These data were presented in mid-December 2015.
There was a significant reduction in grade 3 diarrhea among patients treated with neratinib and prophylactic loperamide (sold under the brand name Imodium, among others), according to data from the phase 3 ExteNET trial. Puma Biotechnology, the company developing neratinib, presented the results on a conference call in mid-December 2015. Diarrhea of any grade was experienced by 60 percent of patients receiving neratinib and prophylaxis.
Neratinib is an experimental drug being investigated as a neoadjuvant therapy for patients with HER2-positive breast cancer and as a treatment for patients with metastatic HER2-positive breast cancer. [More about trials of neratinib here]
Overall, in the ExteNET study, 95.4 percent of patients experienced all-grade diarrhea, with 39.9 percent of patients having an event of at least grade 3. The median duration of diarrhea was five days and 1.4 percent of patients required hospitalization due to this adverse event. Diarrhea led to a dose reduction for 26.4 percent of patients and 16.8 percent 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 3 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 3 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 percent.
In the phase 2 open-label study, patients were enrolled within one year of completing adjuvant treatment with Herceptin (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 1 to 3c disease and could have been HR-positive or -negative. In the original protocol group, a majority of patients were HR-positive (85.2 percent). In the amended treatment cohort, 56.5 percent of patients had HR-positive breast cancer.
In the original protocol group, 18.5 percent of patients experienced grade 3 diarrhea. Of those who experienced a grade 3 event (5 patients), 60 percent were non-compliant to the loperamide regimen. In the amended group, the grade 3 diarrhea rate was 13 percent and 67 percent of patients were non-compliant.
The rates of all-grade diarrhea were 74.1 percent and 43.5 percent 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 four 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 three days in both groups. The median duration of grade 3 diarrhea was one day in the original protocol group and two in the amended arm. Across both groups, 30 percent of patients received additional anti-diarrheal medication.
Dose reductions were required in 7.4 percent and 4.3 percent of patients, in the original and amended groups, respectively. Neratinib was permanently discontinued for 25.9 percent and 4.3 percent of patients in the original and amended groups, respectively. There was one 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 2 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 U.S. and Europe that are currently planned for Q1 2016 and the first half of 2016, respectively,” he said.
In the phase 3 ExteNET study, 2,840 patients who remained disease-free following one year of treatment with adjuvant Herceptin and chemotherapy were randomized to neratinib (1,420) or placebo (1,420). Neratinib was administered for 12 months at 240 mg per day.
In updated three-year findings, the invasive disease free survival (DFS) rate was 92 percent with neratinib versus 89.9 percent for placebo. In those specifically with centrally confirmed HER2-positive/HR-positive breast cancer, the three-year DFS rate was 94.4 percent versus 88 percent, for neratinib and placebo, respectively.
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 percent versus 89.5 percent with placebo.
Other gastrointestinal-related side effects included nausea (43 percent), fatigue (27 percent), vomiting (26.2 percent) and abdominal pain (24.1 percent). In the placebo arm, 35.4 percent of patients had all-grade diarrhea, with a grade 3/4 incidence of 1.6 percent.
Other adverse events of special interest included QT prolongation, which was less common in the neratinib arm (3.5 percent vs 6.6 percent). Left ventricular ejection fraction abnormalities of at least grade 2 were 1.3 percent with neratinib versus 1.1 percent 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.