Society for Endocrinology
Efficacy of systemic therapy in metastatic adrenocortical carcinoma: a meta-analysis of prospective clinical trials
S Shekar(1,2,*, A Hall1,2,*, J Pham1,2, M Crumbaker1,2, J Liu1,2, B Talmor1,2, H W Sim 1,2 and A M Joshua1,2
1The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, New South Wales, Australia
2School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, New South Wales, Australia
Correspondence should be addressed to S Shekar: samanthashekar@gmail.com
*(S Shekar and A Hall contributed equally as co-first authors)
Abstract
Objective: To evaluate pooled prospective trial data investigating efficacy of systemic therapies in metastatic adrenocortical carcinoma (mACC), incorporating subgroup analyses by treatment modality and line, establishing survival and response benchmarks.
Methods: Prospective trials of systemic therapy regimens in mACC published from 2010 to July 2023 were included. Primary endpoints were overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs). ORR was logit- transformed and pooled using a random effects model and inverse variance method. Kaplan-Meier curves for PFS and OS were digitised, and summary curves were constructed using a multivariate extension of the DerSimonian-Laird method.
Results: Across twenty-four studies, 880 patients were included: 386 received chemotherapy, 169 immunotherapies, 288 targeted therapies, and 37 other therapies. Treatment settings were first-line (383 patients, 44%), second-line or beyond (471, 54%), and not reported (26, 3%). Pooled ORR was 9.0% (95% CI 6.0-13.2) with moderate heterogeneity (12 = 54.2%, P < 0.01). Subgroup analysis showed ORRs of 2.9% for targeted therapy, 12.3% for chemotherapy, and 15.3% for immunotherapy. Pooled median OS was 9.9 months (95% CI 7.7-11.9) and pooled median PFS 2.6 months (95% CI 1.9-3.6). The 12-month OS rate was 41.6% (95% CI 33.1-51.2) and the 6-month PFS rate was 24.0% (95% CI 15.2-37.8).
Conclusion: This analysis establishes contemporary benchmarks for systemic treatments in mACC. While chemotherapy and immunotherapy offer modest survival benefits, the limited effectiveness of targeted therapy highlights the paucity of actionable molecular biomarkers. Future trials should aim to surpass the survival outcomes identified in this analysis.
Keywords: adrenocortical carcinoma; systemic therapy; meta-analysis; immunotherapy; chemotherapy
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine cancer of the adrenal cortex with an annual worldwide incidence of 1-2 individuals per million per year (1). The prognosis of patients with ACC is generally poor, with a
median overall survival (OS) of approximately 4 years (2). Surgical resection of the tumour remains the gold standard and the only curative strategy for localised disease. Despite optimal RO resection, 50-80% of
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patients develop recurrent or metastatic disease (3, 4), defined as cancer spread distantly from the primary adrenal cortex. In addition, the detection of ACC in early stages is uncommon, and the majority have metastasised at the time of diagnosis, whereby the 5-year survival rate is less than 15% (5).
Mitotane is an important component of the treatment armamentarium for ACC (6). It is an adrenolytic agent binding to and inducing disruption of mitochondria, resulting in apoptosis of ACC cells (7). While functioning as a cytotoxic agent, it can also interfere with hormone production, allowing its utility in managing functional ACC (6). Its efficacy encompasses the adjuvant setting for resected ACC with moderate to high risk for recurrence, and combined with other drug regimens in the advanced setting (6). Currently, patients with metastatic tumours with good performance status, high volume disease, and/or rapid tumour progression, ineligible for surgery, are treated with etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) in the first-line setting based on data from the landmark FIRM-ACT trial (8). Since then, eleven single-arm studies (three prospective and eight retrospective) with a total of 395 patients have investigated mitotane with or without chemotherapy with objective response rates (ORRs) varying between 7 and 54%, owing to differing response assessment criteria between studies. Despite triple agent chemotherapy, with mitotane, outcomes remain poor, with a median OS around 15 months (9). Since the FIRM-ACT trial, no clinical trial has been successful in improving outcomes of patients with metastatic adrenocortical carcinoma (mACC). IGF1R inhibitor linsitinib failed to demonstrate survival benefit compared to placebo despite preclinical data suggesting overexpression of IGF2 and effectiveness of in vivo inhibition of IGF2/IGF1R in ACC cells (10). The role of immune-checkpoint inhibitors (ICIs) and ICI-based combination therapies in rare tumours such as ACC is heterogeneous and less well established (2, 11). Anti-PD1 antibody pembrolizumab demonstrated an ORR of 14% and a median OS of 24.9 months in 39 ACC patients, seven of whom had microsatellite-stable disease (12). Avelumab, an anti-PD-L1 antibody, had a median OS of 10.6 months in 50 ACC patients, with only three achieving a partial response as their best response (13). Although trials of ICI-based strategies with chemotherapy or mitotane have yet to be conducted, this approach is a potential strategy after mitotane and EDP progression or for unacceptable adverse events (14).
