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Aims: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model‐based clinical pharmacology profiling and benefit–risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. Methods: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure‐response (E‐R) analyses included data from 756 patients from CheckMate 577. E‐R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease‐free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune‐mediated adverse events (Gr2 + IMAEs) for safety. Results: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E‐R relationships within the exposure range produced by the studied regimen. Model‐predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year. Conclusions: The analyses demonstrated a flat E‐R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC. [ABSTRACT FROM AUTHOR]

Protein affinity reagents (e.g., antibodies) are often used for basic research, diagnostics, separations, and disease therapy. Although a lot of "synthetic" protein affinity reagents have been developed as a cost‐effective alternative to antibodies, their low biocompatibility is a considerable problem for clinical application. Lipid nanoparticles (LNP) represent a highly biocompatible drug delivery agent. However, little has been reported that LNP itself works as a protein affinity reagent in living animals. Here, LNP is engineered for binding to and neutralizing a target toxic peptide in living animals by multifunctionalization with amino acid derivatives. Multifunctionalized LNP (MF‐LNP) is prepared using amino acid derivative‐conjugated lipids. Optimized MF‐LNP exhibits nanomolar affinity to the target toxic peptide and inhibits toxic peptide‐dependent hemolysis and cytotoxicity. In addition, MF‐LNP captures and neutralizes the toxic peptide after intravenous injection in the bloodstream; in addition, MF‐LNP does not release the toxic peptide in the accumulated organ. These results reveal the potential of using LNP as a highly biocompatible protein affinity reagent such as an antidote. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time‐varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2‐compartment model with parallel linear (nonspecific) and Michaelis‐Menten elimination from the central compartment and target‐mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target‐mediated elimination rate (Vmax) were statistically significant but not considered clinically relevant (magnitude < 20%). Time‐varying M protein on Vmax was statistically significant, and the magnitude was >20%; however, clinical implications in the setting of combination therapy were not expected. Model‐predicted steady‐state elotuzumab exposure in cycle 12 were similar in Japanese and non‐Japanese patients and in Japanese patients with 0 and ≥1 prior lines of therapy. Elotuzumab 20 mg/kg intravenously every 4 weeks beginning in cycle 19 produced time‐averaged concentrations similar to elotuzumab 10 mg/kg intravenously every 2 weeks, although maximum and minimum concentrations after elotuzumab 20 mg/kg intravenous every‐4‐week dosing were slightly higher and lower, respectively. In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time‐varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma. [ABSTRACT FROM AUTHOR]