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Frontiers in Systemic Therapy for Unresectable or Metastatic Adrenocortical Carcinoma: Harnessing Novel Therapeutic Approaches

Clinical Medicine Insights: Oncology Volume 19: 1-13 @ The Author(s) 2025 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/11795549251364042 journals.sagepub.com/home/onc

Sage

Adam E Singer1 (D, Nikhita Kathuria-Prakash’, David Shabsovich’, Lizette Garcia’, Leland Damron2, Allan J Pantuck3 and Alexandra Drakaki’

Abstract

Adrenocortical carcinoma is a rare, aggressive endocrine malignancy with limited effective systemic therapy options and an overall poor prognosis for unresectable or metastatic disease. Chemotherapy and mitotane are the traditional systemic therapies of choice. More recently, as drug development in oncology has shifted away from chemotherapy, a host of therapeutic approaches targeting novel mechanisms of action has been studied in adrenocortical carcinoma. This review summarizes all nonchemotherapeutic approaches that have been and/or are currently being tested in clinical trials for the treatment of unresectable or metastatic adrenocortical carcinoma.

Keywords

Adrenocortical carcinoma, systemic therapy, tyrosine kinase inhibitors, immune checkpoint inhibitors, radiopharmaceuticals

Received: July 5, 2024; accepted: June 13, 2025

Introduction

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine malignancy with an annual incidence of approxi- mately one per million.1 Nearly half of patients have nodal or distant metastases at the time of presentation.2 Early- stage disease can be treated with surgical resection, which is potentially curative, but the disease frequently relapses after initial resection. Prognosis for unresectable or meta- static disease is very poor, with a median overall survival (OS) of approximately 14 months.1,3

The mainstay of systemic therapy for unresectable or metastatic disease has traditionally been chemotherapy with or without the adrenolytic agent mitotane. The 2012 phase III FIRM-ACT trial definitively established the combination of etoposide, doxorubicin, and cisplatin (EDP) plus mitotane as the preferred first-line option for fit patients.3 Even with this intensive combination regimen, however, objective response rate (ORR) was only 23%, median progression-free survival (PFS) 5 months, and median OS 14.8 months. A host of less intensive chemotherapy regimens has been evaluated in smaller studies over the last several decades (Table 1).4-15

These demonstrate modest efficacy as a whole and are typi- cally reserved for later lines of therapy or for patients who cannot tolerate EDP-mitotane.

The only US Food and Drug Administration (FDA)- approved systemic therapy for ACC is mitotane, and there is a paucity of compendia-listed treatment options.16,17 Additional effective systemic therapies are needed to combat this lethal disease. Accordingly, there has been immense interest in harnessing novel mechanisms of action informed by preclinical work to expand the menu

‘Division of Hematology/Oncology, Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA, USA

2Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA, USA

3Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA

Corresponding Author:

Adam E Singer, UCLA Institute of Urologic Oncology, Edie & Lew Wasserman Building, 300 Stein Plaza, Ste. 344, Los Angeles, CA 90095, USA.

Email: adsinger@mednet.ucla.edu

Đ BY

Table 1. Chemotherapeutic strategies for advanced adrenocortical carcinoma.
Study (year)Study designTrial phaseTreatment regimenNLineORR (%)DCR (%)mPFS (months)mDOR (months)mOS (months)NotesReference
Decker et alProspective, 2-arm,IIMitotane361L or 2L22.2NRNRNR14.0Patients in the doxorubicin arm had4
nonrandomizedDoxorubicin1618.8NRNRprogressed on mitotane or had poor tumor prognostic markers
Bonacci et alProspective, single-armIICisplatin, Etoposide + Mitotane182L33.344.4NRNRNR1L was mitotane, and 14 patients continued mitotane during study5
Williamson et aProspective, single-armIICisplatin, Etoposide followed by Mitotane451L or 2L11.1NRNRNR10.0If 2L, 1L was single-agent mitotane6
Baudin et alProspective, single-armIIIrinotecan122L or later025.0NR1.5NRIn 3 patients, 1L was single-agent mitotane7
Berruti et alProspective, single-armIIEtoposide, Doxorubicin, Cisplatin, Mitotane721L48.676.49.1NR28.58
Sperone et alProspective, single-armIIGemcitabine, Mitotane, 5-fluorouracil or Capecitabine282L or 3L7.146.45.36.09.89
Berruti et alProspective, single-arm| IIPaclitaxel, Sorafenib102L or 3L00Trial terminatedearly10
Fassnacht et alProspective, 2-arm,IIIEtoposide, Doxorubicin,1511L23.258.35.0NR14.8Prior mitotane was allowed. Upon disease progression or unacceptable3
randomizedCisplatin, Mitotane
Streptozosin, Mitotane1539.231.42.1NR12.0toxicity, patients crossed over to the other study arm.
Urup et alProspective, single-armIIDocetaxel, Cisplatin191L21.152.63.0NR12.511
Kroiss et alRetrospective case seriesN/ATrofosfamide ± Mitotane211L or later014.32.8NR6.514 patients received mitotane12
Kroiss et alRetrospective case seriesN/AThalidomide, Mitotane272L or later07.42.6NR8.413
Cosentini et alRetrospective case seriesN/ATemozolomide ± Mitotane282L or later21.435.73.5NR7.212 patients received mitotane14
Laganà et alProspective, single-armI IICabazitaxel252L or later024.01.5NR6.015

RR=response rate; DCR=disease control rate; PFS=progression-free survival (reported as median months); OS=overall survival (reported as median months); CT=chemotherapy; NR=not reported; 1L=first-line; 2 L = second-line; 3 L =third-line.

of treatment options, with many studies completed and many more ongoing.

In this narrative review, we summarize the evidence for nonchemotherapeutic treatment approaches to unresecta- ble or metastatic ACC that have already been tested in clinical studies. Two key areas are not included in this review: (1) biochemical pathways of potential therapeutic interest that have been evaluated only in preclinical stud- ies and (2) approaches expected to be active in ACC tumors harboring specific sensitizing genomic alterations found only in subsets of ACC (e.g., antihuman epidermal growth factor receptor 2 [HER2] agents for ACC tumors that overexpress HER2).

VEGFR TKIS

Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) receptor (VEGFR), such as sunitinib, sorafenib, pazopanib, regorafenib, axi- tinib, cabozantinib, lenvatinib, and tivozanib, have trans- formed the treatment of renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and thyroid cancer, among others. In ACC, angiogenesis is thought to play a key role in tumor growth and survival, as evidenced by the influence of vasculogenic mimicry in tumor growth, over- expression of VEGFR on the surface of tumor cells, and elevated serum levels of VEGF in patients with ACC.18,19 Several completed and 2 ongoing trials have sought to assess the efficacy of VEGFR TKIs in treating unresecta- ble or metastatic ACC.

Sorafenib, sunitinib, and axitinib were the first 3 VEGFR TKIs studied in ACC, all in prospective, phase II trials. Berruti et al10 studied sorafenib in combination with weekly paclitaxel in 25 patients with metastatic ACC who pro- gressed after mitotane and 1 or 2 chemotherapies, with a primary endpoint of PFS. The trial was stopped prema- turely at the time of first radiologic evaluation due to dis- ease progression in all evaluable patients. Kroiss et al20 studied sunitinib in 38 patients with metastatic ACC who progressed after mitotane and 1 to 3 cytotoxic chemothera- pies, including a platinum-based chemotherapy regimen, with a primary endpoint of PFS. Five of 35 evaluable patients (14%) had stable disease (SD), while the remain- der had progressive disease (PD) or died before the first evaluation of disease status. The median PFS was 2.8 months, but in responders the PFS ranged between 5.6 and 11.2 months and OS ranged between 14.0 and 35.0 months. O’Sullivan et al21 studied axitinib in 13 patients with metastatic ACC as a second-line therapy after chemotherapy, with a primary endpoint of PFS. At first interim analysis, all patients had PD, although the rate of growth was slowed in 4 patients.

