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Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma
Chulkue Pak1 . Shinkyo Yoon1 . Jae Lyun Lee1 . Tak Yun2 . Inkeun Park1 (D
Accepted: 11 February 2024 / Published online: 21 February 2024 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Abstract
Purpose of Review To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease.
Recent Findings Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. Summary ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.
Keywords Adrenocortical carcinoma . Advanced . Targeted therapy . Immunotherapy . Genomics
Introduction
Adrenocortical carcinoma (ACC) is an extremely rare tumor originating in the cortex of adrenal glands and has a very poor prognosis. The annual incidence of ACC is reported to be approximately 1 to 2 cases per million people [1]. Although approximately 15% of ACC cases are incidentally discovered through imaging studies, patients with ACC com- monly present with symptoms related to hormonal excess or tumor-related manifestations. Functional tumors, those that secrete hormones, account for about half of all ACC cases. Notably, tumors that hypersecrete cortisol are associated with a poor prognosis [2]. The 5-year survival rates for ACC are approximately 60-80% when it is localized to the adrenal
cortex, 35-50% for locally advanced cases, and 0-28% for cases of distant metastases [3]. In the localized disease, there is a high probability of recurrence following radical surgery even after achieving microscopically free margins (R0), par- ticularly within the initial 2 years at a range of 50-70% [4]. However, when complete resection is feasible, surgery still remains the foremost priority in the treatment of ACC [5 .. ].
Regarding treatment for advanced ACC (recurrent, locoregionally advanced unresectable, or metastatic dis- ease), there are still extremely limited options of effective systemic cancer therapies. Therefore, in this review, we introduce recent findings on prognosis prediction based on genomics, outline the current treatment landscape, and provide insights into ongoing research that encompasses approaches such as targeted therapies and immunotherapies.
☒ Inkeun Park ikpark@amc.seoul.kr
1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of Korea
2 Division of Hematology-Oncology, Rare Cancers Clinic, Center for Specific Organs Center, National Cancer Center, Goyang, Republic of Korea
Prognostic Factors and Genomic Landscape of ACC
The European Network for the Study of Adrenal Tumors (ENSAT) stage is currently the most widely accepted stag- ing system for ACC (Table 1) [6]. It is based on a TNM
| TNM | ENSAT stage | CSM free survival rates | Number of metastatic organs* | mENSAT stage | Overall survival rates 5 years (n=444) |
|---|---|---|---|---|---|
| T1, N0, M0 | I | 73.9% | NA | NA | NA |
| T2, N0, M0 | II | 63.8% | NA | NA | NA |
| T3-4, N0, M0 | III | 44.1% | NA | III | 50% |
| T1-4, N1, M0 | 2 | IVa | 15% | ||
| Any M1 | IV | 6.9% | 3 | IVb | 14% |
| More than 3 | IVc | 2% |
| T stage | |
|---|---|
| T1 | Tumor ≤5 cm |
| T2 | Tumor>5 cm |
| T3 | Infiltration into surrounding tissue |
| T4 | Tumor invasion into adjacent organs or venous tumor thrombus in vena cava or renal vein |
| N stage | |
| N0 | No positive lymph node |
| N1 | Positive lymph node |
| M stage | |
| M0 | No distant metastases |
| M1 | Presence of distant metastases |
ACC Adrenal cortical carcinoma; ENSAT European Network for the Study of Adrenal Tumor; CSM Can- cer-specific mortality; NA Not available mENSAT stage subdivided ENSAT stage III and IV into III, IVa, IVb, and IVc according to the number of tumor-involved organs (including the primary tumor and the ‘N’ as ‘organ’)
classification system (tumor size and extent); however, pre- dicting prognosis solely based on anatomical aspects has limitations [7, 8]. Consequently, there has been research for identifying various prognostic factors, and several predictive models have also been proposed [7, 8]. With recent advances in genomics, the understanding of the pathogenesis of ACC has gradually unfolded, resulting in the demonstration of various prognostic factors and therapeutic targets based on genomics.