Improved treatment of mACC represents a significant unmet medical need due to its rarity and variability in treatment approaches and outcomes, hindering the development of robust multinational trials. Therefore, this study aims to pool prospective trial data from 2010 to July 2023, incorporating subgroup analyses by treatment modality, to establish survival and response benchmarks. These benchmarks provide a contemporary standard for evaluating new therapeutic agents and serve as a foundation for informing future trial designs.
Methodology
Search strategy
This study protocol was registered via PROSPERO (ID: CRD42023430557) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were performed across PubMed, Excerpta Medica Database (Embase), Web of Science, Cochrane Register, and Clinicaltrials.gov for articles published from 2010 to 5 July 2023. To ensure comprehensive inclusion, references and citations of the studies included were also screened. The primary endpoints were ORR, OS, and progression-free survival (PFS). Key search items used in the database search included: ‘adrenal cortex carcinoma’, ‘metastatic’, and ‘clinicaltrials’. The complete search algorithm is detailed in Table 1. Two reviewers independently evaluated study eligibility and performed data extraction using a piloted extraction form to ensure consistency and accuracy.
Eligibility criteria
We included all prospective clinical trials of systemic therapy regimens in mACC since 2010 with at least one primary outcome reported. Articles were limited to those published in English due to the language proficiency of the authors, acknowledging that this may limit the scope of included studies. Trials with fewer than five participants or involving those under 18 years of age were excluded. The review restricted studies that included patients with non-metastatic or non- progressive disease. Review articles, editorials, conference abstracts, and case reports were also excluded from the meta-analysis.
Quality assessment
Two reviewers independently appraised the risk of bias in each study, with a third reviewer resolving any discrepancies. The National Institutes of Health (NIH) quality assessment tool
Table 1 Search strategy used to identify studies of metastatic adrenocortical carcinoma.
Search strategy
1. Exp adrenal cortex carcinoma/
2. Metastatic.mp.
3. [1 AND 2]
4. Clinical trial.mp.
5. Trial.mp.
6. Prospective trial.mp.
7. [4 OR 5 OR 6]
8. [3 AND 7]
9. [limit 8 to yr = ‘2010-current’]
(Supplementary Appendix 1 (see section on Supplementary materials given at the end of the article)) was used to appraise observational and interventional studies. The domains of the NIH Study Assessment tool were used to evaluate the quality of the studies included: i) clear study objective, ii) clear eligibility criteria and selection of study participants representative of clinical populations of interest, iii) sufficiently powered sample size calculation, iv) clearly defined endpoints, v) unbiased assessment of endpoints, vi) less than 20% loss during follow-up, and vii) appropriate statistical analysis. Studies that were at least fair to good quality were included in the analysis.
Statistical analyses
Random effects models were pre-specified instead of fixed effect models due to the anticipated heterogeneity of trial interventions. Heterogeneity was assessed using Cochran’s Q test (P < 0.05 indicating significant heterogeneity) and I 2 statistic (<30% for low heterogeneity, 30-60% for moderate heterogeneity, and >60% for substantial heterogeneity). Differences in patient characteristics between treatment interventions were assessed using chi-squared tests.
For ORR, a logit transformation was applied, followed by pooling using the inverse variance method with the DerSimonian-Laird estimator for between-study heterogeneity. The Hartung-Knapp adjustment was used to improve accuracy under random effects models. The pooled data were back-transformed using
an inverse logit function to provide summary percentages with 95% confidence intervals (CI).
Time-to-event outcomes, including PFS and OS, were extracted digitally from available Kaplan-Meier curves using the IPDfromKM tool validated by Liu et al. and individual patient data (IPD) reconstructed as per methods from Guyot et al. (15, 16). The derived median PFS and OS were validated against those reported in the original studies for consistency. The reconstructed IPD from individual studies was then pooled using a multivariate extension of the DerSimonian-Laird method to generate summary survival curves for PFS and OS (17). From these summary curves, the pooled median PFS, median OS, 6-month PFS, and 12-month OS rates were estimated with 95% CI. Between-strata heterogeneity based on treatment type and treatment line was compared between PFS and OS subgroups. All analyses were conducted using R Version 4.2.2.
Results
Search strategy and characteristics of included trials
Our systematic search returned 151 studies, from which 54 duplicates were removed, illustrated by the PRISMA flowchart in Fig. 1. A total of 73 trials were excluded after evaluating concordance with eligibility criteria (9 paediatric studies, 18 retrospective series, 9 not in mACC setting, 34 not evaluating systemic therapy, and
Identification
PubMed n = 22
Cochrane n = 16
Embase n = 16
ClinicalTrials.gov n =41
Web of Science n = 54
Reference Lists n = 2
Trials identified on literature search (n = 151)
Duplicates removed (n = 54)
Screening
Trials screened against inclusion criteria (n = 97)
Trials excluded (n = 73)
· Paediatric (n = 9)
· Retrospective (n = 18)
· Not mACC (n = 9)
· Not systemic therapy (n = 34)
· Trial in progress (n= 3)
Inclusion
Trials included for meta- analysis (n = 24)
Identification process of articles for inclusion from the literature search.