Cabozantinib is currently under investigation as a treat- ment option for refractory ACC. In a retrospective cohort study by Kroiss et al, 16 patients received off-label cabo- zantinib after mitotane and an average of 3 additional lines of therapy. Three patients achieved a partial response (PR), and 5 patients had SD, with a median PFS of 16 weeks.22

Given this promising data, 2 prospective, phase II trials of cabozantinib are underway (Table 2).23,24

A key consideration in using VEGFR TKIs in ACC is that all VEGFR TKIs are metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer, leading to significant drug interactions with all VEGRF TKIs except lenvatinib. Mitotane’s half-life can be up to 5 months long, and it is often continued during all lines of therapy for ACC, intro- ducing a practical problem of how a VEGFR TKI might be studied (and utilized) effectively. In Kroiss et al,20 mitotane was stopped just prior to enrollment, and several patients still had elevated plasma mitotane levels while on study. Blood levels of sunitinib and its active metabolite were measured and the median concentration was 29.3 ng/ml, far below the known threshold of 50 ng/ml required for sunitinib therapeutic activity. The 2 ongoing cabozantinib trials have incorporated this lesson and require a plasma mitotane concentration of less than 2mg/L prior to study enrollment.23,24

Notably, however, Berruti et al10 required a 1-month washout period between mitotane discontinuation and sorafenib initiation, and mitotane levels were low in most patients. This study still failed to demonstrate activity of sorafenib in ACC, suggesting that subtherapeutic exposure to VEGFR TKIs is not the only factor driving tumor resist- ance to this mechanism of action. Additional research is needed to understand the underlying reasons for this resist- ance and why a small subset of patients has tumors that appear to be sensitive to VEGFR TKIs.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD- L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have revolutionized the treatment of many malignancies, and have been of great interest in ACC. Two retrospective observational studies suggested improved PFS when ICI was administered in combination with chemotherapy and mitotane,25,26 leading to a host of prospective immunother- apy trials in ACC.

Le Tourneau et al27 studied avelumab with or without mitotane in a prospective, phase Ib trial in 50 patients who had received at least 2 prior lines of therapy. Three patients (6%) had PR and an additional 21 patients (42%) had SD. The median PFS was 2.6 months. Carneiro et al28 studied nivolumab as a second-line therapy in a prospective, phase II trial of 10 patients. Two patients had SD (20.0%) and the remainder had PD after a median of 2 doses, with a median PFS of 1.8 months.

Pembrolizumab has been evaluated in 2 independent prospective trials. Habra et al29 studied pembrolizumab in a prospective, phase II trial in patients with rare malignan- cies, including 16 patients with ACC, of whom 14 were evaluable. Two patients had PR (14%) and 7 had SD (50%), for a disease control rate (DCR) of 64%. Raj et al30 studied pembrolizumab in a prospective, phase II trial in 39 patients with ACC. Nine patients (23%) had PR and 7 had SD

Table 2. Ongoing prospective therapeutic trials in unresectable or metastatic adrenocortical carcinoma.
CompoundMechanism of ActionDiseaseTrial AcronymTrial PhaseTrial DesignRandomizedComparatorLine of TherapyPatient TargetEnrollment CountryExpected CompletionReference
CabozantinibVEGFR TKIACC-IISingle-arm-2L and18USACompleted 2024,23
laterawaiting results
CabozantinibVEGFR TKIACCCaboACCIISingle-arm-2L and37Germany202524
later
DostarlimabICI (single-agent)MSI-H solid tumors including ACC-IITwo-armYesChemotherapy1L120France203039
PembrolizumabICI (single-agent)ACCPEMBR-01IISingle-arm--2L24Poland202740
Ipilimumab and nivolumabICI (dual)Rare genitourinary-IISingle-arm-2L and100USA202541
malignancies including ACClater
Ipilimumab and nivolumabICI (dual)Rare malignancies including ACCDARTIITwo-armNoNivolumab2L and later818USA202642
Cabozantinib andVEGFR TKI and ICIACC-IISingle-arm--1L and21USA202548
atezolizumablater
Lenvatinib andVEGFR TKI and ICIACCACCOMPLISHIISingle-arm-2L and30Korea202649
pembrolizumablater
ADCT-701ADCNeuroendocrine-ISingle-arm-2L and70USA202955
malignancies including ACClater
Megestrol acetate andProgesterone analogueACCPESETAIITwo-armYesEDP-mitotane1L80Italy202787
EDP-mitotaneand chemotherapy
Relacorilant andGlucorticoid receptorACC-IbSingle-arm-1L and15USACompleted 2024,94
pembrolizumabmodulator and ICIlaterawaitingresults
mRNA-0523-L001mRNA neoantigenEndocrine malignancies-N/ASingle-arm-1L and21China2025102
vaccineincluding ACClater
B7 H3 CAR-T cellsAutologous CAR-TSolid tumors including3CARISingle-arm--2L and32USA2027106
cellsACClater

Abbreviations: ADC, antibody-drug conjugate; CAR-T, chimeric antigen receptor T-cell therapy; EDP, etoposide, doxorubicin, and cisplatin; ICI, immune checkpoint inhibitor. MSI-H, microsatellite instability high; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor; 1L, first-line; 2L second-line.

(18%), for a DCR of 41%. Notably, pembrolizumab with or without mitotane is NCCN-listed for unresectable or meta- static ACC.17

Klein et al31 studied combination ipilimumab and nivolumab in patients with rare malignancies, including 6 patients with ACC. Two patients had PR (33%) and 2 patients had SD (33%), for a DCR of 66%.

Immune checkpoint inhibitor has demonstrated enhanced efficacy in tumors with high microsatellite instability (MSI- H) or high tumor mutational burden (TMB high), resulting in tumor-agnostic FDA approvals for pembrolizumab in patients with MSI-H or TMB high tumors who have pro- gressed on prior treatment and have no satisfactory alterna- tive options.32,33 ACC is a Lynch syndrome-associated cancer, with 3.2% of ACCs demonstrating mutations in mis- match repair.34 Two of the above trials of ICI in ACC strati- fied patients by MSI-H status in subgroup analyses. In the Klein et al31 study of combination ipilimumab and nivolumab, both patients who had PR had MSI-H tumors, and notably these responses appeared durable, lasting for over 10 and 25 months, respectively. In the Raj et al30 study of pembrolizumab, 6 patients had MSI-H tumors, of whom 2 (33%) had PR and 2 (33%) had SD at 24 months. These results suggest that ICI may be more effective in MSI-H than microsatellite stable (MSS) ACC tumors and may pro- duce more durable responses.

Approximately half of ACC tumors secrete glucocorti- coids, and excess cortisol can lead to immune suppression and theoretically counteract the efficacy of ICI. Three of the above trials stratified patients by cortisol-producing sta- tus in subgroup analyses. In the Carneiro et al28 study of nivolumab, 2 of 10 patients had cortisol-producing tumors and had PD. In the Klein et al31 study of combination ipili- mumab and nivolumab, 2 of 6 patients had cortisol-produc- ing tumors. One patient (50%) had an MSS tumor and had SD; the other (50%) had an MSI-H tumor and had PR. In the Habra et al29 study of pembrolizumab, 7 of 16 patients had cortisol-producing tumors. One (14%) had PR and 3 (43%) had SD, similar to the efficacy observed in the over- all study population. Overall, these results suggest that ICI may retain efficacy in cortisol-producing ACC tumors.