Although the ENSAT stage and Ki67 index are widely used as prognostic factors [9], they have an obvious limi- tation, because patients within the same stage can exhibit different clinical courses. In patients with ACC who under- went adrenalectomy, dividing the groups according to the S-GRAS score (a sum of the following points: tumor stage (I-II=0; III= 1; IV =2), grade (Ki67 index 0-9% =0; 10-19%=1; ≥ 20% =2 points), resection status (R0=0; RX=1; R1=2; R2=3), age (<50 years=0; ≥ 50 years = 1), and hormone excess, tumor or systemic cancer-related symptoms (no=0; yes = 1), generating four groups (0-1, 2-3, 4-5, and 6-9)) demonstrated superior results in predict- ing progression-free survival (PFS) and disease-specific sur- vival than using only the ENSAT stage and Ki67 index [7].
Furthermore, a previous study involving 444 patients with advanced ACC (ENSAT Stage III or IV) demonstrated a stronger correlation with overall survival (OS, P<0.0001)
when using a modified ENSAT staging (Table 1). The mEN- SAT stage was categorized into Stage III, indicating invasion into surrounding tissues/organs or the vena renalis/cava, and Stages IVa, IVb, and IVc, representing the involvement of 2, 3, or> 3 metastatic organs, and the primary tumor and the ‘N’ were included as ‘organ’ [8].
Significant progress has been made in the comprehension of the molecular pathogenesis of ACC in the past decade. Molecular studies have revealed that ACC is commonly driven by specific genetic alterations, including mutations in TP53, CTNNB1, and ZNRF3, and high-level amplification of TERT and IGF2 overexpression [10, 11]. Moreover, col- laborative efforts such as The Cancer Genome Atlas (TCGA) have identified other genes, such as PRKAR1A, RPL22, TERF2, CCNE1, and NF1, that also contribute to the devel- opment of ACC [12]. Several studies have emphasized the importance of alterations in the TP53/Rb and Wnt/ß-catenin pathways as key molecular events in ACC development [12, 13].
Recent research has identified that several additional genetic events occur in tumors of metastatic site compared to that in tumors from primary site. Whole-genome sequencing conducted on 33 tumor samples from metastatic sites from 14 patients with metastatic ACC has revealed that tumors from metastatic sites exhibit a 2.8-fold higher median muta- tion rate than tumors from primary sites [14]. Tumors from
metastatic sites exhibited additional mutations in genes such as ENTHD1, HELZ2, PCDH12, SHANK1, and WDR66. Fur- thermore, there were differences in the signaling pathway alterations between tumors from primary and metastatic sites. Tumors from primary sites were characterized by alter- ations in Wnt/ß-catenin, TP53/Rb signaling, and chromatin remodeling, whereas tumors from metastatic sites exhibited altered ERBB4, GPCR, RAR, and PDGFR signaling [14].
In addition to alterations in genes and signaling pathways, comprehensive genome analyses have revealed several dis- tinct molecular subtypes within ACC, each linked to vary- ing prognostic outcomes. The ENSAT network identified two primary ACC subgroups, C1A(poor prognosis) and C1B(good prognosis) [13], whereas a more extensive dataset from TCGA categorized ACC into three subgroups, referred to as the Cluster of Cluster (CoC) I(good), II(intermediate), and III(poor) [12].
