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Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?
Valentina Cremaschi, Andrea Abate, Deborah Cosentini, Salvatore Grisanti, Elisa Rossini, Marta Laganà, Mariangela Tamburello, Antonella Turla, Sandra Sigala & Alfredo Berruti
To cite this article: Valentina Cremaschi, Andrea Abate, Deborah Cosentini, Salvatore Grisanti, Elisa Rossini, Marta Laganà, Mariangela Tamburello, Antonella Turla, Sandra Sigala & Alfredo Berruti (2022) Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?, Expert Opinion on Pharmacotherapy, 23:12, 1413-1424, DOI: 10.1080/14656566.2022.2106128
To link to this article: https://doi.org/10.1080/14656566.2022.2106128
Published online: 03 Aug 2022.
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Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?
Valentina Cremaschia*, Andrea Abate @Db*, Deborah Cosentinia, Salvatore Grisantia, Elisa Rossinib, Marta Laganàa, Mariangela Tamburellob, Antonella Turlaª, Sandra Sigalab and Alfredo Berrutia
aMedical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy; bSection of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
ABSTRACT
Introduction: Surgery, followed or not by adjuvant mitotane, is the current mainstay of therapy for patients with early-stage adrenocortical carcinoma (ACC). Mitotane, either alone or in association with EDP (Etoposide-Doxorubicin-Cisplatin) combination chemotherapy, is the standard approach for patients with metastatic ACC.
Areas covered: The activity of newer cytotoxic drugs, radioligands, targeted therapies, and immu- notherapy, both in preclinical and clinical studies, will be reviewed in this paper.
Expert opinion: ADIUVO trial revealed that the administration of adjuvant mitotane is not advanta- geous in patients with good prognosis. Future strategies are to intensify efforts in adjuvant setting in patients with high risk of relapse. In patients with advanced/metastatic disease, modern targeted therapies have shown significant cytotoxicity in preclinical studies; however, studies in ACC patients reported disappointing results so far. The absence of targeted agents specifically inhibiting the major molecular pathways of ACC growth is the main cause of the failure of these drugs. Since ACC is often antigenic but poorly immunogenic, the results of immunotherapy trials appeared inferior to those achieved in the management of patients with other malignancies. Radioligand therapy may also be a promising approach. Combination of chemotherapy plus immunotherapy could be interesting to be tested in the future.
ARTICLE HISTORY Received 26 April 2022 Accepted 22 July 2022
KEYWORDS Adrenocortical carcinoma; chemotherapy; immunotherapy; mitotane; targeted therapy; theragnostics
1. Introduction
Adrenocortical carcinoma (ACC) is a rare aggressive malig- nancy with an annual incidence of 0.7-2 cases per million people per year [1,2]. Surgery is the mainstay of therapy however, because of the rarity of this disease, ACC diagnosis is often delayed and only a half of patients are amenable to surgical resection with radical intent at first diagnosis [2,3].
Sixty percent of ACC patients have hormone secreting tumors, mainly hypercortisolism (Cushing syndrome) plus/ minus hyperandrogenism [2]. Therefore, the goal of the treat- ment of this disease is the control of both tumor growth and hormone hypersecretion [4,5].
The only pharmacological approach approved by FDA and EMA for the treatment of ACC is mitotane, a drug derived from dichlorodiphenyltrichloroethane (DDT) whose mechanism of cytotoxicity on ACC cells is unknown [6-8]. There is repeated evidence in the literature showing that the drug is fully active when it reaches plasma concentrations above/equal 14 mg/L, while values greater than 20 mg/L are more frequently asso- ciated with central neurological toxicity [9-11]. Mitotane has an adrenocytolytic effect causing adrenocortical insufficiency. So the drug should be administered in association with glu- cocorticoid replacement [8,12]. International guidelines
recommend prescribing mitotane in the adjuvant setting in radically operated patients who are at high risk of relapse [3]. As regards patients with advanced/metastatic disease, mito- tane is prescribed as single agent in patients with oligometa- static disease with an indolent course [13] in association with local regional approaches such as radio-frequency ablation (RFA), trans-arterial chemoembolization (TACE), or radiother- apy [3]. In other cases, the drug is administered in association with EDP chemotherapy (etoposide, doxorubicin, and cispla- tin) [14-16]. There are no standard treatment options in patients progressing to EDP-M. The gemcitabine and capeci- tabine regimen, although occasionally effective, has not shown to improve patient outcome [17-19]. Therefore, few effective therapeutic options are currently available in patients with ACC and new therapeutic strategies are needed. The purpose of this review is to describe the results of new anti- neoplastic therapies both in preclinical studies and in ACC patients.
