1 day per episode. Diarrhea was generally managed with treatment interruptions or in 1 case, dose reduction. No patient discontinued treatment because of diarrhea. There were no grade 4, life-threatening events.
Study results showed that neratinib is effective in heavily pretreated patients with HER2-positive MBC. In patients with ER-positive and HER2-positive MBC, simultaneous inhibition of HER2 with neratinib and ER with fulvestrant improved patient outcomes compared with neratinib alone. Neratinib had a tolerable safety profile, with diarrhea being non–life-threatening and treated with loperamide prophylaxis. Study findings support the HER2/ER crosstalk theory.
Beer H, et al. ONS Abstract IS-4.