Taken as a whole, these prospective ICI studies clearly demonstrate activity of ICI in some cases of unresectable or metastatic ACC. Although response rates are low overall, SD rates tend to be higher, leading to reasonably high DCRs. Nevertheless, ACC appears less responsive to immunotherapy than some other tumor types such as mela- noma, nonsmall cell lung cancer (NSCLC), and RCC. The mechanisms underlying this are likely multifactorial: stud- ies have suggested low TMB, low cancer stemness indices, molecular alterations that result in T-cell exclusion, and a tumor microenvironment that supports immune evasion in the setting of hypercortisolism as possible reasons for decreased sensitivity to ICI in ACC.35-38

Additional prospective trials of dostarlimab in MSI-H ACC and pembrolizumab and combination ipilimumab and nivolumab in MSI-H or MSS ACC are underway (Table 2).39-42 In addition, with inhibition of novel checkpoints

such as lymphocyte-activation gene 3 (LAG3) and T-cell immunoreceptor with immunoglobulin and immunorecep- tor tyrosine-based inhibition motif domain (TIGIT) under investigation across tumor types, and the FDA approval of combination nivolumab and the anti-LAG3 checkpoint inhibitor relatlimab for unresectable or metastatic mela- noma,43 novel checkpoint inhibitors may be investigated in ACC in the future.

Combination VEGFR TKIs and ICI

More recently, attention has shifted to the use of combina- tion VEGFR TKIs and ICI in unresectable or metastatic ACC. Such combinations are the mainstay of treatment in RCC and HCC, and are used in the certain treatment sce- narios in some other tumor types as well. There is thought to be mechanistic synergy between the 2 drug classes: VEGF promotes cancer immune evasion through a variety of mechanisms, and inhibition of VEGFR can normalize abnormal tumor vasculature, allowing for increased infil- tration of immune effector cells into tumors and the result- ant conversion of the tumor microenvironment from an immunosuppressive to an immunosupportive one.44

Bedrose et al45 reported a retrospective case series of combination lenvatinib and pembrolizumab as salvage therapy for heavily pretreated metastatic ACC. Eight patients were treated with this combination after a median of 4 prior lines of therapy, including prior VEGFR TKI and ICI monotherapies. Two patients (25%) had PR and 1 patient (12.5%) had SD, with a median PFS of 5.5 months.

Two prospective trials of combination VEGFR TKI and ICI have been completed to date. Grande et al46 studied combination cabozantinib and atezolizumab in a prospec- tive, phase II trial of advanced and refractory endocrine and neuroendocrine tumors in 6 cohorts, one of which was ACC, which enrolled 24 patients. Patients in the ACC cohort had disease progression on at least one prior line of therapy, and 13 of 24 (54%) had received at least 2 prior lines of therapy. Two patients (8.3%) had PR that lasted for 5.4 and 17.4 months, while the remainder of patients had PD. Median PFS was 2.9 months. Mitotane discontinuation status and MSI-H status were not reported, and results were not stratified by tumor cortisol-producing status.

Wei et al47 studied combination apatinib and camreli- zumab, a VEGFR TKI and PD-1 inhibitor, respectively, under investigation in China for a variety of malignancies, as sec- ond-line therapy in 21 patients with unresectable or metastatic ACC. Eleven patients (52%) had PR and 9 patients (43%) had SD, for a DCR or 95%. Median PFS was 12.6months and median OS was 20.9 months. Eight of 21 patients had corti- sol-producing tumors; of these, 2 (25%) had PR, 5 (63%) had SD, and 1 (13%) had PD. Two of 21 patients had MSI-H tumors, neither of which were cortisol-producing; of these, 1 (50%) had PR and 1 (50%) had SD. Mitotane discontinuation status was not reported. In exploratory analyses, a higher baseline CD8-positive T-cell percentage and peripheral blood CD4- and CD8-positive T cell abundance were both associ- ated with treatment response.

The results of Wei et al stand in contrast to those of Grande et al. This may have been partially influenced by study design: all patients in Wei et al47 had received only one prior line of therapy, while just over half of patients in Grande et al46 had received at least 2 prior lines of therapy. Ultimately, though, the underlying reasons for the disparate outcomes in these 2 studies are currently unclear. At the time of writing of this review, these 2 studies have been published in abstract form only; full publications may shed more light on their results.

Two additional prospective trials of combination VEGFR TKI and ICI in unresectable or metastatic ACC are underway: a second trial of cabozantinib and atezolizumab and a trial of lenvatinib and pembrolizumab (Table 2).48,49

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) consist of a monoclonal antibody linked to a cytotoxic payload, usually a chemo- therapeutic agent. The monoclonal antibody is designed to recognize an antigen present on tumor cells. When the ADC binds to its target antigen, it releases its payload directly to the tumor cell. Successful ADCs target antigens present in high concentrations on tumor cells and low con- centrations on normal tissues, which maximizes therapeutic drug delivery and minimizes adverse effects. Many ADCs are FDA-approved for the treatment of a variety of malignancies.50

There is emerging interest in using ADCs to treat unre- sectable or metastatic ACC. Identifying antigen candidates has been a challenge, as ACC has among the least potential overexpressed targets of any cancer.51,52 Nevertheless, 3 ADCs with unique targets have been developed to date.

Lemech et al53 studied ABBV-176, an ADC targeting the prolactin receptor linked to a cytotoxic pyrrolobenzodiaze- pine (PBD) dimer, in a phase I trial that enrolled 19 patients with various tumor types, including 2 with ACC. There were no objective responses and patients experienced sig- nificant toxicities with ABBV-176, leading to study termi- nation. Another ADC, ADCT-701, which targets DLK1, a Notch ligand, linked to a PBD dimer, demonstrated effi- cacy in preclinical ACC xenografts, and a phase I trial is underway (Table 2).54,55 A third ADC, ADCT-211, which targets interleukin 13 receptor subunit alpha 2 (IL13RA2) linked to a PBD dimer, has shown antitumor activity in in vitro and in vivo studies, and a phase I trial is expected.56

Clinical data from studies of ADCs in ACC remain largely immature, and it remains to be seen whether this class of drugs will have efficacy in treating ACC.

IGF Pathway Inhibition

The insulin-like growth factor (IGF) pathway consists of 3 receptors with corresponding ligands which are crucial for cellular signaling and proliferation. This pathway has been shown to be upregulated in 90% of ACC tumors, which has led to investigation into its therapeutic targeting.57

Three single-arm trials of IGF 1 receptor (IGF-1R) inhibitors in ACC have been completed. Haluska et al58

studied figitumumab, a monoclonal antibody targeting IGF-1R, in a phase I trial of 14 patients with progressive metastatic ACC. There were no objective responses. Six patients (43%) had SD at 3 months, and all patients dis- continued figitumumab by 5 months due to PD or adverse events. Naing et al59 studied cixutumumab, a monoclo- nal antibody targeting IGF-1R, in combination with the mammalian target of rapamycin (mTOR) inhibitor tem- sirolimus in a phase I trial of 26 patients with metastatic ACC. Patients were heavily pretreated, with a median of 4 prior therapies. There were no objective responses, but 11 patients (42%) had SD for at least 6 months. Lerario et al60 studied cixutumumab in combination with mito- tane in a prospective, single-arm trial of 20 patients with metastatic ACC in the first-line setting. One patient (5%) had PR and 7 patients (35%) had SD, while the remain- der progressed. The median PFS was only 6 weeks. This study was ultimately terminated due to poor accrual and limited efficacy.

