Alan H. Auerbach
Grade 3 diarrhea occurred in 16% of patients treated with neratinib and prophylactic loperamide, representing a significant reduction compared with phase III findings from the ExteNET trial, according to an open-label study presented by Puma Biotechnology in a conference call. Diarrhea of any grade was experienced by 60% of patients receiving neratinib and prophylaxis.
Overall, in the ExteNET study, 95.4% of patients experienced all grade diarrhea, with 39.9% of patients having a grade ≥3 event. The median duration of diarrhea was 5 day and 1.4% of patients required hospitalization due to this adverse event. Diarrhea led to a dose reduction for 26.4% of patients and 16.8% of patients discontinued therapy due to diarrhea.
“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,” Alan H. Auerbach, chief executive officer, president, and chairman of the board of Puma, said during a web presentation of the data. “The grade 3 diarrhea seen in the trial generally occurred during in the first 28 days, and the majority was seen in the first week.”
The open-label study was initiated to address neratinib-associated diarrhea experienced by patients enrolled in the phase III ExteNET study, in which patients did not receive prophylactic loperamide. In other studies assessing neratinib in patients with metastatic cancer, high-dose loperamide prophylaxis successfully reduced the rate of grade 3 diarrhea to between 0% and 17%.
In the phase II open-label study, patients were enrolled within 1 year of completing adjuvant treatment with trastuzumab. Neratinib was administered at 240 mg daily for 12 months and loperamide was given daily for the first two cycles.
In the original protocol, 27 patients received loperamide at 16 mg on day 1 followed by 12 mg per day on days 2 and 3 and 6 to 8 mg on days 4 to 56. After an amendment to the protocol to simplify treatment, 23 patients received loperamide at 12 mg per day for the first two weeks followed by 8 mg per day until day 56.
Patients were allowed to receive other prior adjuvant or neoadjuvant therapy. All patients had stage I to IIIc disease and could have been HR-positive or -negative. In the original protocol group, a majority of patients were HR-positive (85.2%). In the amended treatment cohort, 56.5% of patients had HR-positive breast cancer.
In the original protocol group, 18.5% of patients experienced grade 3 diarrhea (95% CI, 6.3-38.1). Of those who experienced a grade 3 event (n = 5), 60% were non-compliant to the loperamide regimen. In the amended group, the grade 3 diarrhea rate was 13% (95% CI, 2.8-33.6) and 67% of patients were non-compliant.
The rates of all-grade diarrhea were 74.1% and 43.5% in the original and amended protocol groups, respectively. Grade 4 diarrhea did not occur and hospitalizations were not required. Most treatment-emergent diarrhea occurred within the first 4 weeks.
“The highest incidence of all grade and grade 3 diarrhea is in the first week of treatment. After the third week, the grade 3 diarrhea has not been seen in the trial,” said Auerbach. “The diarrhea with neratinib is an adverse event that occurs early and than after the first week rapidly diminishes over time.”
The median duration of any grade diarrhea was 3 days in both groups. The median duration of grade 3 diarrhea was 1 day in the original protocol group and 2 in the amended arm. Across both groups, 30% of patients received additional anti-diarrheal medication.
Dose reductions were required in 7.4% and 4.3% of patients, in the original and amended groups, respectively. Neratinib was permanently discontinued for 25.9% and 4.3% of patients in the original and amended groups, respectively. There was 1 temporary neratinib discontinuation in the amended group.
“The grade 3 and all-grade diarrhea rates that we are achieving with the use of loperamide prophylaxis given with neratinib in this study are inline with the all grade and grade 3 diarrhea rates for approved oncology drugs that are currently used in clinical practice,” said Auerbach.
Puma plans to continue to evaluate additional patients in the amended cohort of the phase II study. Results are anticipated for the full cohort of 72 patients in 2016. The company plans to submit a new drug application to the FDA and European Medicines agency, based on findings from the ExteNET study and the open-label loperamide prophylaxis trial, noted Auerbach.
“Puma plans to submit the results from this study with its regulatory filings in the US and Europe that are currently planned for Q1 2016 and the first half of 2016, respectively,” he said.
In the phase III ExteNET 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). Neratinib was administered for 12 months at 240 mg per day.
In updated 3-year findings, the invasive DFS rate was 92% with neratinib versus 89.9% for placebo (HR, 0.74; 95% CI, 0.56-0.96; P
= .023). In those specifically with centrally confirmed HER2-positive/HR-positive breast cancer, the 3-year DFS rate was 94.4% versus 88%, for neratinib and placebo, respectively (HR, 0.43; 95% CI, 0.26-0.70; P
In the HR-negative group, there was no improvement seen between the neratinib group and the placebo arm, suggesting a distinct population that benefits from the TKI. In the HR-negative group, invasive DFS rate with neratinib was 88.1% versus 89.5% with placebo (HR, 0.98; 95% CI, 0.67-1.45; P
Other gastrointestinal-related side effects 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 1.6%.
Other adverse events of special interest included QT prolongation, which was less common in the neratinib arm (3.5% vs 6.6%). Left ventricular ejection fraction abnormalities of grade ≥2 were 1.3% with neratinib versus 1.1% with placebo.
Auerbach AH. Phase II open-label study to characterize incidence and severity of diarrhea in patients with early-stage HER2-positive breast cancer treated with neratinib and intensive loperamide prophylaxis [webcast]. Puma Biotechnology Update Call; December 21, 2015. https://event.webcasts.com/viewer/event.jsp?ei=1087734. Accessed December 22, 2015.