3 trials in progress without available published data). Twenty-four studies of fair-to-good quality were included for meta-analysis following appraisal with the NIH assessment tool (Supplementary Appendix 1).
Among these studies, 24 treatment regimens were included, encompassing 880 patients as outlined in Table 2. Three were phase III trials, fifteen phase II trials, and five phase IB trials. Targeted therapy was used in nine treatment arms (288 patients; 32.7% of total patients included), chemotherapy in six treatment arms (386 patients; 43.9%), immunotherapy in seven treatment arms (169 patients; 19.2%), and two arms of other treatment modalities (37 patients; 4.2%). Targeted therapies included bevacizumab, figitumumab, sunitinib, cixutumumab, dovitinib, axitinib, linsitinib and nevanimibe. Other agents included IL-12-PE, a recombinant cytotoxin of human interleukin-13 and Pseudomonas exotoxin A, and the BH3 mimetic gossypol. Baseline patient characteristics within treatment groups were evenly balanced and summarised in Table 2. Specific efficacy and survival outcomes of each study were summarised in Table 3.
Efficacy
Treatment response
All twenty-three studies reported data on the ORR. Pooled ORR across all studies was 9.0% (95% CI 6.0-13.2) with moderate heterogeneity (I 2 = 54.2%, P < 0.01).
Subgroup analysis by treatment type showed that ORR was 2.9% for targeted therapy (95% CI 2.0-4.3; 12 = 0%, P = 0.99), 12.3% for chemotherapy (95% CI 5.4-25.6; 12 = 69%, P < 0.01), and 15.3% for immunotherapy (95% CI 9.0-24.8; [2 = 10.3%, P = 0.355) (Fig. 2).
Subgroup analysis by treatment line demonstrated a pooled ORR of 38.8% for first-line trials (95% CI 0.03-0.35; [2 = 78.7%, P = 0.0028) and 61.2% for second-line or further line trials (95% CI 0.03-0.08; [2 = 0%, P = 0.9134) (Fig. 3).
Progression-free survival
The median PFS was reported in ten treatment regimens with 605 patients. The pooled median PFS was 2.6 months (95% CI 1.9-3.6), as summarised in Fig. 4. The pooled 6-month PFS was 24.0% (95% CI 15.2-37.8).
Differences in PFS by treatment type were suggested (P = 0.048). Median PFS was 2.7 months for patients receiving targeted therapy (95% CI 1.7-4.9), 3.0 months for patients receiving chemotherapy (95% CI 2.1-5.6), and 2.1 months for patients receiving immunotherapy (95% CI 1.7-3.3). The pooled 6-month PFS was 15.7% for targeted therapy (95% CI 5.8-42.6), 26.5% for chemotherapy (95% CI 10.8-65.4), and 27.3% for immunotherapy (95% CI 16.7-44.6).
Differences in PFS between treatment lines were evident (P = 0.002). Median PFS was 3.45 months for first-line trials (95% CI 2.43 0 7.27) and 2.52 months for second-line or further trials (95% CI 1.76-4.24).
Overall survival
The median OS was reported in ten treatment regimens with 605 patients. The pooled median OS was 9.9 months (95% CI 7.7-11.9) and pooled 12-month OS was 41.6% (95% CI 33.1-51.2), as summarised in Fig. 5.
Differences in OS by treatment type were evident (P = 0.004). Median OS was 7.4 months for patients receiving targeted therapy (95% CI 4.7-12.0), 11.2 months for patients receiving chemotherapy (95% CI 6.9-14.7), and 10.6 months for those receiving immunotherapy (95% CI 4.4-13.2). The pooled 12-month OS was 30.4% with targeted therapy (95% CI 15.9-58.3), 45.4% with chemotherapy (95% CI 33.7-61.2), and 45.3% with immunotherapy (95% CI 36.2-56.6).
Differences in OS between treatment lines were evident (P < 0.001). Median OS was 13.58 months for first-line trials (95% CI 10.79-15.35) and 8.09 months for second- line or further trials (95% CI 5.2-11.44).
Discussion
Metastatic adrenocortical carcinoma (mACC) is an aggressive disease with a high risk of recurrence (18). Despite a spectrum of therapeutic agents, mACC remains relatively resistant to steroidogenesis inhibitors, chemotherapy, targeted therapy and immunotherapy (18). In the genomic era, understanding ACC biology may accelerate identification of new therapeutic targets, predictive biomarkers of response and immune regulation. Establishing an efficacy and survival benchmark to guide future trial designs is essential. To the best of our knowledge, this is the first systematic review and meta-analysis summarising the efficacy of all available systemic therapies in patients with mACC.