Fassnacht et al61 studied linsitinib, a small molecule inhibitor of IGF-1R, in a phase III trial of 139 patients with progressive metastatic ACC. Patients were randomized to linsitinib or placebo. There was no difference in OS (the primary endpoint) or PFS between the arms. Interestingly, 3 patients in the linsitinib arm (3%) had PR lasting for sev- eral years each. All 3 patients had low-grade ACC with Ki-67 ≤20%. There was also a trend toward higher DCR in the linsitinib arm. Nevertheless, this study did not meet its primary endpoint and was a negative trial.

Despite preclinical work showing the importance of the IGF pathway in ACC, clinical studies did not show consist- ent benefit, and no further efforts are underway to target the IGF pathway in ACC.

FGFR Pathway Inhibition

The fibroblast growth factor receptor (FGFR) pathway is involved in several key cellular functions. ACC tumors have been shown to harbor a number of alterations in FGFR signaling, prompting investigation into therapeutic target- ing of this pathway.62

García-Donas et al63 studied dovitinib, a TKI that inhibits multiple targets including FGFR1/3, in a prospec- tive, phase II trial of 17 patients with unresectable or met- astatic ACC. Prior therapy only with mitotane was allowed. One patient (6%) had PR and 4 patients (23%) had SD lasting at least 6 months, with a median PFS of 1.8 months. This study did not meet its primary endpoint of ORR and was a negative trial. Papadopoulos et al64 studied derazantinib, a TKI that inhibits multiple targets including pan-FGFR, in a phase I trial of 80 patients, including 4 patients with ACC. One patient with an ACC tumor harboring an FGFR1 amplification had SD and was on study for 3.5 years. A second patient with an ACC tumor without FGFR amplifications had SD and was on study for at least 12 months.

Neither dovitinib nor derazantinib is FDA approved, and to our knowledge further testing of these drugs in ACC has halted. Since the above trials were conducted, however, the

FDA has approved 4 other FGFR inhibitors for other dis- ease indications: the pan-FGFR inhibitors erdafitinib and futibatinib, and the FGFR1/2/3 inhibitors pemigatinib and infigratinib (accelerated approval for infigratinib was later voluntarily withdrawn by the manufacturer due to poor enrollment on the confirmatory trial).65,66 None of these agents has been tested in ACC. Given the potentially encouraging signals in García-Donas et al and Papadopoulos et al, notably the long duration of SD observed in some patients, these newer generation FGFR inhibitors may hold promise if formally trialed in ACC.

EGFR Pathway Inhibition

Epidermal growth factor receptor (EGFR) plays an impor- tant role in normal epithelial cell physiology and is overex- pressed or mutated in many cancers, promoting tumorigenesis. Epidermal growth factor receptor driver mutations, most notably in NSCLC, confer sensitivity to EGFR inhibitors, while EGFR overexpression typically does not.67,68 In ACC, over 75% of tumors express EGFR, but mutations in EGFR are rare.69

Two trials of EGFR pathway inhibition in ACC have been completed. Samnotra et al70 studied the first-genera- tion EGFR inhibitor gefitinib as monotherapy in a prospec- tive, phase II trial of 19 patients with progressive ACC. All patients had PD. Quinkler et al71 studied the first-genera- tion EGFR inhibitor erlotinib in combination with gemcit- abine in a prospective trial of 10 patients with progressive ACC after 2 to 4 prior lines of therapy. One patient (10%) had SD that lasted for 8 months, while the remainder had PD. Of note, the patient with SD had an ACC tumor with the lowest EGFR expression of any of the 10 patients.

Epidermal growth factor receptor pathway inhibition in ACC has yielded disappointing results, likely owing to the low rate of EGFR mutations in ACC, and EGFR inhibitors are no longer being investigated in ACC.

PI3K/AKT/mTOR Pathway Inhibition

The phosphoinositide 3-kinase (PI3K)/AKT/mTOR signal- ing pathway is involved in cellular metabolism and growth and has been implicated in ACC tumorigenesis. Preclinical studies have demonstrated potential efficacy of mTOR inhibitors in human ACC cell lines.72

Fraenkel et al73 studied the mTOR inhibitor everolimus as monotherapy in 4 patients with progressive ACC. All 4 patients had PD 1 to 4months after starting therapy. Ganesan et al74 studied the mTOR inhibitor temsirolimus in combination with lenalidomide in a phase I trial of 43 patients with advanced cancer, including 3 patients with ACC. One patient (33%) had SD for at least 6 months. As noted above, Naing et al59 studied the mTOR inhibitor tem- sirolimus in combination with the IGF-1R inhibitor cixutu- mumab in a phase I trial of 26 patients with metastatic ACC. Patients were heavily pretreated, with a median of 4 prior therapies. There were no objective responses, but 11 patients (42%) had SD for at least 6 months.

More recently, Hong et al75 studied eganelisib, a first-in- class PI3K-y inhibitor, as monotherapy or with nivolumab, in a phase I trial of 219 patients with progressive advanced cancer, including 6 patients with ACC. All ACC patients received combination eganelisib and nivolumab. One patient (17%) had PR that lasted 11.4 months. The remain- ing 5 patients did not have an objective response, but their best response (SD versus PD) was not reported.

While most of the patients treated with PI3K or mTOR inhibitors in these trials had PD, some patients experienced disease control, highlighting the need for further investiga- tion into the PI3K/AKT/mTOR pathway in treating ACC.

SOAT1 Inhibition

Sterol-O-acyl transferase 1 (SOAT1), also known as acyl- coenzyme A: cholesterol acyltransferase 1 (ACAT1), is involved in cholesterol processing in the adrenal cortex.76 In preclinical studies, mitotane has been shown to inhibit SOAT1, leading to accumulation of toxic lipids and subse- quent apoptosis of ACC cells.77 As a result, SOAT1 was initially investigated as a prognostic marker in ACC but showed mixed results.77-79 More recently, Smith et al80 studied the adrenal-specific SOAT1 inhibitor nevanimibe in a phase I trial of 63 patients with progressive metastatic ACC. There were no objective responses, but 13 of 48 eval- uable patients (27%) had SD at 2 months and 4 patients (8%) had SD at 4 months. Of note, very few dose-limiting toxicities occurred, a maximum tolerated dose could not be defined, and expected exposure levels necessary to achieve apoptosis were not reached, which may have contributed to the limited efficacy of nevanimibe in this study.

There are no other clinical studies of SOAT1 inhibition in ACC ongoing at this time, but several other compounds have been shown to target SOAT1 in preclinical studies, including the SOAT1 inhibitor avasimibe and the BCR- ABL TKI nilotinib.81 These may be of interest in future clinical studies in ACC.

Progesterone

Abiraterone acetate (AA) is a potent inhibitor of 17a- hydroxylase/17,20-lyase, a key enzyme in adrenal steroidogen- esis, which may help suppress excess cortisol from steroid-secreting ACC tumors. Preclinical studies investigating the effect of AA on ACC cell lines also demonstrated a cyto- toxic effect that is thought to be mediated by a drug-induced increase in progesterone levels.82 Increased progesterone levels in turn lead to activation of progesterone receptors, which alter cellular programs via their classical action as nuclear transcrip- tion factors as well as so-called extranuclear effects. Several subsequent preclinical studies demonstrated a cytotoxic effect of progesterone itself, alone or in combination with ribociclib or tamoxifen, on a variety of ACC cell lines.83-86

Based on this preclinical work, a prospective, rand- omized phase II trial is underway of patients with unresect- able or metastatic ACC randomized to EDP-mitotane with or without the progesterone analog megestrol acetate in the first-line setting (Table 2).87

Relacorilant

Approximately half of ACC tumors secrete excess glucocorti- coids, and hypercortisolism is correlated with worse survival in patients with ACC. Glucocorticoids exert an immunosup- pressive effect through a broad array of mechanisms and are notably associated with T-cell depletion in ACC.88,89 This, in turn, is thought to contribute to ICI resistance.