2. Drugs tested in preclinical studies
The amount of scientific publications testing preclinically drugs already clinically available or in development has been steadily increasing in the last five years.
Article highlights
· Current systemic strategies in the management of patients with adrenocortical carcinoma are adjuvant mitotane to be prescribed in radically operated patients with high risk of relapse and either mitotane alone or mitotane in association with Etoposide, Doxorubicin and Cisplatin (EDP-M) in patients with advanced/meta- static disease.
. ACC patients with low/intermediate risk of relapse after surgery (stage I-III, Ki67<10%) have a relatively good prognosis and may not need adjuvant mitotane.
. Currently, no molecular-targeted therapy has been shown to be effective in the management of patients with pre-treated metastatic ACC.
· Immunotherapy has shown better results than targeted therapy but for now very far from those obtained in other neoplasms in which this therapy is approved and in current use.
· As in other neoplasms, the theragnostic approach is interesting.
This box summarizes key points contained in the article.
2.1. Drug repurposing in ACC
The so-called drug repurposing or repositioning is playing an increasing role in identifying molecules potentially active in ACC [20]. Drug repurposing/repositioning represents a useful opportunity, since, due to the rarity of the disease, de novo drug development turns out to be an even longer and more complex process than in tumors characterized by a higher incidence. An example of studies dealing with drug repurpos- ing is provided, for instance, by the evidence of a cytotoxic role of statins in ACC (Table 1), usually given in clinics to counteract iatrogenic dyslipidemia induced by mitotane.
Although interesting, the main limitation of these studies lies in the statin concentration used, which may not always be achievable in patients with the clinic-approved doses [27]. Burn et al published a preclinical paper describing the activity of nevanimibe hydrochloride (ATR-101), which selectively inhi- bits adrenal cortex function, leading to apoptosis in adreno- cortical cells when administered at high doses. However, when this drug was investigated in a phase 1 study, the results were not satisfactory, also due to the difficulty in reaching effective blood concentrations in enrolled patients [28].
Our group demonstrated an antitumor activity of abirater- one acetate, a drug currently in use in metastatic prostate cancer. Our preclinical in vitro and in vivo studies on ACC models indicated that the mechanism of abiraterone cytotoxic effect was the increase in intracellular progesterone concen- trations [29,30], which could have an antineoplastic activity in ACC. This hypothesis was then validated by further studies demonstrating a direct cytotoxic effect of progesterone (alone or combined with mitotane) in different ACC cell mod- els, expanding the experimental tools available to study at preclinical levels a phenotypically heterogenous disease such as ACC [31,32]. Interestingly, we demonstrated that progester- one was able to reduce the ß-catenin nuclear translocation [31] in NCI-H295R cells that carry a ß-catenin pathogenic mutation [33]. Moreover, on the basis of the detectable, albeit scarce, the presence of estrogen receptor ß in different cellular models of ACC, we studied the combination of progesterone with the selective estrogen receptor modulator tamoxifen,
which did not show superior cytotoxicity compared to proges- terone alone [32]. These encouraging preclinical results of progesterone prompted us to design a randomized phase II clinical study aimed to explore the antitumor effect of the progestin analog megestrol acetate in ACC patients.
2.2. Chemotherapy drugs
The triple chemotherapy EDP is part of the first-line pharma- cological approach for advanced or not completely resectable ACC [3], indicating that ACC is responsive to alkylating agents such as platinum. Based on this premise, we recently evalu- ated the effect of trabectedin, endowed with the alkylating properties, in different ACC cell models. Our results demon- strated that trabectedin, either alone or combined with mito- tane, is cytotoxic in both primitive (NCI-H295R) or metastatic (MUC-1) cell lines as well in primary cell cultures established from metastatic patients [34]. Interestingly, we also observed that trabectedin cytotoxic effect in NCI-H295R cells was at least in part mediated by the reduction of ß-catenin nuclear traslocation [34]. The role of chemotherapeutic agents was further strengthened by the effect observed with taxanes and, in particular with cabazitaxel, which proved to be cyto- toxic in several ACC cell models, regardless of the presence of the P-gp efflux pump responsible for multidrug resistance [35].