Currently, the best outcomes in mACC are with chemotherapy using etoposide, doxorubicin and cisplatin (EDP) or streptozotocin (S), both in combination with mitotane (M) (19). Following the landmark FIRM-ACT study in locally advanced, inoperable or mACC, EDP-M was established in the first-line setting with a significantly higher ORR of 23% and median PFS of 5.0 months compared to S-M with an ORR of 9.2% and median PFS of 2.1 months (8). Despite high antitumour efficacy, EDP-M did not translate to a significant improvement in OS compared to S-M (14.8 vs 12 months, P = 0.07) (8), perhaps owing to an anticipated poor prognosis, smaller effect size than initially hypothesised, and a cross-over of patients at first-line S-M failure to EDP-M (8). Our subgroup analysis of chemotherapy trials was in concordance with the
| Reference | Study design | Treatment subgroup | Intervention (dosage) | Sample size | Male (%) | Median age (range) | ECOG 0-1 (%) |
|---|---|---|---|---|---|---|---|
| Wortmann et al. (36) | II | Targeted therapy | Bevacizumab (5 mg/kg) + capecitabine (950 mg/m2) | 10 | 7 (70) | 46 (38-73) | NR |
| Sperone et al. (21) | II | Chemotherapy | Gemcitabine (800 mg/m2) + 5-fluorouracil (200 mg/m2) or capecitabine (1,500 mg) | 28 | 12 (43) | 45 (23-72) | 25 (89) |
| Haluska et al. (25) | Ib | Targeted therapy | Figitumumab (20 mg/kg) | 14 | 6 (43) | 46 (22-77) | 14 (100) |
| Kroiss et al. (23) | II | Targeted therapy | Sunitinib (50 mg/d) | 35 | 17 (44) | 51 (22-72) | NR |
| Berruti et al. (22) | II | Chemotherapy | Paclitaxel (60 mg/m2) + sorafenib (400 mg) | 10 | 4 (40) | 46 (30-69) | 10 (100) |
| Fassnacht et al. (8) | III | Chemotherapy | Mitotane (2 g); etoposide (100 mg/m2); doxorubicin (40 mg/m2); cisplatin (40 mg/m2) or streptozocin (1-2 g) | 304 | 121 (40) | 51 (19-77) | 269 (88) |
| Naing et al. (37) | Ib | Targeted therapy | Cixutumumab (3-6 mg/kg) and temsirolimus (25-37.5 mg) | 26 | 13 (50) | 47 (20-74) | NR |
| Urup et al. (38) | II | Chemotherapy | Docetaxel (60 mg/m2) and cisplatin (50 mg/m2) | 19 | 9 (47) | 50 (22-70) | 15 (79) |
| Garcia-Donas et al. (39) | II | Targeted therapy | Dovitinib (500 mg) | 17 | 5 (29) | 53 (26-72) | 15 (88) |
| Lerario et al. (40) | II | Targeted therapy | Cixutumumab (10 mg/kg) and mitotane (2 g) | 20 | 13 (65) | 50.2 (22-80) | 20 (100) |
| O'Sullivan et al. (24) | II | Targeted therapy | Axitinib (5 mg) | 13 | NR | NR | NR |
| Liu-Chittenden et al. (41) | Ib | Other | IL-13-pseudomonas exotoxin (1-2 µg/kg) | 8 | 3 (38) | 42 (18-65) | 7 (88) |
| Fassnacht et al. (10) | III | Targeted therapy | Linsitinib (150 mg) | 90 | 30 (33) | 50 (19-85) | 85 (94) |
| Le Tourneau et al. (13) | Ib | Immunotherapy | Avelumab (10 mg/kg) | 50 | 24 (48) | 50 (21-71) | 50 (100) |
| Carneiro et al. (28) | II | Immunotherapy | Nivolumab (240 mg) | 10 | 3 (30) | 57 (31-67) | 8 (80) |
| Xie et al. (42) | II | Other | Gossypol (20 mg) | 29 | 14 (48) | 50 (28-76) | 27 (93) |
| Habra et al. (43) | II | Immunotherapy | Pembrolizumab (200 mg) | 16 | 8 (50) | 48 (31-78) | 16 (100) |
| Raj et al. (44) | II | Immunotherapy | Pembrolizumab (200 mg) | 39 | 15 (38) | 62 (19-87) | 39 (100) |
| Smith et al. (45) | Ib | Targeted therapy | Nevanimibe (1.6 mg/kg) | 63 | 29 (46) | 47 (NR) | 63 (100) |
| Naing et al. (46) | II | Immunotherapy | Pembrolizumab (200 mg) | 15 | NR | NR | NR |
| Klein et al. (29) | II | Immunotherapy | Ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) | 6 | 2 (33) | 50 (22-71) | 6 (100) |
| Lagana et al. (20) | II | Chemotherapy | Cabazitaxel (25 mg/m2) | 25 | 7 (28) | 50 (20-69) | 7 (28) |
| Baudin et al. (47) | Ib/II | Immunotherapy | EO2401 and nivolumab | 33 | 8 (24) | 47 (NR) | 31 (94) |
ECOG, Eastern Cooperative Oncology Group.
