Transarterial chemoembolization (TACE) is widely used for patients with intermediate stage hepatocellular carcinoma (HCC) and immunotherapy has become standard of care treatment for patients with advanced stage HCC [
1-
3]. Many patients undergo locoregional therapies including TACE prior to immune checkpoint inhibitor (ICI) therapy. There is considerable evidence that locoregional therapies prime immune responses [
4,
5], but it is not known whether patients who underwent prior locoregional therapies have a better response to ICI therapy and clinical outcome. To study this question, we decided to study two different patient cohorts: Patients from IMbrave 150, a large randomized phase III trial leading to the approval of atezolizumab plus bevacizumab as first-line systemic therapy in patients with HCC [
6] and patients from a recently published phase II trial testing the combination of tremelimumab plus durvalumab [
7].
From IMbrave150 study (atezolizumab plus bevacizumab or sorafenib), patients were stratified according to prior TACE or not; endpoints included progression-free survival (PFS) and overall survival (OS), with tumor response assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Kaplan-Meier/log-rank and Cox proportional hazards models were applied (two-sided). Cox proportional hazards analyses for PFS and OS were performed using univariable Cox regression models. Clinical information was obtained via Vivli under data request ID 00009815. In exploratory analyses, we also evaluated prior radiation, ablation, and surgery using the same modeling approach. The IMbrave150 study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all participants provided written informed consent in the parent trial. The present post-hoc analysis used de-identified data obtained through Vivli and did not involve direct interaction with participants.
From National Institutes of Health (NIH) ICI cohort (tremelimumab plus durvalumab) patients with unresectable HCC received tremelimumab plus durvalumab. Patients were treated with tremelimumab at a dosage of 75 mg every 4 weeks along with durvalumab at a dosage of 1,500 mg every 4 weeks for four courses and treated with durvalumab at a dosage of 1,500 mg until disease progression or intolerability. Patients were stratified by prior TACE; endpoints included PFS (per RECIST v1.1) and OS. Kaplan-Meier/log-rank (as implemented in the R survfit package) and Cox proportional hazards (coxph fun function in R) models were applied (two-sided) [
8]. Cox proportional hazards analyses for PFS and OS were performed using univariable Cox regression models. Because of the limited number of events and the relatively small sample size, multivariable analyses were not performed in this study. All information according to this study has been described previously [
7]. In exploratory analyses, we also evaluated prior radiation, ablation, and surgery using the same modeling approach. The NIH cohort was approved by the National Cancer Institute (NCI) Institutional Review Board (No. 16-C-0135). The ClinicalTrials.gov identifier was NCT01853618 and the EudraCT identifier was 2019-002767-98. All patients provided written informed consent for participation and data collection. The current analysis was performed in accordance with the approved protocol and applicable regulations.
We performed a retrospective analysis of the effect of prior TACE on the outcome in patients treated with atezolizumab plus bevacizumab, sorafenib, and tremelimumab plus durvalumab using two different patient cohorts (
Fig. 1). In the IMbrave150 cohort, 223 patients treated with atezolizumab plus bevacizumab were analyzed. Across progression endpoints, prior TACE did not have consistent benefit in PFS. Interestingly, patients who received prior radiation had significantly better PFS. In contrast, OS was worse in the prior-TACE subgroup by Cox analysis (hazard ratio [HR], 1.534; 95% confidence interval [CI], 1.061–2.217;
P=0.02). IMbrave150 had a sorafenib arm as a control arm, which allowed us to study the effect of prior TACE on outcome in patients treated with sorafenib. Eighty-six patients treated with sorafenib were analyzed. Prior ablation was associated with longer PFS; however, patients with an ablation history had a significantly higher risk of mortality in terms of OS. Prior TACE showed a trend toward worse OS (HR, 1.606; 95% CI, 0.966–2.767;
P=0.07).
Next, we studied the effect of prior TACE on outcome in patients treated with tremelimumab plus durvalumab. In the NIH cohort, 41 patients treated with tremelimumab plus durvalumab were analyzed. Clinically, patients with a prior TACE history showed a favorable trend compared with TACE-naïve patients. HR suggested numerically lower risk of disease progression and mortality in the TACE-pretreated subgroup, although these associations did not reach statistical significance (RECIST v1.1: HR, 0.64; 95% CI, 0.37–1.10; P=0.082; OS: HR, 0.71; 95% CI, 0.39–1.29; P=0.099).
