E-R analysis for efficacy and safet

E-R analysis for efficacy and safety in the target patient population (early stage HER2+ patients) is not available as PK data was not collected in the registration study. Sponsor’s E-R analysis, conducted in advanced / metastatic breast patients, showed a positive correlation between the objective response rate and steady sate neratinib exposure and flat relationships between systemic toxicities and steady state exposure. The median starting dose and the median average daily dose in the E-R datasets are 240 mg, similar to what was observed the registration study. According to PPK analysis, mandatory use of anti-diarrhea treatment is expected to minimize Any Grade diarrhea events and increase bioavailability by approximately 10% at most (assuming no DDI between neratinib and the anti-diarrhea drug). Such an increase in neratinib exposure should not be of concern given the flat E-R relationship on systemic toxicity. On the other hand, E-R analysis for efficacy in advanced / metastatic breast patients suggests a risk of losing activity when neratinib exposure is significantly reduced. For instance, the probability of response decreases from 37% in a typical patient (i.e. body weight=70 kg, age=53 y.o., bilirubin=10 mg/L, and ALT=20.09 IU/L) taking 240 mg neratinib QD to 20% in a patient taking 80 mg neratinib QD (i.e. a 67% reduction in exposure).