Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint inhibitor antibodies

Desnoyer, Aude; Broutin, Sophie; Delahousse, J; Maritaz, Christophe; Blondel, Louis; Mir, Olivier; Chaput, Nathalie; Paci, Angélo

doi:10.1016/j.ejca.2020.01.003

Cited by 57 publications

(48 citation statements)

References 57 publications

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“…43 According to population PK analyses, ethnicity (Asian vs Caucasian) is a key factor that may affect antibody clearance 44 but others have suggested that efficacy in different ethnicities are unrelated to antibody clearance. 45 In our meta-analysis, we did not rule out the studies of nonsignificant trials, because treatment effects may still not be homogeneously absent across the study population. 44 However, the overall type I error could be substantially inflated.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy

et al. 2020

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Background: Subgroup analysis of clinical trials of PD-1/PD-L1 inhibitors have reported ethnic differences in outcomes. We systematically collected published data and performed a meta-analysis to compare therapeutic efficacy in Asian and non-Asian patients receiving PD-1/PD-L1 inhibitors. Methods: Eligible studies included phase II and III prospective clinical trials with available subgroup data on Asian versus non-Asian populations. Overall survival (OS) and progression-free survival (PFS) were used to evaluate differences in outcome between Asian versus non-Asian cancer patients. Results: A total of 11,020 cancer patients from 19 prospective randomized controlled clinical trials were included. The overall estimated HR for OS was 0.69 with 95% CI of 0.61-0.77 in Asian versus 0.82 with 95% CI of 0.77-0.88 in non-Asian patients. The estimated hazard ratio (HR) for PFS measured 0.54 (95% CI, 0.32-0.76) and 0.69 (95% CI, 0.54-0.85) in Asian and non-Asian patients, respectively. Pooled ratios of OS HRs and PFS HRs reported in Asian versus non-Asian cancer patients were 0.84 (95% CI, 0.75-0.94) and 0.78 (95% CI, 0.59-0.97), respectively. Conclusions: This meta-analysis shows for the first time that Asian cancer patients have a significantly improved survival benefit than non-Asian patients receiving PD-1/PD-L1 inhibitor-based therapy.

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Section: Discussionmentioning

confidence: 99%

A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy

et al. 2020

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“…Early drug development studies provided data on pharmacokinetic (PK) and pharmacodynamic (PD) properties of immune-checkpoint inhibitors, including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies (1,16,17). These are either humanized or fully human monoclonal immunoglobulin (IgG)-1 antibodies, with the exception of the PD-1 inhibitors pembrolizumab and nivolumab, which are IgG4 molecules.…”

Section: Lessons Learnt From Early Phase Development Trialsmentioning

confidence: 99%

“…These are either humanized or fully human monoclonal immunoglobulin (IgG)-1 antibodies, with the exception of the PD-1 inhibitors pembrolizumab and nivolumab, which are IgG4 molecules. As with other monoclonal antibodies, they exhibit a low volume of distribution, low clearance, and long half-lives; their clearance is also minimally affected by renal or hepatic impairment (16,17).…”

Section: Lessons Learnt From Early Phase Development Trialsmentioning

confidence: 99%

“…Clinicopathological features are known to influence the PKs of monoclonal antibodies and may contribute to interpatient variability (16,37). Body weight is the most important patient variable influencing clearance of ICIs.…”

Section: Lessons Learnt From Early Phase Development Trialsmentioning

confidence: 99%

“…Two compartment models best characterize the PK properties of ICIs ( 16 ). Over the dose range studied, linear PK profiles with time-varying clearance have been described for: pembrolizumab (0.3–10 mg/kg) ( 18 – 20 ), nivolumab (0.1–20 mg/kg) ( 21 – 23 ), atezolizumab [1–20 mg/kg including 1,200 mg dose) ( 24 ), and durvalumab (>3 mg/kg) ( 25 , 26 ).…”

Section: Lessons Learnt From Early Phase Development Trialsmentioning

confidence: 99%

See 2 more Smart Citations

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

2020

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Patients with lung cancer are particularly vulnerable to complications from coronavirus disease-2019 (COVID-19). Recurrent hospital visits and hospital admission are potential risk factors for acquiring infection with its causative pathogen, severe acute respiratory syndrome coronavirus−2 (SARS-CoV-2). As immune checkpoint inhibitors (ICIs) constitute the therapeutic backbone for the vast majority of patients with advanced lung cancer in the absence of actionable driver oncogenes, there have been intense discussions within the oncology community regarding risk-benefit of delaying these treatments or use of alternative extended-interval treatment strategies to minimize the risk of viral transmission secondary to unintended nosocomial exposures. In the midst of the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) granted accelerated approval for extended-interval strategy of pembrolizumab at a dose of 400 mg every 6 weeks for all already approved oncologic indications. Herein, we summarize the evidence from the in silico pharmacokinetic modeling/simulation studies supporting extended-interval dosing strategies for the ICIs used in lung cancer. We further review the evolving clinical evidence behind these approaches and predict that they will continue to be used in routine practice even long after the pandemic, particularly for patients with durable disease control.

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The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non‐Small Cell Lung Cancer Treated With a PD‐1/PD‐L1 Blocking Antibody Using Real‐World and Trial Data

Liu

Mathur

et al. 2023

Clin Pharma and Therapeutics

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Clinical trials have demonstrated the benefit of PD‐1/PD‐L1 blocking antibodies for the treatment of patients with advanced non‐small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD‐1/PD‐L1 blocking antibodies in real‐world data (RWD; patient‐level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan–Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis‐generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

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Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint inhibitor antibodies

Cited by 57 publications

References 57 publications

A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy

A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non‐Small Cell Lung Cancer Treated With a PD‐1/PD‐L1 Blocking Antibody Using Real‐World and Trial Data

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