Systemic Treatment of Advanced ACC Mitotane Monotherapy
Mitotane is an adrenocytolytic drug approved for treat- ing inoperable ACC. It is also known as 1-chloro-2-[2,2- dichloro-1-{4-chlorophenyl ethyl]benzene(o,p’-DDD), which stems from the insecticide dichlorodiphenyltrichlo- roethane (DDT), and has been used since the 1960s to selec- tively damage the adrenocortical tissue. Mitotane is a chiral drug composed of two enantiomeric (R and S) molecules. The metabolism of mitotane involves a-hydroxylation and ß-hydroxylation, after which it transforms into active metabolite (o,p’-DDA) [15]. Mitotane induces a cytotoxic effect and reduces steroid production in ACC. Although its mechanism of action has not been completely understood, recent research has revealed the target of mitotane action. Mitotane suppresses the function of sterol-O-acyl trans- ferase 1 (SOAT1) in ACC cells, causing an accumulation of free cholesterol and fatty acids, thereby increasing cho- lesterol levels in patients during mitotane treatment. This process induces ER stress, which downregulates SREBF, a factor that stimulates the transcription of steroid-regulated genes, potentially causing a reduction in steroid production. Continued ER stress can then prompt the intrinsic apop- tosis pathway, contributing to cell death and suggesting a mechanism by which mitotane affects caspase activity and diminishes steroid production in ACC. The expression of SOAT1 in tumor cells was identified as a promising poten- tial biomarker, and SOAT1 could be a relevant target for the adrenolytic effects of mitotane [16]. Moreover, it induces hepatic cytochrome CYP34A, which can result in interac- tions with other medications [15].
The efficacy of mitotane is debated primarily because of the lack of prospective, randomized phase III trials on advanced disease. However, considering that advanced ACC is extremely rare and mitotane is de facto standard, conduct- ing randomized trials is unlikely. Most evidence arises from retrospective studies where varying dosages (thus, varying plasma concentrations) and inconsistent response criteria were used, which make controversy more complicated. The role of mitotane in advanced ACC can be extrapolated from adjuvant treatment for localized disease. A retrospective analysis of 177 postsurgery patients from Italy and Germany showed that mitotane significantly extended the recurrence- free survival (42 months versus 10 and 25 months in control groups) [17]. International guidelines recommend adjuvant mitotane in high risk localized ACC after surgery, but the role of mitotane in low risk localized ACC is controversial [5 .. ]. The recently published ADIUVO trial suggested that adjuvant mitotane in low risk ACC might not be as effective as that in the high risk group [18].
Because mitotane requires several weeks to reach the therapeutic plasma concentration, mitotane monother- apy in advanced ACC can be used in select patients with low tumor burden with less aggressive features [19]. The use of mitotane monotherapy in advanced ACC has been investigated in several retrospective studies. For instance, a study on 36 patients with metastatic ACC treated with mitotane at Memorial Sloan Kettering Cancer Center found modest response rates [three patients (8%) achieved com- plete response (CR), and one patient (3%) achieved partial response (PR)], and all responders had nonfunctional tumors [20]. Another study on 127 patients with advanced ACC receiving mitotane at three German referral centers reported an objective response rate (ORR) of 20% (26 patients) and CR rate of 2% (3 patients). That study suggested two predictive factors, viz., low tumor burden (<10 tumoral lesions, hazard ratio (HR) for progression 0.51 (P=0.002)) and initiation of mitotane at delayed advanced recurrence (> 360 days since initial diagnosis, HR for progression 0.35 (P<0.001)) [21].
For adult patients, the initiation of mitotane treatment involves two options to attain a therapeutic range, viz., a “low-dose regimen” (starting at 1 g/day and increasing to 3 g/ day within 2 weeks) and a “high-dose regimen” (starting at 1.5 g/day and escalating to 6 g/day in 4-6 days). No signifi- cant difference was observed in concentration or side effects between the two methods. However, when combined with chemotherapy, due to the reduced tolerability, a less aggres- sive low-dose regimen might be reasonable, while for mitotane monotherapy, the high-dose regimen can be suitable [22]. This continues until the plasma concentrations of mitotane reach 14-20 mg/L, which are considered the “ideal” therapeutic range, ensuring both the effectiveness and acceptable safety of the drug [23]. There is compelling evidence showing a
direct connection between the plasma levels of mitotane and its effectiveness as an antineoplastic agent. Specifically, achieving plasma levels> 14 mg/L has been associated with an ORR of 55-66%, whereas lower levels are linked to reduced efficacy [24]. Several studies have reported a higher incidence of CNS- related adverse events, especially when plasma mitotane levels exceed 20 mg/L [25]. Therefore, many experts recommended a therapeutic concentration range for mitotane between 14 and 20 mg/L. Recent guidelines emphasize the importance of achieving therapeutic concentrations of mitotane and recom- mend adjusting the dosage based on individual patient cir- cumstances [19]. However, the debate regarding the optimal therapeutic concentration itself is still ongoing.