TACE and ICI are established standard of care treatment options for patients with HCC. TACE is usually offered to patients with disease limited to the liver, patent portal vein and good liver function [
4], while ICI is used in patients not eligible for TACE due to extrahepatic tumor manifestation, main portal vein thrombosis or progression after TACE [
1]. The combination of TACE plus ICI therapy is subject of ongoing clinical trials [
9-
11]. Here we studied the effect of prior TACE on clinical outcome to ICI therapy. Our preliminary cross-cohort comparison indicates a regimen-dependent association between prior TACE and outcomes. In IMbrave150, prior TACE correlated with worse OS under both anti-programmed death-ligand 1 (PD-L1) plus anti-vascular endothelial growth factor (VEGF) therapy (atezolizumab plus bevacizumab) and sorafenib therapy. In contrast, in an NIH ICI cohort treated with anti-PD-L1 plus anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4; tremelimumab plus durvalumab), prior-TACE patients showed a favorable clinical trend. We hypothesize that CTLA-4 co-administration may have facilitated the translation of TACE-induced immune priming into clinical benefit, but larger patient cohorts are clearly needed.
From a biological perspective, TACE can release tumor-associated antigens and remodel the tumor microenvironment toward Interferon/tumor necrosis factor-driven inflammation. However, this inflammatory state may require broader immune priming with CTLA-4 blockade to overcome compensatory immunosuppressive pathways. The observed detriment with anti-PD-L1 plus anti-VEGF, versus the favorable signal with CTLA-4 co-blockade, is consistent with this concept [
12]. Moreover, some reports indicate that anti-PD-L1 combined with anti-CTLA-4 may not impair liver function to the same degree as anti-PD-L1 plus anti-VEGF, although this has yet to be postulated in the absence of head-to-head comparisons [
13,
14].
Limitations of this analysis include the retrospective nature of subgrouping by prior TACE, potential imbalances in baseline characteristics and timing of interventions, and the non-randomized design of the NIH cohort. In addition, because of the limited number of events and the relatively small sample size, survival analyses were performed using univariable Cox regression models without adjustment for baseline clinical characteristics. Therefore, the comparisons between patients with and without prior TACE may have been influenced by selection bias and residual confounding due to baseline imbalances. Further validation in larger cohorts with adequately powered multivariable analyses will be needed.
Detailed TACE characteristics (modality, number of sessions, and timing relative to systemic therapy) were not consistently available, precluding analyses of recent versus remote TACE effects. Our endpoints were defined from systemic therapy initiation, consistent with the parent trials. Evaluating survival from the time of first TACE would address a different clinical question and was not feasible with the de-identified trial dataset structure.
In conclusion, our cross-cohort analysis suggests that the association between prior TACE and subsequent clinical outcomes may differ according to systemic treatment regimen in patients with unresectable HCC. In the IMbrave150 cohort, prior TACE was associated with worse OS in patients treated with atezolizumab plus bevacizumab and showed a similar unfavorable trend in those treated with sorafenib, whereas in the NIH cohort treated with tremelimumab plus durvalumab, prior TACE was associated with a favorable clinical trend. Although these findings are hypothesis-generating and require prospective validation in larger cohorts, they raise the possibility that prior locoregional therapy may differentially influence the efficacy of subsequent systemic therapy. A better understanding of these interactions may help optimize treatment sequencing and improve patient selection in the evolving therapeutic landscape of unresectable HCC.
FOOTNOTES
-
Authors’ contribution
Conceptualization: YM, TFG. Data curation: YM, AAS. Formal analysis: YM, AAS. Funding acquisition: TFG, ER. Investigation: YM, AAS. Methodology: YM, AAS, ER, TFG. Project administration: TFG. Resources: TFG. Software: YM, AAS. Supervision: TFG, ER. Validation: YM, AAS. Visualization: YM, AAS. Writing - original draft: YM, TFG. All authors reviewed and edited the manuscript and approved the final version.
-
Acknowledgements
This manuscript is based on research using data from data contributor Roche that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication. TFG is supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011343 and ZIA BC 011870). The study was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. YM received a fellowship award from JSPS.
-
Conflicts of Interest
There is no conflict of interest according to this study.
Figure 1.Forest plots of hazard ratios with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) according to each pretreatment locoregional therapy (surgery, radiation, TACE, and ablation) within each treatment group (IMbrave150, atezolizumab + bevacizumab and sorafenib; NIH, tremelimumab + durvalumab). P-values were calculated using the log-rank test. Atez+Bev, atezolizumab + bevacizumab; TACE, transarterial chemoembolization; NIH, National Institutes of Health; Trem+Durva, tremelimumab plus durvalumab.
Abbreviations
cytotoxic T lymphocyte-associated protein 4
immune checkpoint inhibitor
National Cancer Institute
National Institutes of Health
programmed death-ligand 1
progression-free survival
Response Evaluation Criteria in Solid Tumors
transarterial chemoembolization
vascular endothelial growth factor
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