Relacorilant is a glucocorticoid receptor modulator that is currently being investigated in the treatment of both Cushing syndrome and solid tumors.90-93 A phase Ib trial of combination pembrolizumab and relacorilant in patients with unresectable or metastatic ACC with excess glucocor- ticoid production is underway (Table 2).94

Radiopharmaceuticals

Theranostic radiopharmaceuticals are compounds that are labeled with radionuclides and can be used for both diag- nostic (i.e., imaging) and therapeutic purposes depending on the specific conjugated radionuclide: gamma and posi- tron emitters for imaging, and beta-minus or alpha emitters for therapeutic targeting. They are in active use in a variety of cancers, notably in prostate cancer (prostate specific membrane antigen-targeted approaches) and neuroendo- crine tumors (somatostatin receptor-targeted approaches), and under investigation in many others, including ACC.95,96 The utility of these agents is dependent on the robustness of target expression in tumor tissue.

Three trials of radiopharmaceuticals in ACC have been completed to date. Hahner et al97 studied iodine-123 meto- midate (123I-IMTO) for PET/CT imaging and iodine-131 metomidate (131I-IMTO) for first-line or subsequent treat- ment of unresectable or metastatic ACC. Fourty-nine patients were enrolled, of whom 13 (27%) had tumors with very high 123I-IMTO uptake; 2 of these patients subse- quently disenrolled from the study, and 1 patient died shortly after treatment with 131I-IMTO due to septic shock. Of the 10 patients treated with 131I-IMTO with follow-up imaging, 1 (10%) had PR and 5 (50%) had SD. The median PFS in these 6 patients was 14 months. 131I-IMTO was gen- erally well-tolerated, with reversible bone marrow suppres- sion being the most commonly observed adverse effect.

Grisanti et al98 studied gallium-68 dodecane tetraacetic acid Tyr3-octreotide (68Ga-DOTATOC) for PET/CT imaging and yttrium-90/lutetium-177 DOTATOC (90Y/177Lu- DOTATOC) for treatment of progressive metastatic ACC. 19 patients were enrolled, of whom 10 (53%) had tumors with 68Ga-DOTATOC uptake of any-grade intensity in metastatic sites, but only 2 of whom (11%) had tumors with strong uptake in a diffuse/multiple pattern that was deemed clini- cally significant. These 2 patients were treated with 90Y/177 Lu- DOTATOC. One patient had PR that lasted 12 months, and other had SD that lasted 4 months. Mild back pain and grade 2 lymphopenia were observed in one patient.

Hahner et al99 later studied (R)-1-[1-(4-[iodine-123]iodo- phenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide (123I-IMAZA) for PET/CT imaging and iodine-131 IMAZA (131I-IMAZA) for treatment of progressive unresect- able or metastatic ACC. 69 patients were enrolled, of whom

13 (19%) had tumors with strong uptake of 123I-IMAZA in all metastatic sites. All 13 patients were treated with 131I-IMAZA, and one was lost to follow-up. Of the 12 patients treated with 131I-IMAZA with follow-up imaging, 5 (42%) had SD. Median PFS was 4.1 months in the entire cohort, 14.3 months in the 5 patients who had SD, and 3.2 months in the 7 patients who had PD. 131I-IMAZA was generally well-tolerated, and, as with 131I-IMTO, reversible bone marrow suppression was the most commonly observed adverse effect.

A phase I trial of 68Ga-R8760, a radiopharmaceutical tar- geting the melanocortin 2 receptor (MC2R), for imaging of metastatic ACC is currently enrolling.100 To our knowledge, a counterpart therapeutic radiopharmaceutical targeting MC2R has not yet been developed.

Overall, the utility of radiopharmaceuticals in ACC is limited by the lack of robust target expression in most ACC tumors. However, for the subset of patients whose tumors do demonstrate robust expression, some promising results have been observed, and further investigation of these com- pounds is warranted. The additional benefit of a theranostic approach is that patients can effectively be screened with the diagnostic radiopharmaceutical for potential efficacy before undergoing treatment with the therapeutic counter- part, saving patients with poor target expression from a therapy that is unlikely to work. This screening mechanism is especially important in ACC due to its aggressive nature and poor survival.

Vaccines

There is emerging interest in using therapeutic vaccines to treat ACC. One trial has been completed to date of the vac- cine EO2401, which includes microbiome-derived peptides with molecular mimicry to 3 tumor-associated antigens known to be upregulated in ACC: IL13RA2, BIRC5, and FOXM1. Baudin et al101 studied EO2401 in combination with nivolumab in 33 patients with progressive (26 patients) or treatment-naïve (7 patients) metastatic ACC. Four patients (12%) had PR and 8 patients (24%) had SD. Median PFS was 1.9 months. The safety profile was con- sistent with nivolumab monotherapy except for a higher rate of injection site reactions.

A phase I trial is underway of the individualized mRNA neoantigen vaccine mRNA-0523-L001 for patients with advanced endocrine tumors, including ACC (Table 2).102

Overall, it remains to be seen whether therapeutic vac- cines will have efficacy in treating ACC.

CAR-T

Chimeric antigen receptor T (CAR-T) cells have an estab- lished role in the treatment of hematologic malignancies but remain under investigation for solid tumors. In ACC, several potential immunotherapeutic targets have been identified in preclinical studies, including B7H3, ROR1, and an antigen that yet to be disclosed.103-105 B7H3 may be of particular interest as a promising target, as B7H3 CAR-T cells have shown activity in children and young adults with

solid tumors.106 A phase I trial of autologous B7H3 CAR-T cells in children with advanced solid tumors, including ACC, is underway (Table 2).107

Conclusion

Unresectable or metastatic ACC remains a challenging dis- ease with a poor prognosis for which more active therapies are being aggressively sought. In past eras, multiple single- agent chemotherapies and combination chemotherapy regi- mens were trialed, culminating in the establishment of the EDP-mitotane regimen as accepted first-line therapy. Over the past decade, attention has shifted to targeted and molec- ularly-defined approaches. Many of these approaches have been tested in clinical trials, almost all of which are early phase, with clinical data that have been reviewed here. Moreover, many more which have shown promise in pre- clinical studies have not yet entered clinical trials.

The body of clinical trials of nonchemotherapeutic approaches highlights the challenges of treating this aggres- sive disease. Across all trials reviewed here, objective responses were rare and most patients experienced disease progression. However, rates of SD were nontrivial in some trials, and some patients with an objective response or SD enjoyed a duration of response of months or even years. The presence of these rare encouraging outcomes under- scores the need for better patient selection for novel thera- pies and the development of robust biomarkers to guide management decisions and predict prognosis.

It has been difficult for most ACC trials to meet ORR, PFS, or OS primary endpoints owing to small sample sizes and high rates of nonresponse (even EDP-mitotane did not improve OS over single-agent streptozocin). Accordingly, there is interest in developing additional secondary endpoints in ACC trials, and it is our view that even SD can be clinically significant in ACC due to its very short median OS.

While many of the approaches reviewed here have dem- onstrated negative results, others have yielded encouraging signals. More work remains to be done to build on these findings and develop effective novel therapies for this dev- astating disease.