Cytotoxic Chemotherapy
EDP + Mitotane
The current standard first-line treatment for patients with advanced ACC is the etoposide, doxorubicin, cisplatin (EDP) plus mitotane regimen (EDP-M). Being the largest and the only successful randomized controlled trial con- ducted till date, the First International Randomized trial in Locally Advanced and Metastatic Adrenocortical Car- cinoma Treatment (FIRM-ACT) enrolled 304 patients and randomly allocated them to receive mitotane combined with either EDP (EDP-M) or streptozotocin (Sz-M). The EDP-M group had a remarkably higher ORR (23% com- pared to 9%) and a longer median PFS (5 versus 2.1 months) than the streptozotocin group. Nevertheless, despite these advantages, the difference in the median OS did not reach statistical significance (14.8 versus 12 months, HR 0.79, 95% confidence interval 0.61-1.02, P=0.07). This lack of significant difference in the OS of the EDP-M group, despite the improved PFS, could potentially be attributed to the study’s crossover design. In the Sz-M group, 101 of 153 patients received EDP-M as a second-line treatment, whereas 84 of 151 patients in the EDP-M group crossed over to second-line Sz-M. EDP-M also demonstrated superior- ity as a second-line treatment compared with second-line Sz-M, with a median PFS of 5.6 versus 2.2 months, and the median OS from the start of second-line therapy was 10.3 and 7.4 months, respectively. Although there were no signifi- cant differences in the rates of serious adverse events (SAEs) between the two treatment options, the EDP-M group had numerically higher SAEs, especially bone marrow toxicity and infection [26].
Second-line Cytotoxic Chemotherapy After EDP-M Failure
When EDP-M fails, there are extremely limited options for patients with advanced ACC. Unlike EDP-M, no regimen
has been validated in randomized phase III trial. There- fore, treatment decision is generally based on small-sized phase II trials or retrospective cohort analyses. Streptozo- tocin, which was used as the control in FIRM-ACT, gem- citabine + capecitabine, and temozolomide are considered second-line options, but the evidence supporting them is not robust and further research is necessary.
Gemcitabine + Capecitabine
A phase II clinical trial investigated the efficacy and toxicity of gemcitabine (800 mg/m2 on days 1 and 8 every 21 days) with either metronomic fluoropyrimidines (i.v. 5-fluoroura- cil protracted infusion, 200 mg/m2/daily without interrup- tion until progression) or capecitabine (1500 mg/daily) as a second- or third-line chemotherapy in 28 patients with pretreated advanced ACC. One patient achieved CR, and PR was observed in one patient, with an ORR of 7%. Hormonal response was observed in 3 patients (21.4%, PR) [27].
Temozolomide
Temozolomide (TMZ) exerted antitumor effects on human ACC cells in vitro, causing apoptosis, cytotoxicity, and cell cycle arrest in most ACC cell lines [28]. Based on these findings, a 2019 retrospective analysis in Italy examined 28 patients with metastatic ACC treated with TMZ and found that 35.8% of them achieved disease control (1 CR, 5 PR, and 4 stable disease (SD)) with a median PFS of 3.5 months and an OS of 7.2 months [29]. That study also identified a possible predictive role for the DNA repair gene MGMT, as better disease response was observed in patients with MGMT methylation [28, 29]. TMZ was generally well tolerated, with most toxicities being minor. Although TMZ exhibited potential in managing advanced ACC, its benefits were brief, and further studies are required to determine its early use and potential molecular subtypes for treatment [29].