2.3. Targeted therapy agents and immune check point inhibitors
Molecular screenings have provided some promising insights on proteins involved in the cell cycle as potential targets in the ACC treatment [36]. In particular, the CDK4 gene was found overexpressed in 62% of ACC samples [37]. Therefore, the cyclin dependent kinases (CDK) seem to be a druggable target in ACC. An overview of preclinical studies involving CDK inhi- bitor is presented in Table 1. Commercially available CDK inhibitors, such as palbociclib and ribociclib, as well as the non-commercially available alvocidib, either alone or in com- bination with other targeted therapies, demonstrated a clear cytotoxic effect on ACC cells in vitro. IGF (insulin-like growth factor) pathway is frequently mutated in ACC [38], being a potential target. The effect of molecules interfering with this pathway in the context of ACC has been under evaluation for several years both at preclinical and clinical level, although disappointing results have been reported in clinics [39]. Looking at the preclinical data, encouraging results were obtained using a combination approach of linsitinib with mTOR (mammalian target of rapamycin) inhibitors. In NCI- H295R cells and in its sub-clone HAC15, linsitinib showed an antiproliferative effect, which was increased by the combina- tion with sirolimus and everolimus [40].
As a relevant number of receptor tyrosine kinases were frequently found overexpressed in ACC [41], many preclinical ACC papers were focused on other tyrosine kinases inhibitors (TKIs). A recent study showed that sorafenib, an anti- angiogenetic drug, is able to induce apoptosis in NCI- H295R cells; however, authors did not recommend its use in patients with ACC, as a proportion of cells survived the cytotoxic effect of the drug [42]. Interesting data came from
| Drug | Preclinical model | Combined drugs | Key results | Reference |
|---|---|---|---|---|
| Rosuvastatin | NC-H295R cell line culture | Mitotane | Rosuvastatin-induced cell viability and apoptosis. Enhanced effect of the combination. | [21] |
| Simvastatin | NC-H295R cell line; (SW-13 and Y1 cell line *) cultures + NCI-H295R cell xenograft in athymic mice | - | Simvastatin-induced reduction of cell viability and estradiol production. Simvastatin-induced reduction of tumor volume and weight. | [22] |
| Palbociclib | NCI-H295R cell line + primary cell cultures | - | Expression of CDK4/6 target in all cell models. Cytotoxic effect in all cell models, regardless of the presence of pRb. | [23] |
| Palbociclib Ribociclib | NCI-H295R cell line (SW-13 cell line *) | - | Palbociclib-induced reduction of cell viability in both cell lines. Ribociclib effect was described only in SW-13 cells. Palbociclib- induction of GSK3 active form in NCI-H295R cells. | [24] |
| Alvocidib (clinical development) | NCI-H295R cell lines in 2D and 3D cultures + NCI-H295R cell xenograft in athymic mice | Carfilzomib | Alvocidib-induced antiproliferative and proapoptotic effects. In vivo lower tumor burden. Enhanced effect of the combination both in vitro and in vivo. | [25] |
| Palbociclib | NCI-H295R and MUC-1 cell lines | Linsitinib | Major sensitivity to palbociclib of cells expressing high levels of CDK4. Additive effect with linisitinib. | [37] |
| Ribociclib | NCI-H295R and MUC-1 cell lines + metastasis-derived primary cell cultures | Progesterone Mitotane | Ribociclib-induced cytotoxicity and reduction of proliferation rate. Enhanced effect of the combination with progesterone and/or mitotane. | [26] |
* SW-13 cells not express ACC biomarkers [102] while Y1 cells are a murine model od adrenal cortex [103]
ACC: adrenocortical carcinoma; CDK: cyclin dependent kinase; pRB: retinoblastoma protein
a study that evaluated the effect of another TKI, nilotinib, a multi targeted drug which inhibits the kinases BCR-ABL, KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11, and ZAK. In in vitro models of ACC, using both 2D and 3D cell cultures, authors demonstrated that mitotane was less effec- tive in 3D compared to 2D NCI-H295R cells, while nilotinib cytotoxic effect was superimposable in the two experimental cell models [43]. Interestingly, the 3D cultures represent an evolution of 2D cultures, toward a better, albeit simplified, representation of the in vivo setting, useful for drug screening.