| Reference | Intervention (dosage) | ORR of evaluable patients (%) | Median PFS (months) | Median OS (months) |
|---|---|---|---|---|
| Wortmann et al. (36) | Bevacizumab (5 mg/kg) + capecitabine (950 mg/m2) | 0/10 (0) | 1.9 | 4.1 |
| Sperone et al. (21) | Gemcitabine (800 mg/m2) + 5-fluorouracil (200 mg/m2) or capecitabine (1,500 mg) | 2/28 (7) | 5.3 | 9.8 |
| Haluska et al. (25) | Figitumumab (20 mg/kg) | 0/14 (0) | NR | NR |
| Kroiss et al. (23) | Sunitinib (50 mg/d) | 0/35 (0) | 2.8 | 5.4 |
| Berruti et al. (22) | Paclitaxel (60 mg/m2) + sorafenib (400 mg) | 0/10 (0) | NR | NR |
| Fassnacht et al. (8) | Mitotane (2 g) + etoposide (100 mg/m2) + doxorubicin (40 mg/m2) + cisplatin (40 mg/m2) | 35/151 (23) | 5.3 | 14.8 |
| Naing et al. (37) | Cixutumumab (3-6 mg/kg) and temsirolimus (25-37.5 mg) | 0/26 (0) | NR | NR |
| Urup et al. (38) | Docetaxel (60 mg/m2) and cisplatin (50 mg/m2) | 4/19 (21) | 3 | 12.5 |
| Garcia-Donas et al. (39) | Dovitinib (500 mg) | 0/17 (0) | 1.8 | NR |
| Lerario et al. (40) | Cixutumumab (10 mg/kg) and mitotane (2 g) | 1/20 (5) | 1.4 | NR |
| O'Sullivan et al. (24) | Axitinib (5 mg) | 0/13 (0) | 5.5 | 13.7 |
| Liu-Chittenden et al. (41) | IL-13-pseudomonas exotoxin (1-2 µg/kg) | 0/8 (0) | NR | NR |
| Fassnacht et al. (10) | Linsitinib (150 mg) | 3/90 (3) | 1.4 | 10.6 |
| Le Tourneau et al. (13) | Avelumab (10 mg/kg) | 3/50 (6) | 2.6 | 10.6 |
| Carneiro et al. (28) | Nivolumab (240 mg) | 1/10 (10) | 1.8 | 21.2 |
| Xie et al. (42) | Gossypol (20 mg) | 0/29 (0) | 1.9 | 8.5 |
| Habra et al. (43) | Pembrolizumab (200 mg) | 2/14 (14) | NR | NR |
| Raj et al. (44) | Pembrolizumab (200 mg) | 9/39 (23) | 2.1 | 24.9 |
| Smith et al. (45) | Nevanimibe (1.6 mg/kg) | 0/63 (0) | NR | NR |
| Naing et al. (46) | Pembrolizumab (200 mg) | 2/13 (15) | NR | NR |
| Klein et al. (29) | Ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) | 2/6 (33) | NR | NR |
| Lagana et al. (20) | Cabazitaxel (25 mg/m2) | 0/25 (0) | 1.5 | 6 |
| Baudin et al. (47) | EO2401 and nivolumab | 4/33 (12) | 1.9 | NR |
ORR, objective response rate; PFS, progression-free survival; OS, overall survival; NR, no response.
established efficacy of first-line EDP-M with an ORR of 12.3% and median PFS 3.0 months.
Establishing an OS standard across existing systemic therapies is critical for informing prognosis and guiding future clinical trials in mACC. Using our summary survival curves as a reference for trial planning, we estimated the sample sizes needed to detect meaningful improvements in PFS and OS. To detect an increase in the 6-month PFS rate from 24.0 to 42.5% (hazard ratio ~0.60), 41 participants would be required, with a one-sided alpha of 5 and 80% power using the exact binomial test. A new treatment would warrant further investigation if at least 15 of these 41 participants had a PFS beyond 6 months. Similarly, to identify an increase in the 12-month OS rate from 41.6 to 59.1% (hazard ratio ~0.60), 54 participants would be required, with a one-sided alpha of 5 and 80% power using the exact binomial test. A new treatment would warrant further investigation if at least 29 of these 54 participants had an OS beyond 12 months.
mACC patients progressing on mitotane or those demonstrating a rapid tumour growth pattern are usually treated with chemotherapy (20). With only nine phase II chemotherapy studies, experience with cytotoxic chemotherapy is limited (20). In the second-line setting, gemcitabine with 5-fluorouracil or capecitabine has been
increasingly considered, with a median PFS of 5.3 months, median OS of 9.8 months, disease response in 7.2% of patients, and 46.4% with disease stabilisation at 4 months (21). In four cases (14.3%), disease response lasted between 10 and 19+ months (21). Cabazitaxel remains a poorly active second/third-line treatment, with PFS and OS results inferior to other second-line chemotherapy regimens (20). Establishing a standard for treatment response continues to be a challenge, particularly for active salvage treatments post progression on first-line chemotherapy.