Targeted Therapy
Referring to the genomic landscape where no well- established actionable target exists, targeted therapies for advanced ACC can be classified into several categories such as insulin-like growth factor (IGF) receptor inhibitors and multikinase vascular endothelial growth factor receptor (VEGFR) inhibitors (Fig. 1).
IGF-1 Receptor (IGF-1R) Inhibitors
Overexpression of IGF2 is one of the most common molecular alterations found in 90% of ACC. The signal- ing of IGF-2 is transmitted through IGF-1 receptor and insulin receptor [30].
· AXITINIB · CABOZANTINIB SUNITINIB
DOVITINIB
· LINSITINIB
· CIXUTUMUMAB
· FIGITUMUMAB
· CABOZANTINIB
VEGFR
FGFR
IGFIR
C-MET
Wnt
VEGFR
PI3K
EGANELISIB
· AVELUMAB · ATEZOLIZUMAB
· PEMBROLIZUMAB · NIVOLUMAB
Endothelial cell
PLK1
TKM-080301
ß-Cat
AKT
APC
VEGF
PDL1
PD1
RAF
mTOR
T-cell
MEK
MHC
TCR
DNA ANY Nucleus
IHAНА
-MITOCHONDRIA-
SOATI
MITOTANE
ADRENOCORTICAL CARCINOMA CELL
· NEVANIMIBE HCI
Linsitinib An inhibitor of IGF-IR and insulin receptor, was investigated in a double-blinded, randomized phase III study involving 139 participants (90 received linsitinib and 49 received a placebo) who failed one or more previous treat- ments. Unfortunately, linsitinib did not achieve any signifi- cant OS or PFS benefit (P=0.77 and P=0.30, respectively). Among the 90 patients in the linsitinib group, only 3 (3%) achieved a PR, and 14 (15.6%) showed SD [31].
Cixutumumab A recombinant human monoclonal antibody that targets IGF-1R, was investigated with mitotane as an ini- tial treatment for advanced ACC in a multicenter phase II trial. However, the trial was closed early because of poor accrual. Of 20 patients, 8 showed therapeutic benefits (1 PR and 7 SD, disease control rate 40%) with a median PFS of 6 weeks (range 2.66-48) [32]. Cixutumumab was also evaluated, in combina- tion with the mammalian target of rapamycin inhibitor tem- sirolimus, in patients with refractory ACC. Among 26 enrolled patients, 42% achieved SD, but there was no CR or PR [33].
Figitumumab A monoclonal antibody against IGF-1R, was exam- ined in 14 patients with treatment-refractory, metastatic ACC, of whom 8 exhibited SD, but there was no confirmed response [34].
Overall, the use of IGF-1R inhibitors in advanced ACC exhibits modest activity, at least, and hence not used in clini- cal practice.
VEGFR Tyrosine Kinase Inhibitors (TKIs)
In addition to the previously mentioned IGF, another growth factor, VEGF, is also known to be highly expressed
in ACC cells. It exerts its influence on cell growth through the VEGFR, affecting cellular proliferation [30].
Sunitinib Is an oral multikinase inhibitor targeting VEGFR1-2, c-KIT, PDGFR, and Fms-like tyrosine kinase 3. A phase II clinical trial investigating its efficacy in advanced ACC showed that only 5 of 35 patients achieved SD. The combined use of mitotane might negatively affect the response to sunitinib, considering that mitotane is an inducer of CYP3A4 that metabolizes sunitinib [35].
Dovitinib An orally administered multikinase inhibitor, is designed to act on fibroblast growth factor receptors, plate- let-derived growth factor receptors, and VEGF receptors. A phase II trial demonstrated no objective responses with dovitinib, although SD lasting for more than 6 months was observed in 23% of patients [36].
Axitinib A specific inhibitor targeting VEGFRs 1-3, was investigated in a phase II trial involving 13 patients who had previously undergone chemotherapy, with or without mito- tane, for metastatic ACC. Although there were no objective responses during the treatment, eight patients-maintained SD for more than 3 months. The median PFS and OS were 5.5 and 26.9 months, respectively. These survival durations suggest that some patients in the study had a relatively indo- lent form of the disease [37].
