Assessment of nivolumab (Nivo) benefit-risk profile from a 240-mg flat dose versus a 3-mg/kg dosing regimen in patients (Pts) with solid tumors

Nivo 3 mg/kg every 2 weeks (Q2W) has shown overall survival (OS) benefit over the standard of care in multiple advanced cancers and is currently approved for treatment of renal cell carcinoma (RCC), melanoma (MEL), and squamous and non-squamous non-small cell lung cancer (SQ/NSQ NSCLC) in the US, EU, and other countries. Nivo, a programmed death-1-blocking antibody, displays flat exposure-response (E-R) relationships. Relative to body weight (BW)-based dosing, a flat dose is expected to reduce prescription dosing errors, shorten pharmacy preparation time, and improve ease of administration. This integrated analysis evaluated the exposure, efficacy, and safety of a 240-mg flat dose relative to 3-mg/kg dosing in the approved indications. A flat dose of 240 mg was selected based on equivalence to the approved 3-mg/kg dose at the median BW of ∼80 kg in pts with solid tumors. Demographic data from pts with RCC (n = 603), MEL (n = 826), or SQ/NSQ NSCLC (n = 648) across 9 CheckMate studies were included in the pooled dataset. Exposures produced by doses of 3 mg/kg or 240 mg Q2W were simulated based on established quantitative pharmacokinetic models and further used to predict efficacy and safety from E-R models in each tumor type. A safety review of clinical data in pts with solid tumors who received nivo 3 or 10 mg/kg was conducted to evaluate the association between BW or exposure measures and incidence of adverse events (AEs). The geometric mean of summary measures of nivo exposure predicted from the 240-mg flat dose Q2W was ≤5% different than corresponding exposures produced by 3-mg/kg Q2W dosing. The predicted OS benefit and risk of AEs leading to discontinuation or death were similar across tumor types for both dosing regimens. Subgroup safety analyses did not demonstrate a clinically meaningful relationship between nivo exposure or BW and frequency or severity of AEs. Based on model-predicted nivo pharmacokinetics, efficacy, and safety, clinical safety review, and an understanding of nivo E-R relationships, no clinically meaningful difference in the benefit-risk profile of nivo is expected with 240-mg Q2W vs 3-mg/kg Q2W dosing in RCC, MEL, or NSCLC.