Evaluation of atezolizumab immunogenicity: Efficacy and safety (Part 2)

Peters, Solange; Galle, Peter R.; Bernaards, Coen A.; Ballinger, Marcus; Bruno, René; Quarmby, Valerie; Ruppel, Jane; Vilimovskij, Alexandr; Wu, Benjamin; Sternheim, Nitzan; Reck, Martin

doi:10.1111/cts.13149

Cited by 19 publications

(22 citation statements)

References 41 publications

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“…18 The clinical impact of atezolizumab immunogenicity was evaluated previously across the monotherapy and combination therapy clinical studies. 19,20 The results showed that ADA impacts atezolizumab CL minimally (16% increase in time-stationary popPK model and 9% increase in time-varying popPK model), 9,12 and that its impact on atezolizumab exposure was not clinically meaningful. 19 There was no statistically significant impact on efficacy or safety across the exposure ranges tested.…”

Section: Discussionmentioning

confidence: 98%

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation

Liu¹,

Marchand²,

Liu

et al. 2022

The Journal of Clinical Pharma

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Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phase I and eight phase III studies, to determine the exposure–response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840 mg q2w, 1200 mg q3w, and 1680 mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose‐linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840 mg q2w, 1200 mg q3w, and 1680 mg q4w for single‐agent and combination therapy use in the USA and EU.

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Section: Discussionmentioning

confidence: 98%

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation

Liu¹,

Marchand²,

Liu

et al. 2022

The Journal of Clinical Pharma

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“…All EC and IRB forms are provided as Appendix S3. Some of the trials investigated in recent analyses of atezolizumab immunogenicity were not considered in the present study due to a lack of consent language for exploratory genetic analyses in the trial protocols 5,6 …”

Section: Methodsmentioning

confidence: 99%

“…Some of the trials investigated in recent analyses of atezolizumab immunogenicity were not considered in the present study due to a lack of consent language for exploratory genetic analyses in the trial protocols. 5,6 Detection and analysis of ADA and NAb status ADA and NAb incidences were systematically and consistently assessed in atezolizumab-treated patients in all studies. Analytical methods were developed and run in accordance with industry best practices and health authority guidelines, and are described in more detail in Appendix S1.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

“…2 Two recently published articles evaluated the impact of atezolizumab ADA and NAb on pharmacokinetics and clinical efficacy. 5,6 A trend towards lower atezolizumab exposure was observed in patients with ADA and NAb, but patients had sufficient exposure regardless of ADA status. Metaanalysis in over 10 trials showed that in spite of numerical differences in overall and progression-free survival in some studies, ADA-positive patients from studies with an overall treatment effect did benefit from atezolizumab.…”

Section: Introductionmentioning

confidence: 96%

“…By definition, NAb can inhibit the function of a protein therapeutic in vitro regardless of their in vivo clinical relevance 2 . Two recently published articles evaluated the impact of atezolizumab ADA and NAb on pharmacokinetics and clinical efficacy 5,6 . A trend towards lower atezolizumab exposure was observed in patients with ADA and NAb, but patients had sufficient exposure regardless of ADA status.…”

Section: Introductionmentioning

confidence: 99%

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Allelic variation in HLA‐DRB1 is associated with development of antidrug antibodies in cancer patients treated with atezolizumab that are neutralizing in vitro