The efficacy of cabozantinib, an inhibitor of c-MET, VEGFR2, AXL, and RET, in 16 patients with progressive ACC was retrospectively investigated, of whom 3 achieved PR and 5 achieved SD, resulting in a median PFS and OS of 16 and 58 weeks, respectively [38]. A phase II trial of
cabozantinib involving 18 patients with advanced ACC reported ORR and DCR of 11% and 78%, respectively, and the median PFS and OS were 7.2 months (95% CI 3.3- 9.2 months) and 23.9 months (95% CI 12.9 to not reached) [39.].
Currently, VEGFR TKIs are the drugs being investigated most extensively as monotherapy or in combination with immunotherapeutics.
SOAT1 Inhibitor
Nevanimibe HCl (ATR-101), an oral adrenal-specific SOAT1 inhibitor, could diminish adrenal steroid output at minimal doses and caused cellular apoptosis in adrenocorti- cal cells and canine adrenal cortex at elevated doses [40]. In a phase I study involving 63 patients with metastatic ACC who had previously failed systemic chemotherapy, nevanimibe was administered orally with doses ranging up to~6000 mg BID, but no CR or PR were observed, although 27% of the patients had SD at 2 months. The most common adverse events (AEs) were related to the gastrointestinal sys- tem (76%), including diarrhea (44%) and vomiting (35%). Other AEs observed included fatigue (30%), dysuria (22%), and dyspnea (16%). Despite its safety, the current formula- tion of nevanimibe demonstrated limited efficacy in patients with advanced ACC because of unattainable exposure levels required for an apoptotic effect [41].
PI3Ky Inhibitor
Eganelisib (IPI-549) is an orally consumed PI3Kỵ inhibi- tor with remarkable anticancer properties, both individually and when combined with PD-1/PD-L1 inhibitors, as demon- strated in preclinical research. A phase 1/1b study evaluated the safety and tolerability of eganelisib as monotherapy and in combination with nivolumab, although one patient with ACC achieved PR in the dose escalation cohort with com- bination treatment, none out of five patients with advanced ACC showed response in the dose expansion cohort [42].
PLK-1 Inhibitor
PLK1 is prominently expressed during cell division, and its elevated expression is observed in various cancer types [43]. TKM-080301 is a PLK1-targeted small inter- fering RNA (siRNA). In a phase I/II study, 16 patients received treatment doses of 0.6 or 0.75 mg/kg/week for up to 18 cycles, and tumor responses were evaluated in 8 of them. A significant decrease in tumor size was detected in a 51-year-old man with metastatic intraperi- toneal nonfunctional ACC, and the removed tumor exhib- ited almost total necrosis. Several patients stopped the
treatment for various reasons, including disease progres- sion, and frequently reported side effects that included fever, chills, back discomfort, reactions to infusion, and nausea [44].
Monotherapy with targeted therapies has not demon- strated significant efficacy as initially anticipated. In con- trast to cancer types where other targeted therapies show effectiveness, ACC is thought to be driven by a more com- plex interplay of driver mutations. Therefore, it is hoped that ongoing research into various combination therapies may yield more promising results for ACC in the future.
Immune Checkpoint Inhibitors
Recent research has confirmed that PD-L1 expression occurs in both ACC cells membrane and immune cells [45]. Based on this finding, there’s an expectation that immune check- point inhibitors may be effective in ACC, leading to several ongoing studies in this area.