Acknowledgements

None

ORCID iD

Adam E Singer ID https://orcid.org/0009-0006-5467-9444

Not applicable

Not applicable

Authors’ Contributions

AES, AJP, and AD conceived of the review concept, and AES, NKP, DS, LG, and LD drafted the article. All authors made a

substantial contribution to review design, revised the article, and approved the version to be published.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data sharing not applicable to this article as no datasets were gen- erated or analyzed during the current study.

References

1. Sharma E, Dahal S, Sharma P, et al. The characteristics and trends in adrenocortical carcinoma: a United States population based study. J Clin Med Res. 2018;10:636-640. doi:10.14740/jocmr3503w

2. Bilimoria KY, Shen WT, Elaraj D, et al. Adrenocortical car- cinoma in the United States: treatment utilization and prog- nostic factors. Cancer. 2008;113:3130-3136. doi:10.1002/ cncr.23886

3. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366:2189-2197. doi:10.1056/ NEJMoa1200966

4. Decker RA, Elson P, Hogan TF, et al. Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery. 1991;110:1006-1013.

5. Bonacci R, Gigliotti A, Baudin E, et al. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Br J Cancer. 1998;78:546-549. doi:10.1038/ bjc.1998.530

6. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer. 2000;88:1159- 1165.

7. Baudin E, Docao C, Gicquel C, et al. Use of a topoi- somerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma. Ann Oncol. 2002;13:1806-1809. doi:10.1093/annonc/mdf291

8. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxo- rubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12:657-666. doi:10.1677/erc.1.01025

9. Sperone P, Ferrero A, Daffara F, et al. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/ third-line chemotherapy in advanced adrenocortical carci- noma: a multicenter phase II study. Endocr Relat Cancer. 2010;17:445-453. doi:10.1677/ERC-09-0281

10. Berruti A, Sperone P, Ferrero A, et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012;166:451-458. doi:10.1530/EJE-11-0918

11. Urup T, Pawlak WZ, Petersen PM, Pappot H, Rørth M, Daugaard G. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. Br J Cancer. 2013;108:1994-1997. doi:10.1038/bjc.2013.229

12. Kroiss M, Deutschbein T, Schlötelburg W, et al. Salvage treatment of adrenocortical carcinoma with trofosfamide. Horm Cancer. 2016;7:211-218. doi:10.1007/s12672-016- 0260-7

13. Kroiss M, Deutschbein T, Schlötelburg W, et al. Treatment of refractory adrenocortical carcinoma with thalidomide: analysis of 27 patients from the European network for the study of adrenal tumours registry. Exp Clin Endocrinol Diabetes. 2019;127:578-584. doi:10.1055/a-0747-5571

14. Cosentini D, Badalamenti G, Grisanti S, et al. Activity and safety of temozolomide in advanced adrenocortical carcinoma patients. Eur J Endocrinol. 2019;181:681-689. doi:10.1530/EJE-19-0570

15. Laganà M, Grisanti S, Ambrosini R, et al. Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma. ESMO Open. 2022;7:100422. doi:10.1016/j.esmoop.2022.100422

16. Haider MS, Ahmad T, Groll J, Scherf-Clavel O, Kroiss M, Luxenhofer R. The challenging pharmacokinetics of mito- tane: an old drug in need of new packaging. Eur J Drug Metab Pharmacokinet. 2021;46:575-593. doi:10.1007/ s13318-021-00700-5

17. NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors (Version 1), 2023.

18. Zhang F, Lin H, Cao K, et al. Vasculogenic mimicry plays an important role in adrenocortical carcinoma. Int J Urol. 2016;23:371-377. doi:10.1111/iju.13070

19. Pereira SS, Oliveira S, Monteiro MP, Pignatelli D. Angiogenesis in the normal adrenal fetal cortex and adren- ocortical tumors. Cancers. 2021;13:1030. doi:10.3390/ cancers 13051030

20. Kroiss M, Quinkler M, Johanssen S, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97:3495- 3503. doi:10.1210/jc.2012-1419

21. O’Sullivan C, Edgerly M, Velarde M, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab. 2014;99:1291-1297. doi:10.1210/jc.2013-2298

22. Kroiss M, Megerle F, Kurlbaum M, et al. Objective response and prolonged disease control of advanced adren- ocortical carcinoma with cabozantinib. J Clin Endocrinol Metab. 2020;105:1461-1468. doi:10.1210/clinem/dgz318

23. A phase II study to evaluate the effects of cabozantinib in patients with unresectable/metastatic adrenocortical carci- noma. Accessed June 19, 2024. https://clinicaltrials.gov/ study/NCT03370718

24. A multicenter, open-label, phase ii study to evaluate the efficacy and safety of cabozantinib in advanced (unresecta- ble or metastatic) adrenocortical carcinoma. Accessed June 19, 2024. https://clinicaltrials.gov/study/NCT03612232

25. Head L, Kiseljak-Vassiliades K, Clark TJ, et al. Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. J Endocr Soc. 2019;3:2295-2304. doi:10.1210/js.2019-00305

26. Remde H, Schmidt-Pennington L, Reuter M, et al. Outcome of immunotherapy in adrenocortical carcinoma: a retro- spective cohort study. Eur J Endocrinol. 2023;188:485- 493. doi:10.1093/ejendo/lvad054

27. Le Tourneau C, Hoimes C, Zarwan C, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6:111. doi:10.1186/ s40425-018-0424-9

28. Carneiro BA, Konda B, Costa RB, et al. Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. J Clin Endocrinol Metab. 2019;104:6193-6200. doi:10.1210/jc.2019-00600

29. Habra MA, Stephen B, Campbell M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer. 2019;7:253. doi:10.1186/s40425-019-0722-x

30. Raj N, Zheng Y, Kelly V, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol. 2020;38:71-80. doi:10.1200/JCO.19.01586

31. Klein O, Senko C, Carlino MS, et al. Combination immu- notherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. Oncoimmunology. 2021;10:1908771. doi:10. 1080/2162402X.2021.1908771

32. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. Accessed June 19, 2024. https://www.fda.gov/drugs/resources-informa- tion-approved-drugs/fda-grants-accelerated-approval- pembrolizumab-first-tissuesite-agnostic-indication

33. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. Accessed June 19, 2024. https:// www.fda.gov/drugs/drug-approvals-and-databases/fda- approves-pembrolizumab-adults-and-children-tmb-h- solid-tumors

34. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31:3012-3018. doi:10.1200/ JCO.2012.48.0988

35. Shi X, Liu Y, Cheng S, et al. Cancer stemness associated with prognosis and the efficacy of immunotherapy in adrenocortical carcinoma. Front Oncol. 2021;11:651622. doi:10.3389/fonc.2021.651622

36. Fiorentini C, Grisanti S, Cosentini D, et al. Molecular drivers of potential immunotherapy failure in adreno- cortical carcinoma. J Oncol. 2019;2019:6072863. doi:10.1155/2019/6072863

37. Georgantzoglou N, Kokkali S, Tsourouflis G, Theocharis S. Tumor microenvironment in adrenocortical carcinoma: barrier to immunotherapy success? Cancers. 2021;13:1798. doi:10.3390/cancers13081798

38. Xu F, Guan Y, Zhang P, et al. Tumor mutational burden pre- sents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adreno- cortical carcinoma. BMC Endocr Disord. 2022;22:130. doi:10.1186/s12902-022-01017-3

39. Dostarlimab as first-line treatment for patients with dMMR/ MSI (non-colorectal/non-endometrial) locally advanced or metastatic cancer: a randomized phase 2 trial (Cohort Pan-MSI ACSE) with crossover in the standard arm at pro- gression. Accessed June 19, 2024. https://clinicaltrials.gov/ study/NCT06333314