Hammer¹,

Ruppel²,

Kamen³

et al. 2022

Clinical Translational Sci

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The treatment of diseases with biologic agents can result in the formation of antidrug antibodies (ADA). Although drivers for ADA formation are unknown, a role for antigen presentation is likely, and variation in human leukocyte antigen (HLA) genes has been shown to be associated with occurrence of ADA for several biologics. Here, we performed an HLA-wide association study in 1982 patients treated with the anti-PD-L1 antibody atezolizumab across eight clinical trials. On average, 29.8% of patients were ADA-positive (N = 591, range of 13.5%-38.4% per study) and 14.6% of patients were positive for ADA that were neutralizing in vitro (neutralizing antibodies [NAb], N = 278, range of 6.4%-21.9% per study). In a meta-analysis of logistic regression coefficients, we found statistically significant associations between HLA class II alleles and ADA status. The topassociated alleles were HLA-DRB1*01:01 in a comparison of ADA-positive versus ADA-negative patients (p = 3.4 × 10 −5 , odds ratio [OR] 1.96, 95% confidence interval [95% CI] 1.64-2.28) and HLA-DQA1*01:01 when comparing NAb-positive with ADA-negative patients (p = 2.8 × 10 −7 , OR 2.31, 95% CI 1.98-2.66). Both alleles occur together on a common HLA haplotype, and analyses considering only NAb-negative, ADA-positive patients did not yield significant results, suggesting that the genetic association is mainly driven by NAb status. In conclusion, our study showed that HLA class II genotype is associated with the risk of developing ADA, and specifically NAb, in patients treated with atezolizumab, but the effect estimates suggest that immunogenetic factors are not sufficient as clinically meaningful predictors. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Antidrug antibodies (ADA) can impact the efficacy of therapeutics, but the mechanisms underlying their formation are poorly understood. Allelic variation

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Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma

et al. 2022

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ImportanceAdministration of atezolizumab could be immunogenic and induce undesirable antidrug antibody (ADA) responses. This may interfere with atezolizumab-mediated actions, affecting drug clearance and serum concentration or inducing antibody neutralization.ObjectiveTo determine the clinical and immunological associations of highly elevated ADA levels with clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC).Design, Setting, and ParticipantsThis cohort study prospectively enrolled 174 patients with advanced HCC treated with first-line Atezo/Bev (discovery cohort: 61 patients from 1 center; validation cohort: 113 patients from 4 centers).ExposuresSerum ADA levels at pretreatment and 3 weeks (cycle 2 day 1 [C2D1]) were analyzed using competitive enzyme-linked immunosorbent assays. In addition, samples were subjected to serological and flow cytometric analyses.Main Outcomes and MeasuresOverall, ADA positivity was associated with treatment outcomes and T-cell functions.ResultsAfter excluding patients with inadequate samples, follow-up loss, or consent withdrawal, 132 patients (discovery cohort: 50 patients; 41 [82.0%] men; median age [IQR], 61 [55-70] years; validation cohort: 82 patients; 70 [85.4%] men; median age [IQR], 61 [53-68] years) were analyzed, and robust ADA (≥1000 ng/mL) responses at C2D1 were identified in 23 (17.4%) of the patients. Patients with progressive disease exhibited higher ADA levels (median [IQR], 65.2 [0-520.4] ng/mL) at C2D1 than in responders (median [IQR], 0 [0-117.5] ng/mL). In both discovery and validation cohorts, patients with high ADA levels at C2D1 were associated with a reduced response rate (discovery cohort: 34% vs 11%; validation cohort: 29% vs. 7%) and worse progression-free survival (discovery cohort: hazard ratio [HR], 2.84; 95% CI, 1.31-6.13; P = .005; validation cohort: HR, 2.52; 95% CI, 1.27-5.01; P = .006) and overall survival (discovery cohort: HR, 3.30; 95% CI, 1.43-7.64; P = .003; validation cohort: HR, 5.81, 95% CI, 2.70-12.50; P = .001) with Atezo/Bev compared with those with low ADA levels. In multivariable Cox regression, the clinical implication of high ADA levels persisted even after adjusting for various confounding factors and was most significant at 1000 ng/mL or greater. Compared with patients with low ADA levels, patients with high ADA levels exhibited reduced serum atezolizumab concentrations, impaired CD8-positive T-cell proliferation, and had decreased interferon-γ and tumor necrosis factor-α from CD8-positive T cells compared with patients with low ADA levels.Conclusions and RelevanceThis cohort study found that highly elevated ADA levels at C2D1 may be associated with poor clinical outcomes in patients with advanced HCC treated with Atezo/Bev. High ADA levels may reduce atezolizumab exposure and attenuate the anticancer efficacy of the drug.

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Evaluation of atezolizumab immunogenicity: Efficacy and safety (Part 2)

Cited by 19 publications

References 41 publications

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation

Allelic variation in HLA‐DRB1 is associated with development of antidrug antibodies in cancer patients treated with atezolizumab that are neutralizing in vitro

Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma

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