OT Breast Cancer

Efficacy of T-DM1 Plus Neratinib in Metastatic HER2-Positive Breast Cancer

By Catlin Nalley

“HER2-positive tumors tend to be more aggressive and while we have good treatment options for those patients a substantial number still become metastatic,” noted Jame Abraham, MD, Director of the Breast Oncology Program at Cleveland Clinic Taussig Cancer Institute and Co-Director of the Cleveland Clinic Comprehensive Breast Cancer Program. “Even in the metastatic setting we have solid therapeutic options, many people still die from HER2-positive disease.”

In first-line treatment of this patient population, the drug of choice is trastuzumab and pertuzumab with taxane, according to Abraham. Standard treatment in the second line is TDM1, an antibody-drug conjugate composed of trastuzumab and the maytansinoid antimicrotubule, DM1. The therapy was granted FDA approval as a second-line treatment for metastatic breast cancer after prior trastuzumab and taxane.

A recent study, presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, investigated the efficacy and safety of T-DM1 plus neratinib, a tyrosine kinase inhibitor, among patients with metastatic HER2-positive breast cancer (Abstract 1027).


Methods, Results

Patients enrolled in the phase I dose-escalation study had prior trastuzumab/pertuzumab as neoadjuvant therapy or in the first-line. Other eligibility requirements included measurable disease, and ECOG PS ≤2, as well as adequate hematologic, renal, and liver function. Individuals with stable brain metastases (CNS) were also eligible.

Twenty-seven trastuzumab/pertuzumab-resistant patients were included in the study. Among them, 26 were evaluable for toxicity, and 20 were evaluable for efficacy. Patients were treated with T-DM1 at 3.6 mg/kg IV q3wk and neratinib at escalating doses of 120, 160, 200, and 240 mg per day using 3+3 design, Abraham reported. During cycle 1, dose-limiting toxicity occurred in six patients.

Researchers determined that the maximum tolerated dose for neratinib was 160 mg/day. Treatment-related grade 3 toxicities included diarrhea (five patients), thrombocytopenia (4 patients), nausea (three patients), and ALT elevation (one patient). “Diarrhea is the main side effect but patients could manage that with the appropriate diarrheal prophylaxis,” noted Abraham.

Study authors found that after 2 cycles, among 20 evaluable patients, three had CRs and nine had PRs (ORR 64%). According to researchers, “the duration of response ranged from 42 days to 650+ days.”

 “Full-dose T-DM1 + neratinib at 160 mg/day was well-tolerated with notable activity. Responses were seen at all dose-levels of neratinib,” study authors concluded. “Limited pharmacokinetic analysis did not show that peak or steady-state concentration of neratinib was related to response. Baseline peripheral blood samples are being assessed for HER2 amplification.”

A phase II study has been launched with a neratinib RP2D of 160 mg per day.


Research Implications

When discussing the impact of the research, Abraham noted, “The most striking finding is the overall response rate of about 60 percent, which is a pretty impressive response rate for this combination.

“This [study] is telling us that we can combine these two therapies, potentially giving us a higher response rate,” he continued. “We have to wait for further studies, but this data suggests that [T-DM1 plus neratinib] is a very active treatment option for HER2-postive metastatic breast cancer.”


Catlin Nalley is associate editor.