Alpha-Fetoprotein as a Potential Surrogate Biomarker for Atezolizumab + Bevacizumab Treatment of Hepatocellular Carcinoma

Zhu, Andrew X.; Dayyani, Farshid; Yen, Chia‐Jui; Ren, Zhenggang; Bai, Yuxian; Meng, Zhiqiang; Pan, Hongming; Dillon, Paul; Mhatre, Shivani K.; Gaillard, Vincent E.; Hernandez, Sairy; Kelley, Robin K.; Sangro, Bruno

doi:10.1158/1078-0432.ccr-21-3275

Cited by 79 publications

(84 citation statements)

References 27 publications

(29 reference statements)

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“…Since AFP level is related to the tumor or patient characteristics, interpretation should be performed with caution. As generally seen in other treatments, a decline in post-treatment tumor marker level is associated with better efficacy of immunotherapy in advanced HCC; the AFP response at 6 weeks after atezolizumab plus bevacizumab initiation especially seemed to be a potential surrogate biomarker for prognosis [43][44][45].…”

Section: Laboratory Testsmentioning

confidence: 69%

Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma?

Lee

Chan

Chon

2022

Cancers

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The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is an important strategy for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10–20% of patients when used as a monotherapy. Therefore, the selection of patients for anti-PD-1/PD-L1 treatment is crucial for both patients and clinicians. This review aimed to explore the existing literature on tissue or circulating markers for the identification of responders or non-responders to anti-PD-1/PD-L1 in HCC. For the clinically available markers, both etiological factors (viral versus non-viral) and disease extent (intra-hepatic vs. extrahepatic) impact the responses to anti-PD-1/PD-L1, warranting further studies. Preliminary data suggested that inflammatory indices (e.g., neutrophil-lymphocyte ratio) may be associated with clinical outcomes of HCC during the anti-PD-1/PD-L1 treatment. Finally, although PD-L1 expression in tumor tissues is a predictive marker for multiple cancer types, its clinical application is less clear in HCC due to the lack of a clear-cut association with responders to anti-PD-1/PD-L1 treatment. Although all translational markers are not routinely measured in HCC, recent data suggest their potential roles in selecting patients for anti-PD-1/PD-L1 treatment. Such markers, including the immune classification of HCC, selected signaling pathways, tumor-infiltrating lymphocytes, and auto-antibodies, were discussed in this review.

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Section: Laboratory Testsmentioning

confidence: 69%

Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma?

Lee

Chan

Chon

2022

Cancers

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“…On the contrary, an increase in AFP levels was an early predictor of treatment failure both in the IMbrave150 trial and in a subsequent retrospective analysis. 68 , 94 However, 5 of the 43 patients who experienced a >10% increase in AFP at week 6 receiving the combination within the IMbrave150 trial still achieved an objective response at a later time point. 68 …”

Section: Introductionmentioning

confidence: 99%

“… 68 , 94 However, 5 of the 43 patients who experienced a >10% increase in AFP at week 6 receiving the combination within the IMbrave150 trial still achieved an objective response at a later time point. 68 …”

Section: Introductionmentioning

confidence: 99%

“…Data from. 65 , 66 , 68–71 , 97 Abbreviations : AFP, alpha-fetoprotein; OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; NR, not reached; NE, not estimated. …”

Section: Introductionmentioning

confidence: 99%

“…The role of AFP in monitoring treatment response to ICIs remains less clear, with preliminary reports mainly limited to the atezolizumab–bevacizumab combination. 68 , 94 …”

Section: Introductionmentioning

confidence: 99%

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Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights

Cammarota¹,

Zanuso²,

Pressiani³

et al. 2022

JHC

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Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret – being based on dimensional principles – but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.

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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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Alpha-Fetoprotein as a Potential Surrogate Biomarker for Atezolizumab + Bevacizumab Treatment of Hepatocellular Carcinoma

Cited by 79 publications

References 27 publications

Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma?

Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma?

Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights

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

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