Targeted therapies have demonstrated minimal or no activity, prompting the need for a better understanding of ACC biology and potential molecular pathways to target. Of the combined 61 patients that received VEGF-R tyrosine kinase inhibitors sorafenib, sunitinib and axitinib, none achieved an objective tumour response as per RECIST 1.1 criteria (22, 23, 24). The median PFS of 8-12 weeks with sorafenib and sunitinib respectively remains inferior to that of the EDP regimen and comparable or inferior to single-agent streptozotocin (22, 23, 24). This was reflected in our analysis of patients receiving targeted therapy, where ORR was 2.9% and median PFS was 2.7 months. Accounting for the attenuating anti-tumour response of sunitinib may be the reduction of serum drug levels by mitotane-induced cytochrome P450-3A4 activity, with more than half of
Study
Responses Total Weight ORR [95% CI]
Pooled ORR
Targeted therapy
Wortmann et al
0
10
2.0% 0.00 [0.00; 0.31]
C
Haluska et al
0
14
2.0% 0.00 [0.00; 0.23]
C
Kroiss et al
0
35
2.0% 0.00 [0.00; 0.10]
C
Naing et al
0
26
2.0% 0.00 [0.00; 0.13]
C
Garcia-Donas et al
0
17
2.0% 0.00 [0.00; 0.20]
C
Lerario et al
1
20
3.3% 0.05 [0.00; 0.25]
D
O’Sullivan et al
0
13
2.0% 0.00 [0.00; 0.25]
C
Fassnacht et al
3
90
6.2% 0.03 [0.01; 0.09]
+
Smith et al
0
63
2.0% 0.00 [0.00; 0.06]
C
Total (95% CI)
288
23.4% 0.03 [0.02; 0.04]
+
Heterogeneity: Tau2 = 0; Chi2 = 1.77, df = 8 (P = 0.99); 12 = 0%
Chemotherapy
Sperone et al
2
28
5.0% 0.07 [0.01; 0.24]
E
Berruti et al
0
10
2.0% 0.00 [0.00; 0.31]
C
Fassnacht et al
35
151
10.0% 0.23 [0.17; 0.31]
=
Fassnacht et al
14
153
9.3% 0.09 [0.05; 0.15]
#
Urup et al
4
19
6.4% 0.21 [0.06; 0.46]
+
Lagana et al
0
25
2.0% 0.00 [0.00; 0.14]
C
Total (95% CI)
386
34.7% 0.12 [0.05; 0.26]
Heterogeneity: Tau2 = 0.4294; Chi2 = 16.11, df = 5 (P < 0.01); 12 = 69%
Immunotherapy
Le Tourneau et al
3
50
6.1% 0.06 [0.01; 0.17]
+
Carneiro et al
1
10
3.2% 0.10 [0.00; 0.45]
G
Habra et al
2
14
4.8% 0.14 [0.02; 0.43]
-
Raj et al
9
39
8.3% 0.23 [0.11; 0.39]
=
Naing et al Pembro
2
13
4.8% 0.15 [0.02; 0.45]
D
Klein et al
2
6
4.1% 0.33 [0.04; 0.78]
=
Baudin et al
4
33
6.7% 0.12 [0.03; 0.28]
+
Total (95% CI)
165
37.9% 0.15 [0.09; 0.25]
Heterogeneity: Tau2 = 0.0462; Chi2 = 6.69, df = 6 (P = 0.35); 12 = 10%
Other
Chittenden et al
0
8
1.9% 0.00 [0.00; 0.37] C
Xie et al
0
29
2.0% 0.00 [0.00; 0.12]
C
Total (95% CI)
37
3.9% 0.03 [0.00; 0.99]
Heterogeneity: Tau2 = 0; Chi2 = 0.37, df = 1 (P = 0.54); 12 = 0%
Total (95% CI)
876 100.0% 0.09 [0.06; 0.13]
Heterogeneity: Tau2 = 0.4600; Chi2 = 50.21, df = 23 (P < 0.01); 12 = 54%
Test for subgroup differences: Chi2 = 42.78, df = 3 (P < 0.01)
0
0.2
0.4
0.6
0.8
Figure 2 Forest plot of pooled ORRs in metastatic adrenocortical carcinoma, stratified by treatment subgroup.
patients on concomitant mitotane. This issue was deemed less likely with axitinib as most had discontinued mitotane before study. Despite this, no tumour responses were seen, with a median PFS of 5.5 months and mOS of 13.7 months (24). Growth rate slowed on treatment compared to before axitinib commencement in four of 13 patients (24). As there were no patients with objective tumour response as per RECIST 1.1 criteria, growth rate was assessed using a regression-growth equation. Efforts to genetically profile favourable responders to identify predictive biomarkers will be a key in streamlining and improving future patient selection.
