Highlights
- •Responders to nivolumab treatment had higher nivolumab exposure than progressors.
- •No difference in exposure was seen in patients with and without toxicity.
- •Factors influencing exposure should be clarified in future research.
Abstract
Introduction
Nivolumab treatment is subject to large interpatient variability in both efficacy
and toxicity, which may partly be explained by differences in nivolumab exposure.
Exposure–response relationships in regular healthcare have not been extensively investigated
for nivolumab. Therefore, we aimed to identify possible exposure–response relationships
in nivolumab-treated patients with non–small-cell lung cancer (NSCLC).
Methods
Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between
May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and
outcome data were prospectively collected, were included. Follow-up was carried out
until November 1st 2017. Patients were classified according to the best overall response
(BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities
according to the Common Terminology Criteria for Adverse Events. Nivolumab trough
concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose
delays, and calculated geometric means were tested versus BOR or toxicity using analysis
of variance and an independent samples t-test, respectively. Overall survival (OS) and progression-free survival were compared
between high and low trough concentration groups.
Results
Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean
trough concentrations than patients with progression (n = 33): 47% higher after 2
weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks
(p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001).
Conclusions
This study shows that patients with NSCLC with a response to nivolumab had a higher
nivolumab exposure than patients with progression, indicating a potential exposure–response
relationship. Further clinical research should focus on clarifying these exposure–response
relationships.
Keywords
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References
- Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.Immunity. 1999; 11: 141-151
- Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy.J Immunother Cancer. 2016; 4: 72
- Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366: 2443-2454
- Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639
- Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135
European Medicines Agency. Opdivo (nivolumab) assessment report. Last accessed 29 January 2018.
- The combination of exposure-response and case-control analyses in regulatory decision making.J Clin Pharmacol. 2013; 53: 160-166
- Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer.Clin Pharmacol Ther. 2014; 95: 558-564
- Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients.Clin Cancer Res. 2011; 17: 6329-6337
- Dashboard systems: pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies.J Clin Pharmacol. 2015; 55: S51-S59
- Population pharmacokinetics of obinutuzumab (GA101) in chronic lymphocytic leukemia (CLL) and non-hodgkin's lymphoma and exposure-response in CLL.CPT Pharmacometrics Syst Pharmacol. 2014; 3: e144
- Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma.Clin Cancer Res. 2013; 19: 3977-3986
- New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247
- Development of an enzyme-linked immune sorbent assay to measure nivolumab and pembrolizumab serum concentrations.Ther Drug Monit. 2018; 40: 596-601
- Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.J Clin Oncol. 2010; 28: 3167-3175
- Dose rationalization of pembrolizumab and nivolumab using pharmacokinetic modeling and simulation and cost analysis.Clin Pharmacol Ther. 2018; 103: 582-590
- Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance.Clin Cancer Res. 2018;
- Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated.J Clin Oncol. 2010; 28: 960-966
- Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development.BioDrugs. 2010; 24: 23-39
- Absorption, distribution, metabolism, and excretion (ADME) studies of biotherapeutics for autoimmune and inflammatory conditions.AAPS J. 2012; 14: 714-727
- Multiple roles for the major histocompatibility complex class I- related receptor FcRn.Annu Rev Immunol. 2000; 18: 739-766
- Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action.Cancer Res. 2006; 66: 7630-7638
- In vitro internalization, intracellular transport, and clearance of an anti-CD11a antibody (Raptiva) by human T-cells.J Pharmacol Exp Therapeut. 2004; 310: 896-904
- Evaluation of immunogenicity of nivolumab monotherapy and its clinical relevance in patients with metastatic solid tumors.J Clin Pharmacol. 2017; 57: 394-400
- Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors.CPT Pharmacometrics Syst Pharmacol. 2017; 6: 58-66
- Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.Ann Oncol. 2016; 27: 559-574
- Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis.Clin Pharmacol Ther. 2017; 101: 657-666
- Nivolumab exposure-response analyses of efficacy and safety in previously treated squamous or nonsquamous non-small cell lung cancer.Clin Cancer Res. 2017; 23: 5394-5405
Article info
Publication history
Published online: January 14, 2019
Accepted:
December 5,
2018
Received in revised form:
December 2,
2018
Received:
October 4,
2018
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
ScienceDirect
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- Letter to the Editor: Exposure–response or clearance–response relationship in immune checkpoint therapy?—A comment on ‘correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer’ by Basak et alEuropean Journal of CancerVol. 114
- PreviewIn their manuscript, ‘Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer’, Basak et al [1] hypothesise that patients who were treated with nivolumab and exhibited stable disease and progressive disease would have benefited from an increased systemic exposure and propose that a higher dose of nivolumab should be considered for those patients. They arrive at this conclusion after evaluation of pharmacokinetic and outcome data in patients with non–small-cell lung cancer who all received a dose of 3 mg/kg, where some patients with higher trough concentrations experience a survival benefit.
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