Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.

Abstract

Nivolumab is approved at various doses, including 3mg/kg, 240mg and 480mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses. Patients were either administered 40mg flat dose or 3mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity. Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3mg/kg), while 11 patients received low-dose (40mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group. Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.