Regarding alternative molecular targets, the IGF-1R inhibitor figitumumab demonstrated stable disease in 57% of patients, but did not translate to an objective tumour response or survival benefit (25). A similar finding was seen in a placebo-controlled trial of the IGF-1R inhibitor linsitinib, which failed to improve
median PFS and OS (10). Our subgroup analysis of targeted therapies reaffirmed their limited efficacy compared to chemotherapy and immunotherapy. Future trials should focus on defining predictive biomarkers and exploring the synergism of combination therapies with other molecular targets or concomitant chemotherapy.
In regard to ICI therapy, pembrolizumab in the absence of mitotane demonstrated an ORR of 23%, all achieving partial responses, median PFS of 2.1 months, and median OS of 24.9 months, suggesting modest efficacy as salvage therapy (12). In this study, six patients had MSI-high/MMR-deficient tumours and two patients had Lynch syndrome, both groups demonstrating partial responses (12). Other retrospective studies of pembrolizumab with mitotane also confirmed clinical activity, with two of six patients achieving partial response and four with stable disease (26). Lenvatinib has potential additive activity with pembrolizumab with
| Study | Responses | Total | Weight | ORR [95% CI] | Pooled ORR | |
|---|---|---|---|---|---|---|
| 1st line | ||||||
| Fassnacht et al EDP-M | 35 | 151 | 15.2% | 0.23 [0.17; 0.31] | ||
| Fassnacht et al Streptozocin | 14 | 153 | 14.3% | 0.09 [0.05; 0.15] | ||
| Garcia-Donas et al | 0 | 17 | 3.5% | 0.00 [0.00; 0.20] | ||
| Lerario et al | 1 | 20 | 5.7% | 0.05 [0.00; 0.25] | ||
| Total (95% CI) | 341 | 38.8% | 0.11 [0.03; 0.35] | |||
| Heterogeneity: Tau2 = 0.5686; Chi2 = 14.06, df = 3 (P = 0.0028); 12 = 78.7% | ||||||
| 2nd line+ | ||||||
| Wortmann et al | 0 | 10 | 3.5% | 0.00 [0.00; 0.31] | ||
| Sperone et al | 2 | 28 | 8.4% | 0.07 [0.01; 0.24] | ||
| Haluska et al | 0 | 14 | 3.5% | 0.00 [0.00; 0.23] | ||
| Kroiss et al | 0 | 35 | 3.6% | 0.00 [0.00; 0.10] | ||
| Berruti et al | 0 | 10 | 3.5% | 0.00 [0.00; 0.31] | ||
| O'Sullivan et al | 0 | 13 | 3.5% | 0.00 [0.00; 0.25] | ||
| Chittenden et al | 0 | 8 | 3.5% | 0.00 [0.00; 0.37] | ||
| Fassnacht et al | 3 | 90 | 10.1% | 0.03 [0.01; 0.09] | ||
| Le Tourneau et al | 3 | 50 | 10.0% | 0.06 [0.01; 0.17] | ||
| Habra et al | 2 | 14 | 8.0% | 0.14 [0.02; 0.43] | ||
| Lagana et al | 0 | 25 | 3.6% | 0.00 [0.00; 0.14] | ||
| Total (95% CI) | 297 | 61.2% | 0.05 [0.03; 0.08] | |||
| Heterogeneity: Tau2 = 0; Chi2 = 4.65, df = 10 (P = 0.9134); 12 = 0% | ||||||
Total (95% CI)
638 100.0% 0.07 [0.04; 0.10]
Heterogeneity: Tau2 = 0.5749; Chi2 = 35.14, df = 14 (P = 0.0014); 12 = 60.2% Test for subgroup differences: Chi2 = 2.83, df = 1 (P = 0.0926)
0
0.1
0.2
0.3
0.4
Figure 3 Forest plot of pooled ORRs in metastatic adrenocortical carcinoma, stratified by treatment line.
an ORR of 25% and mPFS of 5.5 months (27). Nivolumab demonstrated moderate clinical activity with a median PFS of 1.8 months, median OS of 21.2 months and a 6-month PFS rate of 20% (28). The JAVELIN trial of the anti-PDL-1 monoclonal antibody avelumab demonstrated a median PFS of 2.6 months, mOS of 10.6 months, and a 12-month OS rate of 43% (13). Median OS was comparable with second-line chemotherapies such as gemcitabine/5FU and streptozotocin, and potentially a better tolerated treatment compared to existing salvage options. Avelumab response rates and mOS were comparable to combination ipilimumab and nivolumab (13, 29). Use of combination strategies did not correlate with higher responses compared to monotherapy. Our pooled analysis for immunotherapy trials demonstrated an ORR of 15.3%, median PFS of 2.1 months, and median OS of 10.6 months, superior to the activity of targeted therapies linsitinib, VEGF-inhibitors and second-line chemotherapies. There is potential prognostic significance in the use of ICIs after mitotane and EDP, and further investigation with randomised controlled trials comparing the two strategies is required.