Pembrolizumab
A phase II study included 16 eligible patients for salvage therapy in cases of advanced ACC. The primary endpoint, the nonprogression rate (NPR) at 27 weeks, was evalu- ated in 14 patients, with 5 of them showing progression- free status at that point, resulting in a 36% NPR (with the 95% confidence interval being 13-65%). According to irRECIST criteria, the radiologic response revealed a 14% ORR, and among the 14 patients evaluated, 57% experienced clinical benefit. Although treatment-related adverse events were generally manageable, two grade 3 immune-related adverse events, viz., colitis and pneumo- nitis, were remarkably significant. PD-L1 expression was not detected in all the 14 evaluated patients, and most of them exhibited microsatellite-SD [46]. In another phase II trial, 39 patients with advanced ACC received pembroli- zumab. The ORR and DCR were 23% and 52%, respec- tively, and the mPFS and mOS were 2.1 months (95% CI 2.0-10.7 months) and 24.9 months (95% CI 4.2 months to not reached), respectively. The response was independ- ent of PD-L1 status, and no relationship was observed between any particular somatic alteration and response [47 .. ].
Nivolumab
A phase II trial involving 10 patients with metastatic ACC who did not respond to previous treatments reported that 1 patient had an unconfirmed PR and 2 patients had SD. The median PFS and OS were 1.8 months (95% CI 0.1-4.3 months) and 21.2 months (95% CI 0.1 to more than 25.6 months), respectively [48].
| Setting | NCT No (trial name) | Phase | Drugs | Targets | Primary end point | Status |
|---|---|---|---|---|---|---|
| 1 st (or later) lines | NCT05634577 | II | Pembroli- zumab + Mitotane | PD-1 | ORR | Recruiting |
| 1 st line | NCT05913427 (PESETA) | II, randomized | EDP + mito- tane +-Megestrol Acetate vs. EDP + mito- tane + placebo | ORR | Recruiting | |
| 1st line | NCT06006013 | II | Atezolizumab + Cabo- zantinib | PD-L1 cMET, VEGFR2, AXL, and RET | ORR | Not yet recruiting |
| 1st line (cohort 2a) and 2nd line (cohort 2b) | NCT04187404 (SPENCER) | I/II | EO2401 + Nivolumab | Tumor vaccine PD-1 | Safety ORR | Recruiting |
| 2nd (or later) lines | NCT05036434 (ACCOMPLISH) | II | Pembrolizumab + Len- vatinib | PD-1 VEGFR1, VEGFR2 and VEGFR3 | ORR | Recruiting |
| 2nd line | NCT04318730 | II | Camrelizumab + Apat- inib | PD-1 VEGFR2 | ORR | Recruiting |
| 2nd line | NCT03612232 (CaboACC) | II | Cabozantinib | cMET, VEGFR2, AXL, and RET | PFS at 4 months | Recruiting |
| 2nd line | NCT03370718 | II | Cabozantinib | cMET, VEGFR2, AXL, and RET | PFS at 4 months | Active, not recruting |
| 2nd (or later) lines | NCT06041516 | I | ADCT-701 | Antibody-drug conjugate, com- posed of a mono- clonal antibody targeting DLK-1 conjugated to SG3199 | Safety | Not yet recruiting |
| 2nd (or later) lines | NCT03746431 | I, II | [225Ac]-FPI-1434 | Radioimmunocon- jugate consisting of a monoclo- nal antibody targeting IGF-1R conjugated to an alpha-emitting radionuclide actinium-225 | Safety ORR | Recruiting |
ACC Adrenal cortical carcinoma; PD-1 Programmed cell death-1; PD-L1 Programmed cell death-ligand 1; c-MET c-mesenchymal-epithelial transition factor; VEGFR Vascular endothelial growth factor receptor; AXL Anexelekto; RET Rearranged during transfection; DLK-1 Delta like protein-1; IGF-1R Insulin like growth factor 1 receptor; ORR Objective response rate; PFS Progression free survival
Avelumab
A phase Ib trial that enrolled 50 patients with metastatic ACC showed that 3 patients achieved PR, and 21 patients had SD as their response, resulting in an ORR of 6.0% and a DCR of 48.0%. The median PFS was 2.6 months (95% CI 1.4-4.0), and the median OS was 10.6 months (95% CI 7.4-15.0) [49].
