Evaluating the efficacy and safety of immune checkpoint inhibitors by detecting the exposure-response: An inductive review

Cheng, Mengfei; Zhang, Shuo; Liu, Jiahui; Jiang, Shuai; Dong, Mei

doi:10.1016/j.intimp.2021.107703

Cited by 3 publications

(3 citation statements)

References 88 publications

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“…Immunotherapy is a new field compared with chemo-and radiation therapies in which the tolerance profile is largely under-explored. The safety concerns are particularly important for patients who paused the initial ICI treatments owing to irAEs [99][100]. Fujisaki et al [101] showed that patients who paused their initial ICI treatment owing to irAEs could tolerate ICI rechallenge and also achieved improved OS (p=0.025).…”

Section: Safety Managementmentioning

confidence: 99%

Current Status in Rechallenge of Immunotherapy

Hu,

Wang,

Jia

et al. 2023

Int. J. Biol. Sci.

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The treatment of malignant tumors has entered the era of immunotherapy, and immune checkpoint inhibitors (ICIs) have brought significant benefits to patients. However, some patients are required to discontinue treatment with ICIs owing to factors such as disease progression and intolerable side effects. Faced with limited subsequent treatment options and complex medical needs, we searched PubMed, Embase, Cochrane library, and the NIH clinical trials database and found that ICI rechallenge could be a relevant clinical strategy. The factors that could affect the rechallenge efficacy include the patients' characteristics, therapeutic strategy selection, and the timing of treatment. Multiple factors are used to identify target population, of which clinical features and PD-L1 expression are more potential. Both single ICI rechallenge and combination therapy may have survival benefits. Patients who have tolerated initial immunotherapy well could undergo ICI rechallenge, while patients who have experienced grade 3 or higher immune-related adverse events should be carefully assessed prior to rechallenge. Interventions and the interval between two courses of ICI will clearly have an impact on the efficacy of subsequent treatment. Preliminary data evaluation supports further investigation on ICI rechallenge to identify the factors that could contribute to its efficacy.

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Section: Safety Managementmentioning

confidence: 99%

Current Status in Rechallenge of Immunotherapy

Hu,

Wang,

Jia

et al. 2023

Int. J. Biol. Sci.

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“…Different approaches have been used to characterize the E-R relationship in ICI therapy (ie, exposure-efficacy or exposure-safety relationships), depending on the type of ICI (eg, anti-CTLA-4 or anti-PD-1) or even depending on the tumor type or clinical trial. 2,[13][14][15][16] Regarding anti-PD-1 and anti-PD-L1 antibodies (eg, pembrolizumab, nivolumab, atezolizumab), most published trials did not find an obvious association of efficacy (eg, OS, PFS, overall response [OR]) or safety (eg, immune-related adverse events or adverse events leading to treatment discontinuation or death) with either the administered dose or the drug concentration in blood. 2,[13][14][15][16][17][18][19] Only rare studies show contradictory results where an E-R relationship for ICI efficacy was found, but these often neglected several key clinical and biological parameters (eg, tumor burden or mAb clearance) in the multivariate…”

Section: Disposition and Mechanisms Of Immune Checkpoint Inhibitor Th...mentioning

confidence: 99%

“…In this case, exposure is then defined as area under the curve of the concentration‐time curve or average concentration (c avg ), or as trough (minimal, c min ) or peak (maximal, c max ) concentration of the first or later treatment cycles (pharmacokinetics [PK]). Different approaches have been used to characterize the E‐R relationship in ICI therapy (ie, exposure‐efficacy or exposure‐safety relationships), depending on the type of ICI (eg, anti‐CTLA‐4 or anti‐PD‐1) or even depending on the tumor type or clinical trial 2,13‐16 . Regarding anti‐PD‐1 and anti‐PD‐L1 antibodies (eg, pembrolizumab, nivolumab, atezolizumab), most published trials did not find an obvious association of efficacy (eg, OS, PFS, overall response [OR]) or safety (eg, immune‐related adverse events or adverse events leading to treatment discontinuation or death) with either the administered dose or the drug concentration in blood 2,13‐19 .…”

Section: Disposition and Mechanisms Of Immune Checkpoint Inhibitor Th...mentioning

confidence: 99%

Molecular prediction of clinical response to anti‐PD‐1/anti‐PD‐L1 immune checkpoint inhibitors: New perspectives for precision medicine and mass spectrometry‐based investigations

Longuespée

Theile

Zörnig

et al. 2022

Intl Journal of Cancer

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Monoclonal antibodies (mAbs) acting as immune checkpoint inhibitors (ICIs) are among the most frequently used immunotherapies in oncology. However, precision medicine approaches to adapt the treatment to the patient are still poorly exploited. Given the risk of severe adverse reactions, predicting patient eligibility for ICI therapy represents a great asset for precision medicine. Today, the extended panel of mass spectrometric approaches, accompanied by newly developed sample preparation methods is a strategy of choice for responder and non‐responder stratification on a molecular basis, and early detection of resistance. In this perspective article, we review the biodisposition of mAbs, the interest in molecular stratification of patients treated with these mAbs, and the possible analytical strategies to achieve this goal, with a major emphasis on mass spectrometric approaches.

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Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors

Cui,

Wang,

Wang

et al. 2024

The Oncologist

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Background and Objectives Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. Methods In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. Results The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. Conclusions No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

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Evaluating the efficacy and safety of immune checkpoint inhibitors by detecting the exposure-response: An inductive review

Cited by 3 publications

References 88 publications

Current Status in Rechallenge of Immunotherapy

Current Status in Rechallenge of Immunotherapy

Molecular prediction of clinical response to anti‐PD‐1/anti‐PD‐L1 immune checkpoint inhibitors: New perspectives for precision medicine and mass spectrometry‐based investigations

Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors

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