Risk stratification and prognostication in mACC remain a challenge given the substantial heterogeneity of the disease. Validated predictive clinicopathological and molecular classification tools assist this process. Retrospective data demonstrate the presence of hepatic and bone metastases, number of metastatic lesions, number of tumoural organs at first metastasis, a high mitotic rate >20 per 50 high-power fields, and atypical mitoses in the primary tumour predict worse survival in mACC (30). Clinical classification is based on TNM-ENSAT stage assessed preoperatively (31). Other prognostic criteria such as grade, primary resection status, patient age, and presence of a secretory syndrome characterised by cortisol
excess independently predict risk of relapse and OS regardless of stage (31). In locally advanced and mACC, a Ki-67 index ≥20% was associated with a reduction in OS (32). Furthermore, excess cortisol was a poor prognostic factor on risk of recurrence after complete surgery and on OS, as confirmed in both localised and mACC (32). Acknowledging the wide spectrum of clinical subtypes in mACC, the expected impact of systemic therapies can vary according to risk category. Retrospective data suggest patients with an ECOG 0-1 performance status with low disease burden might be considered for mitotane monotherapy, whereas patients with high disease burden might benefit from cytotoxic chemotherapy (33).
Molecular classification can be useful in localised ACC, but most mACC cases would automatically be classified as poor or intermediate risk (34). Studies have defined distinct molecular profiles in ACC, where alterations in driver genes ZNRF3, MEN1 and MMR-related genes characterised a poor outcome; alterations in CDKN2A, NF1, PRKAR1A, and TP53 were associated with intermediate prognosis; and a better prognosis was characterised by alterations in CDK4, CTNNB1, MLL4 and RB1 (35). Patients with actionable mutations identified by molecular profiling may be potential candidates for targeted therapies; however, many studies remain investigational given the rarity of this subset.
While useful for benchmarking and regulatory purposes, this study’s limitations include heterogeneity between study designs and treatment strategies. A rigorous statistical analysis was undertaken as previously described to mitigate presumed heterogeneity of trial interventions. Many studies did not include published Kaplan-Meier curves, and thus complete digitisation of all trial data in the survival outcome meta-analysis was not possible.
A
1.0 1
0.9
0.8
Proportion alive and progression free
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Time (months)
B
1.0
Targeted therapy
0.9-
Chemotherapy
Immunotherapy
0.8
Proportion alive and progression free
0.7
0.6.
0.5
0.4.
0.3.
0.2.
0.1.
0.0
0
6
12
18
24
30
Time (months)
C
1.0
0.9
1st line
2nd line+
0.8
Proportion alive and progression free
0.7
0.6
0.5
0.4
0.3
0.2-
0.1
0.0
0
6
12
18
24
30
Time (months)
A
1.0
0.9
0.8
0.7
Proportion alive
0.6
0.5
0.4.
0.3
0.2
0.1
0.0
0
6
12
24
Time (months)
18
30
B
1.0
Targeted therapy
0.9
Chemotherapy
Immunotherapy
0.8
0.7
Proportion alive
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Time (months)
C
1.07
0.9
1st line
2nd line+
0.8
0.7
Proportion alive
0.6
0.5-
0.4
0.3
0.2.
0.1.
0.0
0
6
12
18
24
30
Time (months)
Conclusions
Our systematic review and meta-analysis establish a contemporary benchmark for the efficacy of systemic treatments in mACC. Pooled analysis of chemotherapy trials reaffirms it as a superior first-line therapy compared to other systemic options, with a mPFS of 3.0 months and mOS of 11.2 months. Second-line chemotherapy had limited efficacy when compared with ICIs. Disease stability was attained in a few patients treated with VEGF-inhibitors and IGF-1R inhibitors, but this did not translate to improved survival outcomes. In our analyses, ICIs had modest activity, with an ORR of 15.3%, mPFS 2.1 months and mOS 10.6 months. ICIs had superior efficacy compared to current targeted therapy benchmarks and may be a potential option after EDP-M progression. Conducting randomised prospective trials in this rare cancer context can be challenging and we suggest that future trials should aim to exceed the PFS and OS outcomes established in this pooled analysis to provide sufficient clinical momentum to initiate randomised trials.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EO-25-0027.
Declaration of interest
The authors declare their affiliations with St Vincent’s Hospital Sydney, The Kinghorn Cancer Centre Sydney, Garvan Institute of Medical Research Darlinghurst, University of New South Wales Faculty of Medicine and Health Sydney, NHMRC Clinical Trials Centre University of Sydney, and Chris O’Brien Lifehouse Department of Medical Oncology Sydney. HWS acknowledges institutional research funding from AbbVie and Bristol-Myers Squibb and has received honoraria from Eli Lilly and Servier. The other authors have no conflicts of interest to disclose in relation to this manuscript.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
SS and AH contributed data, performed analysis and wrote the paper. JP contributed data and assisted in analysis. MC conceived analysis and contributed to final paper completion. JL and BT conceived analysis. HWS and AJ conceived and performed analysis and contributed to final paper completion.
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