Neratinib Benefit in Breast Cancer Sustained in 5-Year ExteNET Analysis

Alan H. Auerbach

Treatment with neratinib reduced the risk of invasive disease recurrence or death by 26% compared with placebo as extended adjuvant therapy for patients with HER2-positive early stage breast cancer following 12 months of trastuzumab (Herceptin), according to a 5-year analysis of the phase III ExteNET trial.

In the analysis, which was announced by the developer of the TKI, Puma Biotechnology, the 5-year invasive disease-free survival (DFS) rate with neratinib was 90.4% compared with 87.9% with placebo (HR, 0.74; P = .017). For those in the study with both HR-positive and HER2-positive breast cancer, the 5-year invasive DFS rate with neratinib was 91.7% versus 86.9% with placebo (HR, 0.59; P = .002).

The 5-year analysis was not originally planned as part of the study and was requested as part of a new drug application (NDA) for neratinib in the United States and for a marketing authorization application (MAA) in Europe. The primary endpoint of the study was the 2-year invasive DFS rate, which was 93.9% with neratinib and 91.6% with placebo (HR, 0.67; P = .009).

“We are very pleased with the interim 5-year invasive DFS results from the ExteNET trial with neratinib,” Alan H. Auerbach, chief executive officer and president of Puma, said in a statement. “We believe these results support the long term clinical benefit of neratinib in the extended adjuvant treatment of patients with early stage HER2-positive breast cancer who have completed prior trastuzumab-based adjuvant therapy. We look forward to obtaining the full 5-year DFS data, which we anticipate will be available in 2017.”

In the phase III study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to neratinib (n = 1420) or placebo (n = 1420). The interval between receiving trastuzumab and entering the trial was approximately 4.5 months. Neratinib was administered for 12 months at 240 mg per day.

The median age of patients in the study was 52 years and approximately 23.8% had node negative disease, with 46.6% of patients having 1 to 3 positive nodes and 29.6% had ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in the majority of patients (77%). Appropriate endocrine therapy was administered to 94% of patients with HR-positive breast cancer.

HER2 testing in the study was conducted by local assessment (25%) or central review (75%). In evaluable patients with HER2 testing completed by central review (n = 1777), the 5-year invasive DFS rate was 90.8% with neratinib versus 88.1% with placebo (HR, 0.70; P = .026).

In initial assessments of safety across the full study population, 95.4% of patients treated with neratinib experienced all-grade diarrhea, of which 39.9% was grade 3/4 in severity. The trial design did not mandate antidiarrhea prophylaxis. Other gastrointestinal-related adverse events included nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%). In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of just 1.6%.

A subsequent phase II study was conducted to examine prophylactic loperamide to address the high-rate of grade 3/4 diarrhea. Data from this study were presented during a webcast by Puma and showed that grade 3 neratinib-related diarrhea was reduced to approximately 16% with loperamide. The rates of all-grade diarrhea ranged from 74.1% to 43.5%, depending on the loperamide treatment scheduled.

“The results of the study demonstrate that using the loperamide prophylaxis regimen reduced both the all-grade diarrhea and the grade 3 diarrhea down to much more acceptable levels than what was seen in the phase III ExteNET trial,” said Auerbach, while presenting the phase II analysis.

An MAA was submitted to the European Medicines Agency for neratinib in late June 2016. Along with the announcement of the 5-year analysis, Puma also noted that it had submitted an NDA to the FDA that included data from the ExteNET trial and the phase II loperamide investigation. The FDA will assign a review timeline for this application within 60 days.

“We are very pleased to announce this important regulatory milestone,” said Auerbach. “We look forward to working with the FDA during their review of this submission.”

Neratinib continues to be explored across a number of settings alone and as part of combination regimens. The agent is being looked at in combination with T-DM1 (ado-trastuzumab emtansine; Kadcyla) for patients with metastatic breast cancer (NCT02236000). Additionally, a phase II study is looking at the treatment with or without fulvestrant, depending on estrogen receptor status, for patients with HER2-mutant breast cancer (NCT01670877).

In a phase III study, neratinib plus capecitabine is being compared with lapatinib and capecitabine for patients with HER2-positive metastatic breast cancer following 2 or more prior therapies. This study, which is known as NALA, has a primary endpoint of progression-free survival and plans to enroll 600 patients. The study was opened in March 2013 and has an estimated primary completion date of May 2017 (NCT01808573).

As part of the update, the company also provided 3- and 4-year data for invasive DFS. After 3 years, the invasive DFS rate was 92.5% versus 90.3% and after 4 years the rates were 91.4% and 89.2%, in the neratinib and placebo arms, respectively. For those with HR-positive tumors (n = 1631), the 3-year DFS rates were 93.8% versus 89.9% and the 4-year rates were 92.9% and 88.6%, for neratinib and placebo, respectively.