40. A multicentre, open-label phase 2 study to evaluate the efficacy and safety of pembrolizumab in the treat- ment of advanced, progressive adrenocortical carcinoma. Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT05563467

41. A phase II study of nivolumab combined with ipilimumab for patients with advanced rare genitourinary tumors. Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT03333616

42. DART: dual anti-CTLA-4 and Anti-PD-1 blockade in rare tumors. Accessed June 19, 2024. https://clinicaltrials.gov/ study/NCT02834013

43. FDA approves Opdualag for unresectable or metastatic melanoma. Accessed June 19, 2024. https://www.fda. gov/drugs/resources-information-approved-drugs/fda- approves-opdualag-unresectable-or-metastatic-mela- noma

44. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangio- genics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325-340. doi:10.1038/nrclinonc.2018.29

45. Bedrose S, Miller KC, Altameemi L, et al. Combined len- vatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. J Immunother Cancer. 2020;8:e001009. doi:10.1136/jitc-2020-001009

46. Grande E, Benavent Viñuales M, Molina-Cerrillo J, et al. Cabozantinib plus atezolizumab in locally advanced/meta- static adrenocortical carcinoma: results from a multi-cohort basket phase II trial, CABATEN/GETNE-T1914. J Clin Oncol. 2024;42.

47. Wei Z, Zhu Y, Cai L, Peng X. Camrelizumab plus apat- inib for previously treated advanced adrenocortical carci- noma: a single-arm, open-label, phase 2 trial. J Clin Oncol. 2024;42:10371.

48. Phase II open label, single-arm study of cabozantinib in combination with atezolizumab in the treatment of locally advanced or metastatic adrenocortical carcinoma. Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT06006013

49. A prospective phase II trial of pembrolizumab plus len- vatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy. Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT05036434

50. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conju- gate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7:93. doi:10.1038/ s41392-022-00947-7

51. Bosi C, Bartha Á, Galbardi B, et al. Pan-cancer analysis of antibody-drug conjugate targets and putative predictors of treatment response. Eur J Cancer. 2023;195:113379. doi:10.1016/j.ejca.2023.113379

52. Moek KL, de Groot DJA, de Vries EGE, Fehrmann RSN. The antibody-drug conjugate target landscape across a broad range of tumour types. Ann Oncol. 2017;28:3083- 3091. doi:10.1093/annonc/mdx541

53. Lemech C, Woodward N, Chan N, et al. A first-in-human, phase 1, dose-escalation study of ABBV-176, an anti- body-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors. Invest New Drugs. 2020;38:1815-1825. doi:10.1007/s10637-020-00960-z

54. Sun NY, Kumar S, Weiner A, et al. Abstract 6573: targeting DLK1, a Notch ligand, with an antibody-drug conjugate in adrenocortical carcinoma. Cancer Res. 2024;84:6573. doi:10.1158/1538-7445.AM2024-6573

55. A first-in-human phase I trial with antibody drug conju- gate ADCT-701 in neuroendocrine tumors and carcinomas.

Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT06041516

56. Zammarchi F, Havenith K, Leatherdale B, et al. Abstract 1604: preclinical development of ADCT-211, a novel pyr- rolobenzodiazepine dimer-based antibody-drug conjugate targeting solid tumors expressing IL13RA2. Cancer Res. 2023;83:1604.

57. Giordano TJ, Thomas DG, Kuick R, et al. Distinct tran- scriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol. 2003;162:521-531. doi:10.1016/S0002-9440(10)63846-1

58. Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical car- cinoma. Cancer Chemother Pharmacol. 2010;65:765-773. doi:10.1007/s00280-009-1083-9

59. Naing A, Lorusso P, Fu S, et al. Insulin growth factor recep- tor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer. 2013;108:826-830. doi:10.1038/bjc.2013.46

60. Lerario AM, Worden FP, Ramm CA, et al. The combina- tion of insulin-like growth factor receptor 1 (IGF1R) anti- body cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical car- cinoma: a multi-institutional NCI-sponsored trial. Horm Cancer. 2014;5:232-239. doi:10.1007/s12672-014-0182-1

61. Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI- 906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, ran- domised, phase 3 study. Lancet Oncol. 2015;16:426-435. doi:10.1016/S1470-2045(15)70081-1

62. Tamburello M, Altieri B, Sbiera I, et al. FGF/FGFR sign- aling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carci- noma. Endocrine. 2022;77:411-418. doi:10.1007/s12020- 022-03074-z

63. García-Donas J, Hernando Polo S, Guix M, et al. Phase II study of dovitinib in first line metastatic or (non resectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03. J Clin Oncol. 2014;32.

64. Papadopoulos KP, El-Rayes BF, Tolcher AW, et al. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017;117:1592- 1599. doi:10.1038/bjc.2017.330

65. Katoh M, Loriot Y, Brandi G, Tavolari S, Wainberg ZA, Katoh M. FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. Nat Rev Clin Oncol. 2024;21:312-329. doi:10.1038/s41571-024- 00869-z

66. WITHDRAWN: FDA grants accelerated approval to infi- gratinib for metastatic cholangiocarcinoma. Accessed June 19, 2024. https://www.fda.gov/drugs/resources-informa- tion-approved-drugs/withdrawn-fda-grants-accelerated- approval-infigratinib-metastatic-cholangiocarcinoma

67. McLoughlin EM, Gentzler RD. Epidermal growth factor receptor mutations. Thorac Surg Clin. 2020;30:127-136. doi:10.1016/j.thorsurg.2020.01.008

68. Zubair T, Bandyopadhyay D. Small molecule EGFR inhibitors as anti-cancer agents: discovery, mechanisms of action, and opportunities. Int J Mol Sci. 2023;24:2651. doi:10.3390/ijms24032651

69. Adam P, Hahner S, Hartmann M, et al. Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod Pathol. 2010;23:1596-1604. doi:10.1038/ modpathol.2010.153

70. Samnotra V, Vassilopoulou-Sellin R, Fojo AT, et al. A phase II trial of gefitinib monotherapy in patients with unre- sectable adrenocortical carcinoma (ACC). J Clin Oncol. 2007;25.

71. Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93:2057- 2062. doi:10.1210/jc.2007-2564

72. De Martino MC, Feelders RA, Pivonello C, et al. The role of mTOR pathway as target for treatment in adrenocortical cancer. Endocr Connect. 2019;8:R144-R156. doi:10.1530/ EC-19-0224

73. Fraenkel M, Gueorguiev M, Barak D, Salmon A, Grossman AB, Gross DJ. Everolimus therapy for progressive adreno- cortical cancer. Endocrine. 2013;44:187-192. doi:10.1007/ s12020-013-9878-1

74. Ganesan P, Piha-Paul S, Naing A, et al. Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. Invest New Drugs. 2013;31:1505- 1513. doi:10.1007/s10637-013-0013-1

75. Hong DS, Postow M, Chmielowski B, et al. Eganelisib, a first-in-class PI3Ky inhibitor, in patients with advanced solid tumors: results of the phase 1/1b MARIO-1 trial. Clin Cancer Res. 2023;29:2210-2219. doi:10.1158/1078-0432. CCR-22-3313

76. Lee HT, Roark WH, Picard JA, et al. Inhibitors of acyl- CoA:cholesterol O-acyltransferase (ACAT) as hypo- cholesterolemic agents: synthesis and structure-activity relationships of novel series of sulfonamides, acylphos- phonamides and acylphosphoramidates. Bioorg Med Chem Lett. 1998;8:289-294. doi:10.1016/s0960-894x(98)00011-0

