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Review
. 2024 Feb 23;16(5):900.
doi: 10.3390/cancers16050900.

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis

Obada Ababneh  1 , Alina Ghazou  1 , Mohmmad Alawajneh  1 , Saleh Alhaj Mohammad  1 , Abdullah Bani-Hani  1 , Nasr Alrabadi  2 , Aditya Shreenivas  3
Affiliations
Review

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis

Obada Ababneh et al. Cancers (Basel). .

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10-19%, I2 = 0%), and the DCR was 43% (95% CI = 37-50%, I2 = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85-23.05), and the median PFS was 2.8 months (95% CI = 1.8-5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care.

Keywords: adrenocortical carcinoma; immune checkpoint inhibitors; immunotherapy; meta-analysis.

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Conflict of interest statement

Aditya Shreenivas is an advisory board member for Taiho Oncology and Iylon Pvt. Ltd., receives research support from Natera and Caris, and is a member of the virtual tumor board Target Cancer Foundation. All the other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The interaction between immune cells, endothelium, and tumor cells highlights possible treatment strategies. Tumor cells express PD-L1 and CTLA-4, which inhibit the immune system. Endogenous cortisol excess can decrease antigen presentation, inhibit T cell activation, decrease CD8+ T cell infiltration, weaken immune attack, and cause potential immunotherapy failure. Mitotane works by inhibiting the CYP11A1, CYP11B1, CYP11B2, and 3β-HSD enzymes, leading to decreased cortisol secretion. Targeting angiogenesis through multikinase inhibitors can also be helpful in controlling disease. In addition to inhibiting angiogenesis, lenvatinib can alter the immune tumor microenvironment.
Figure 2
Figure 2
PRISMA flow diagram. After applying our search strategy, 2112 unique reports were found. A total of 20 reports satisfied our eligibility criteria, of which 11 studies had sufficient data to be included in our meta-analysis.
Figure 3
Figure 3
Forest plots demonstrating (A) ORR and (B) DCR. ORR was 14% with no difference between monotherapy and combination therapy (14% vs. 17%, p-value = 0.66). DCR was 43% with no difference between monotherapy and combination therapy (42% vs. 50%, p-value = 0.44). Each red square represents the effect size of a study, and the black diamond represents the pooled effect size. ORR: objective response rate, DCR: disease control rate [16,17,21,23,24,25,29,30,31,32].
Figure 4
Figure 4
Forest plots demonstrating (A) PR, (B) SD, and (C) PD. The PR, SD, and PD rates were 14%, 29%, and 49%, respectively. A random model was used for SD and PD due to significant heterogeneity (I2 > 50%). Each red square represents the effect size of a study and the black diamond represents the pooled effect size. PR: partial response, SD: stable disease, PD: progressive disease [16,17,21,23,24,25,29,30,31,32].
Figure 5
Figure 5
Forest plots demonstrating (A) mOS and (B) mPFS. The pooled mOS was 13.9 (95% CI: 7.85–23.05), and the pooled mPFS was 2.8 (95% CI: 1.8–5.4). mOS: median overall survival, mPFS: median progression-free survival [16,17,23,24,29,31,32].
Figure 6
Figure 6
Funnel plots evaluating publication bias of published studies that reported (A) ORR and (B) DCR. Egger’s test revealed the presence of publication bias in the case of ORR (p-value = 0.01) but no publication bias in the case of DCR (p-value = 0.213). ORR: objective response rate, DCR: disease control rate.
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This research received no external funding.