Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study

Abstract

Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0–163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time. Trial registration: JAPIC, JapicCTI-173600.

A New Method for Optimizing Sepsis Therapy by Nivolumab and Meropenem Combination: Importance of Early Intervention and CTL Reinvigoration Rate as a Response Marker

“…Cytokine analysis showed no evidence for cytokine storm (19). These findings were corroborated in another clinical trial-a multicenter, open label, phase I/II study (54). It appears, then, that in sepsis, administration of nivolumab in combination with the Standard of Care treatment has not yielded safety findings that justify a compromise of treatment efficacy for the sake of alleviating a safety concern.…”

“…The results of this trial did not reveal any unexpected safety findings, nor did it report any drug-related severe adverse events, or evidence for "cytokine storm" in patients. Moreover, in another study by Watanabe et al, the toxicity in exposure to a single dose of nivolumab, 960 mg, was comparable with that of nivolumab, 3 mg/kg every 2 weeks, in the oncological setting (54). Since Hotchkiss et al's trial had a larger sample size, we chose to model the PK/PD dynamics according to their study.…”

New Agents in Development for Sepsis: Any Reason for Hope?

“…No relation was evidenced between ALC and cytokine level in the nivolumab group, irrespective of the dose administered [86]. Recently, a Phase 1/2 study evaluated two regimen of a single dose (480 mg or 960 mg) of intravenous nivolumab in patients with vasopressor-dependent sepsis and a low ALC (≤ 1100/μL) [87]. In this small study population of 13 patients, nivolumab seemed to improve ALC and mHLA-DR expression [87].…”

“…Recently, a Phase 1/2 study evaluated two regimen of a single dose (480 mg or 960 mg) of intravenous nivolumab in patients with vasopressor-dependent sepsis and a low ALC (≤ 1100/μL) [87]. In this small study population of 13 patients, nivolumab seemed to improve ALC and mHLA-DR expression [87]. Combination immunotherapy associating nivolumab and interferon-gamma may also be considered as rescue therapy in refractory fungal infection, but its clinical value remains to be confirmed [88].…”

Immune Response Resetting as a Novel Strategy to Overcome SARS-CoV-2–Induced Cytokine Storm

“…Blockade of the PD-1/PD-L1 pathway is an attractive means of reverting exhaustion (97). The anti-PD-1 mAb nivolumab was well tolerated in two early phase clinical trials for sepsis (NCT02960854 and JapicCTI-173600) (98,99). Similarly, the anti-PD-L1 mAb BMS-936559 was well tolerated and did not induce hypercytokinemia in a phase Ib study (NCT02576457E) (100).…”