77. Sbiera S, Leich E, Liebisch G, et al. Mitotane inhibits Sterol-O-Acyl transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocorti- cal carcinoma cells. Endocrinology. 2015;156:3895-3908. doi:10.1210/en.2015-1367

78. Weigand I, Altieri B, Lacombe AMF, et al. Expression of SOAT1 in adrenocortical carcinoma and response to mitotane monotherapy: an ENSAT multicenter study. J Clin Endocrinol Metab. 2020;105:dgaa293. doi:10.1210/ clinem/dgaa293

79. Lacombe AMF, Soares IC, Mariani BM, de P, et al. Sterol O-acyl transferase 1 as a prognostic marker of adrenocor- tical carcinoma. Cancers. 2020;12:247. doi:10.3390/can- cers12010247

80. Smith DC, Kroiss M, Kebebew E, et al. A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocorti- cal carcinoma. Invest New Drugs. 2020;38:1421-1429. doi:10.1007/s10637-020-00899-1

81. Tu T, Zhang H, Xu H. Targeting sterol-O-acyltransferase 1 to disrupt cholesterol metabolism for cancer therapy. Front Oncol. 2023;13:1197502. doi:10.3389/fonc.2023.1197502

82. Fiorentini C, Fragni M, Perego P, et al. Antisecretive and antitumor activity of abiraterone acetate in human adren- ocortical cancer: a preclinical study. J Clin Endocrinol Metab. 2016;101:4594-4602. doi:10.1210/jc.2016-2414

83. Fragni M, Fiorentini C, Rossini E, et al. In vitro antitu- mor activity of progesterone in human adrenocortical

carcinoma. Endocrine. 2019;63:592-601. doi:10.1007/ s12020-018-1795-x

84. Abate A, Rossini E, Tamburello M, et al. Ribociclib cytotox- icity alone or combined with progesterone and/or mitotane in in vitro adrenocortical carcinoma cells. Endocrinology. 2022;163:bqab248. doi: 10.1210/endocr/bqab248

85. Rossini E, Tamburello M, Abate A, et al. Cytotoxic effect of progesterone, tamoxifen and their combination in experimental cell models of human adrenocortical can- cer. Front Endocrinol. 2021;12:669426. doi:10.3389/ fendo.2021.669426

86. Tamburello M, Abate A, Rossini E, et al. Preclinical evi- dence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines. Int J Mol Sci. 2023;24:6829. doi:10.3390/ijms24076829

87. Cremaschi V, Cosentini D, Abate A, et al. 40TiP Activity of the addition of progesterone to standard EDP-M scheme in patients with advanced adrenocortical carcinoma: a randomized, placebo-controlled phase II trial (PESETA). ESMO Open. 2023;8:101061.

88. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent devel- opments and mechanistic insights. Mol Cell Endocrinol. 2011;335:2-13. doi:10.1016/j.mce.2010.04.005

89. Landwehr LS, Altieri B, Schreiner J, et al. Interplay between glucocorticoids and tumor-infiltrating lympho- cytes on the prognosis of adrenocortical carcinoma. J Immunother Cancer. 2020;8:e000469. doi:10.1136/jitc- 2019-000469

90. Pivonello R, Bancos I, Feelders RA, et al. Relacorilant, a selective glucocorticoid receptor modulator, induces clinical improvements in patients with cushing syn- drome: results from a prospective, open-label phase 2 study. Front Endocrinol. 2021;12:662865. doi:10.3389/ fendo.2021.662865

91. Munster PN, Greenstein AE, Fleming GF, et al. Overcoming taxane resistance: preclinical and phase 1 studies of relacorilant, a selective glucocorticoid recep- tor modulator, with nab-paclitaxel in solid tumors. Clin Cancer Res. 2022;28:3214-3224. doi:10.1158/1078-0432. CCR-21-4363

92. Colombo N, Van Gorp T, Matulonis UA, et al. Relacorilant + nab-paclitaxel in patients with recurrent, platinum-resist- ant ovarian cancer: a three-arm, randomized, controlled, open-label phase II study. J Clin Oncol. 2023;41:4779- 4789. doi:10.1200/JCO.22.02624

93. Olawaiye A, Monk BJ, Herzog TJ, et al. ROSELLA: a phase 3 study of relacorilant in combination with nab- paclitaxel versus investigator’s choice in advanced, platinum-resistant, high-grade epithelial ovarian, pri- mary peritoneal, or fallopian-tube cancer. J Clin Oncol. 2022;40.

94. Study of relacorilant in combination with pembrolizumab for patients with adrenocortical carcinoma which produces too much stress hormone (Cortisol). Accessed June 19, 2024. https://clinicaltrials.gov/study/NCT04373265

95. Michalski K, Schlötelburg W, Hartrampf PE, et al. Radiopharmaceuticals for treatment of adrenocortical carcinoma. Pharmaceuticals. 2023;17:25. doi:10.3390/ ph17010025

96. Barca C, Griessinger CM, Faust A, et al. Expanding theranostic radiopharmaceuticals for tumor diagnosis and therapy. Pharmaceuticals. 2021;15:13. doi:10.3390/ ph15010013

97. Hahner S, Kreissl MC, Fassnacht M, et al. [131I]iodometo- midate for targeted radionuclide therapy of advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2012;97:914-922. doi:10.1210/jc.2011-2765

98. Grisanti S, Filice A, Basile V, et al. Treatment With 90Y/177Lu-DOTATOC in patients with metastatic adreno- cortical carcinoma expressing somatostatin receptors. J Clin Endocrinol Metab. 2020;105:dgz091. doi:10.1210/clinem/ dgz091

99. Hahner S, Hartrampf PE, Mihatsch PW, et al. Targeting 11-beta hydroxylase with [131I]IMAZA: a novel approach for the treatment of advanced adrenocortical carci- noma. J Clin Endocrinol Metab. 2022;107:e1348-e1355. doi:10.1210/clinem/dgab895

100. Phase 1 Study of 68Ga-R8760. Accessed June 19, 2024. https://clinicaltrials.gov/study/NCT05999292

101. Baudin E, Jimenez C, Fassnacht M, et al. EO2401, a novel microbiome-derived therapeutic vaccine for patients with adrenocortical carcinoma (ACC): preliminary results of the SPENCER study. J Clin Oncol. 2022;40.

102. Treatment of advanced endocrine tumor with iindividu- alized mRNA neoantigen vaccine (mRNA-0523-L001).

Accessed June 19, 2024. https://www.clinicaltrials.gov/ study/NCT06141369

103. Epperly R, Pinto EM, Santiago T, et al. Abstract 1197: B7-H3-CAR T cells for the treatment of pediatric adreno- cortical carcinoma. Cancer Res. 2023;83:1197.

104. Schauer MP, Altieri B, Redondo-Frutos RA, et al. ROR-1 specific CAR-T cells with CRISPR/CAS9 mediated glu- cocorticoid receptor-knockout exert potent antitumor effi- cacy in advanced adrenocortical carcinoma. Endocrine Abstracts. 2023;93:OC20.

105. Schauer MP, Landwehr LS, Justus W, et al. CAR-T cell therapy exerts effective antitumor efficacy under immu- nosuppressive conditions in adrenocortical carcinoma. Endocrine Abstracts. 2023;90.

106. Pinto NR, Albert CM, Taylor M, et al. STRIVE-02: a first- in-human phase 1 trial of systemic B7H3 CAR T cells for children and young adults with relapsed/refractory solid tumors. J Clin Oncol. 2022;40.

107. B7-H3-specific chimeric antigen receptor autologous T-cell therapy for pediatric patients with solid tumors (3CAR). Accessed June 19, 2024. https://clinicaltrials.gov/study/ NCT04897321

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