Neratinib is basically useless and has unmanageable side effects. Puma can publicly acknowledge only one of these problems, so here we are, with the company testing various diarrhea prophylaxis strategies to support an argument that a 2% increase in five-year disease-free survival among early-stage HER2+ breast cancer patients is somehow worth all this misery.
To recap from the early neratinib data, everyone experienced diarrhea; about 40% of patients not receiving loperamide prophylaxis experienced grade 3 or greater diarrhea. Grade 3 diarrhea is defined as an “increase of greater than 7 stools/day over baseline, incontinence”, and grade 4 is life-threatening. This is untenable for a population that has completed surgery, chemotherapy and Herceptin and is without residual disease (i.e., a population that is completely fine and most likely cured), so here we are with the diarrhea control study.
Patients were initially enrolled to receive 4 mg of oral loperamide with the first neratinib dose, then 2 mg every four hours on days 1-3, then 2 mg every 6-8 hours from day 4 to 56. Among these patients, 82% reported diarrhea; 25% of cases were grade 2 and 21% were grade 3 or higher. So that was a letdown. There was a protocol modification to 4 mg of oral loperamide with the first neratinib dose, then 4 mg three times per day on days 1-14, then 4 mg twice per day from days 15 to 56. 70% of patients in this cohort reported diarrhea; 19% of cases were grade 2 and 29% were grade 3 or higher.
How do you solve this one? You add a steroid to the loperamide. With 9 mg of oral budesonide on days 1 to 28, 69% of patients reported diarrhea, but the severity was reduced to a 19% incidence of grade 2 and a 13% incidence of grade 3 or higher diarrhea.
As steroids go, budesonide is rather mild, with fewer side effects than, say, prednisone. It’s commonly given for Crohn’s Disease. But it’s still a steroid, which can affect everything from sleep patterns to the immune system to bone health to mood, not to mention causing the dreaded puffy face. Is this an optimal recovery strategy for patients who just completed cancer treatment?
Neratinib continues to be an egregious example of overtreatment and waste; fiddling with doses and schedules of anti-diarrhea treatments can’t mask the disregard for patient comfort, patient safety and true clinical need.