Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study

Abstract

Objective Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. Design Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at six German reference centres between 2016 and 2022. Methods Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAE) were assessed. Results In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR 24% (16-41). PFS was 3.0 months (95%CI 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs. 2.5 (2.0- 3.0) months (HR 0.29, 95%CI 0.13-0.66, p=0.001) and OS of 28.2 (9.5-46.8) vs. 7.0 (4.1-10.2) months (HR 0.34, 95%CI 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs. 2.3 (1.6-3.0, p<0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. Conclusions In the real-life setting we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab treated patients require confirmation.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma – A Single Center Case Series

“…Indeed, in ACC PD-L1 is expressed on less than 5% of tumor cells in 89% of tumors 8 . Accordingly, we did not find an association of response of ACC to immunotherapy with any established marker in a series of 54 patients treated with CPI on a compassionate use basis 9 .…”

“…However, this did not explain the different outcomes. In a large retrospective case series, mitotane treatment appeared to be associated with shorter progression-free and overall survival in patients treated with pembrolizumab and nivolumab 9 .…”

“…These studies demonstrated relatively low efficacy 2 3 4 5 6 . The largest and most recent retrospective analysis reported objective response rates of 13.5% to immune checkpoint blockade in ACC 9 .…”

“…Tumoral immune infiltration is comparably low in ACC and the glucocorticoid excess present in approximately 60% of ACC has been associated with even more sparse tumor infiltrating cells of the adaptive immune system 10 . Treatment-emergent resistance mechanisms may be relevant in ACC as indicated by the potentially adverse impact of mitotane treatment on response to CPI 9 . Importantly, immunogenic tumor antigens in ACC have not been identified.…”

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

“…Among these, 20 unique studies with 22 treatment arms were included ( Figure 2 ). There were eight phase II trials [ 16 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], two phase I trials [ 17 , 28 ], three retrospective cohorts [ 29 , 30 , 31 ], one case series [ 32 ], and six case reports [ 33 , 34 , 35 , 36 , 37 , 38 ], with a total of 248 ACC patients. Monotherapy of an anti-PD-L1 or anti-PD1 treatment was used in 12 treatment arms.…”