Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1)

Wu, Benjamin; Sternheim, Nitzan; Agarwal, Priya; Suchomel, Julia; Vadhavkar, Shweta; Bruno, René; Ballinger, Marcus; Bernaards, Coen A.; Chan, Phyllis; Ruppel, Jane; Jin, Jin; Girish, Sandhya; Joshi, Amita; Quarmby, Valerie

doi:10.1111/cts.13127

Cited by 37 publications

(49 citation statements)

References 35 publications

(89 reference statements)

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“…Interestingly, there appear to be unique and shared covariates associated with efficacy, PK, and ADA development. 18 …”

Section: Discussionmentioning

confidence: 99%

“…Initial descriptive analyses of treatment-emergent ADA from atezolizumab clinical trial data-conducted using industrystandard approaches to ADA data interpretation 15 without the use of landmark analysis or adjustment for baseline characteristics-had suggested a trend of lower atezolizumab exposure in treatment-emergent ADA+ patients, which was not clinically relevant as most patients were still expected to have trough concentrations above levels required for target saturation. 18 Atezolizumab also exhibits a flat exposure-response relationship, 39,41 with the impact of ADA on clearance being only 9% as estimated by a time-varying population PK model. 42 Shorter survival in ADA+ patients compared with ADA-patients was also previously reported but was confounded by imbalances in baseline prognostic factors.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, there appear to be unique and shared covariates associated with efficacy, PK, and ADA development. 18 In conclusion, this is the first comprehensive ADA analysis of atezolizumab trial data, using both study-bystudy and integrated analyses. To our knowledge, this is one of the largest and most comprehensive ADA analyses completed for a therapeutic protein.…”

Section: F I G U R Ementioning

confidence: 92%

“…The efficacy findings in ADA+ patients are consistent with the lack of clinically meaningful decrease in exposure and the strategy for dosing over any potential ADA effect. 18 Some numerical differences in AE frequencies were seen between ADA/NAb subgroups, possibly due to the underlying baseline differences in patient health status between the subgroups; no adjustment was possible on these data. Collectively, a positive benefitrisk balance is observed with atezolizumab treatment for approved indications regardless of ADA status.…”

Section: F I G U R Ementioning

confidence: 98%

“…Atezolizumab (anti–PD‐L1) has been approved in various types of cancers. 16 , 17 Across multiple studies, expanded analyses of ADA against atezolizumab have been conducted, showing incidence rates of 13%–54% overall and 4%–28% for NAb, 18 with no consistent trends of association among incidence rates and tumor type, line of therapy, treatment schedule, or monotherapy versus combination therapy.…”

Section: Introductionmentioning

confidence: 99%

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

Peters¹,

Galle

Bernaards³

et al. 2021

Clinical Translational Sci

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Antibody therapeutics can be associated with unwanted immune responses resulting in the development of anti-drug antibodies (ADA). Optimal methods to evaluate the potential effects of ADA on clinical outcomes in oncology are not well established. In this study, we assessed efficacy and safety, based on ADA status, in patients from over 10 clinical trials that evaluated the immune checkpoint inhibitor atezolizumab as a single agent or as combination therapy for several types of advanced cancers. ADA can only be observed post randomization, and imbalances in baseline prognostic factors can confound the interpretation of ADA impact. We applied methodology to account for the confounding effects of baseline clinical characteristics and survivorship bias on efficacy. Adjusted meta-analyses revealed that despite numerical differences in overall survival and progression-free survival between ADA-positive and ADA-negative patients from some studies, ADA-positive patients from studies with an overall treatment effect derived benefit from atezolizumab, compared with their adjusted controls.Based on large, pooled populations from atezolizumab monotherapy or combination studies, unadjusted descriptive analyses did not identify a clear relationship between ADA status and frequency or severity of adverse events. Data also suggested that any ADA impact is not driven by neutralizing activity. Collectively, this exploratory analysis suggests that the potential for ADA development should not impact treatment decisions with atezolizumab. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Treatment-emergent anti-drug antibodies (ADA) directed against anticancer therapeutics, including atezolizumab, might affect efficacy and safety.

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“…Interestingly, there appear to be unique and shared covariates associated with efficacy, PK, and ADA development. 18 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 92%

Section: F I G U R Ementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Peters¹,

Galle

Bernaards³

et al. 2021

Clinical Translational Sci

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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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High Levels of Antidrug Antibodies Against Atezolizumab as a Predictive Marker for Clinical Outcomes in Patients With Hepatocellular Carcinoma

Shigematsu

Inamura

2023

JAMA Oncol

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To the Editor We read with great interest the cohort study by Kim and colleagues 1 and appreciate the authors' efforts to determine the adverse prognostic association of high-level serum antidrug antibody (ADA) against atezolizumab in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab. We have 3 concerns regarding the interpretation of the findings and hope that the authors would consider them.The first concern is the authors' speculation that "high ADA levels may reduce atezolizumab exposure and attenuate the anticancer efficacy of the drug." 1 Using data from various clinical trials, other studies have found that serum atezolizumab concentrations exceeded the target saturation level of 6 μg/mL in more than 90% of patients regardless of ADA status, 2,3 suggesting that ADA development has no clinically meaningful association with atezolizumab exposure. In fact, as Figure 2B of the article shows, 1 more than 85% of patients with high ADA levels (≥1000 ng/mL) achieved the atezolizumab target exposure, indicating that ADA does not appear to be associated with atezolizumab outcomes by itself. We would be grateful if the authors would elaborate on how ADA is associated with atezolizumab outcomes.The second concern is the effect of confounding between baseline disease characteristics and ADA on atezolizumab pharmacokinetics and clinical outcomes. 1 For example, the frequency of ADA development is high in patients with increased tumor burden and elevated systemic inflammation (eg, highvolume tumor, high neutrophil-to-lymphocyte ratio, and highlevel α-fetoprotein [AFP]) at baseline, but these baseline characteristics are also associated with increased atezolizumab clearance and poor prognosis. 2,3 As eFigure 5A of the article shows, 1 the adverse prognostic indicator neutrophil-lymphocyte ratio did not affect survival when analyzed in conjunction with ADA, suggesting the confounding association. It would be helpful if the authors could provide the baseline characteristics of ADA-high and ADA-low patients, allowing for the assessment of nonnegligible confounding effects.The last concern pertains to the utility of ADA as a predictor for clinical outcomes compared with existing or emerging markers. Comprehensive molecular research has identified AFP expression in the HCC microenvironment as 1 predictor of atezolizumab and bevacizumab inefficacy. 4 In this article, 1 baseline serum AFP, similar to ADA, was independently associated with worse overall survival. On-treatment serum AFP has been recently identified as a promising biomarker for response to atezolizumab and bevacizumab in HCC. 5 Therefore, we would appreciate it if the authors would discuss whether ADA or on-treatment AFP is more accurate for predicting therapeutic response. Candidate biomarkers are emerging and must be ranked for performance.

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Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1)

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 37 publications

References 35 publications

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

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

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

High Levels of Antidrug Antibodies Against Atezolizumab as a Predictive Marker for Clinical Outcomes in Patients With Hepatocellular Carcinoma

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