Nivolumab Plus Ipilimumab
The prospective, multicenter clinical trial CA209-538 evalu- ated the efficacy and safety of nivolumab plus ipiliumumab
in patients with advance rare cancers. Six patients with advanced ACC were enrolled, and the results revealed ORR and DCR of 33% and 66%, respectively [50].
In another multicohort phase II trial that evaluated the efficacy of nivolumab and ipilimumab in patients with advanced rare genitourinary cancers, 16 patients with ACC were included, and the response rate and DCR were found to be 6% and 50%, respectively [51].
Overall, immune checkpoint inhibitors demonstrated inconsistent results across trials and drugs. The exact rea- sons for these outcomes are not yet fully understood. ACC tends to have a lesser extent of immune cell infiltration
compared to other cancer types. Additionally, ACC is per- ceived to have a lower immunogenic property compared to other solid cancers. It is hypothesized that the intratumoral glucocorticoid concentration is postulated to be high due to the activation of the production process, regardless of serum levels, and high glucocorticoid in tumor microenvironment might be associated with less efficient immune cell function [52]. However, there was an indication that immunotherapies might work in at least some subset of advanced ACC. Cur- rently, immunotherapies are under investigation in advanced ACC, especially as a combination with VEGFR TKIs.
Combination Therapy
Lenvatinib + Pembrolizumab
A retrospective review of lenvatinib/pembrolizumab as a salvage treatment for eight patients with advanced ACC reported that six (75%) and five (62.5%) patients had dis- ease progression upon previous therapy with immune check- point inhibitors and multikinase inhibitors, respectively. The median PFS was 5.5 months (95% CI 1.8 to not reached). Among these patients, two (25%) achieved PR, one (12.5%) had SD, and five (62.5%) experienced PD. Importantly, none of the eight patients had to discontinue therapy due to adverse events [53].
Cabozantinib + Atezolizumab
A prospective basket phase II trial was conducted on 93 patients, of whom 24 had ACC. The ORR was 8.3%, with a median PFS of 2.9 months (95% CI 2.8-5.7) for those with ACC. Adverse reactions of grade ≥ 3 were observed as fatigue (7.5%), neutropenia (6.5%), and increase in liver enzyme levels (6.5%). Two patients died due to drug-induced ischemic stroke and pancreatitis [54.].
Ongoing Studies
Various studies on combination therapies are being con- ducted for advanced ACC, and in addition, research is ongoing on antibody-drug conjugates (ADCs) and cancer vaccines targeting solid tumors, including ACC (Table 2).
Conclusion
Advanced ACC remains a challenging disease to treat. Although surgery is the mainstay of treatment for localized disease and some advanced cases, the high rate of recurrence and limited effective systemic therapies for advanced disease make it crucial to understand the disease biology better and
identify novel therapeutic targets. The genomic landscape of ACC has provided some insights into the pathogenesis and potential therapeutic targets. Combination therapies of mitotane with either cytotoxic agents or targeted agents, may provide a higher efficacy, but it comes at the expense of increased toxicity. Immunotherapies with PD-1 inhibitors have demonstrated potential but with variable results. Com- bination therapies of targeted agents with immunotherapies, such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab, comprise an active investigational area. Overall, although there are multiple avenues being inves- tigated for advanced ACC treatment, there remains a clear need for further research to establish robust and effective therapeutic strategies. An international collaboration is essential in conducting translational research and clinical trial in orphan diseases like ACC.
Author contributions C.P. and I.P. made substantial contributions to the conception and design of the work, and wrote the main manuscript test. C.P. prepared figure 1. C.P., I.P., and J.L. made interpretation of clinical trial data S.Y., T.Y., and J.L. revised it critically All authors reviewed the draft and approved the version to be published.
Funding This article is supported in part by grants from the National Cancer Center, Korea (NCC-2110300).
Declarations
Competing Interests The authors declare no competing interests.
Conflict of Interest The authors have no competing interests to declare that are relevant to the content of this article.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References
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