Germano et al evaluated the effect of the mTOR inhibitor everolimus, the somatostatin analog pasireotide and mitotane in a combined setting. Pasireotide was previously used to inhibit hormonal secretion in ACC cells [44]. The results of this study underlined the everolimus ability to reduce the NCI- H295R cell viability; however, an antagonistic cytotoxic effect was observed when the drug was combined with mitotane and pasireotide. The authors recommended paying particular attention to combinations of targeted therapy agents with mitotane, to avoid a reduction in the activity of the former [45]. Finally, the immune checkpoint inhibitors (ICI) are the most promising immunotherapy agents in cancer pharmacol- ogy [46]. Due to its peculiar characteristics, in terms of immu- nogenicity and immunosuppressive milieu [47], identifying an effective immunotherapy approach in ACC is challenging. Lang and coll. developed for the first time a humanized ACC patient-derived xenograft mouse model, which may be useful to study immunotherapy in this rare malignancy [48]. Authors demonstrated that pembrolizumab treatment of humanized mice induces a significant tumor growth inhibition and an increased human CD8+ lymphocytes infiltrate. Interestingly, the patient from which the xenograted cells were derived was treated with pembrolizumab and a significant response and immune marker modifications, similar to those observed in the animal model, were observed. This advanced technical methodology makes possible to create an animal avatar for the individual patient [48]. However, authors themselves admitted that this approach is very expensive, time-
consuming, and difficult to apply routinely. This model any- way, together with the different experimental models of ACC developed over time, could allow the identification of a target population of patients potentially suitable to immunotherapy. Results from clinical trials of different ICIs in advanced ACC revealed that none of the commonly used predictive factors of immunotherapy (such as PD-L1, TMB, and TILs) are, in fact, good predictors of response.
2.4. Herbal drug and dietary supplements
Few papers focused on the evaluation of the effect of herbal drug and dietary supplements in preclinical models of ACC. Compounds or extracts tested are various and include, for example, curcumin [49,50], mentha longifolia extract [51], ori- ganum vulgare extract [52], and a vitamin D metabolite [53]. Interestingly, some of these papers also evaluated the effect of these compounds on the molecular pathways involved in ACC growth, such as the Wnt/B-catenin pathway. Even if it was not a preclinical study, it deserves to be mentioned in this context that the administration of herb artemisinin obtained a long- lasting disease response (12 months) in a metastatic heavily pretreated ACC patient [54]. The mechanism of antineoplastic effect of this herb could be blocking the activation of intracel- lular Wnt/B-catenin pathway.
3. Adjuvant clinical trials
Retrospective surgical series revealed that 40% to 70% of patients with stage I-III radically operated ACC are expected to undergo disease relapse, mainly within the first 2 years from surgery [55]. This provides a strong rationale for testing adju- vant therapies in this clinical setting. Given the rarity of this disease, the available literature data on the efficacy of adju- vant mitotane in patients with ACC relate to non-randomized retrospective studies. The most important study in this setting was an Italian-German one that compared the outcome of patients followed in centers who systematically administered
mitotane in adjuvant setting with the outcome of patients followed in centers adopting a post-surgical follow-up [56,57]. The results of all retrospective studies published so far, which were summarized in a published meta-analysis [2], show that the administration of adjuvant mitotane is asso- ciated with a homogeneous reduction in the risk of mortality of ACC patients.
On the basis of these data, international guidelines recom- mend adjuvant mitotane in ACC patients with a high risk of recurrence after surgery [2,3]; however, there are not clear recommendations for patients with low-risk disease. The ADIUVO trial was the first prospective multinational multicen- ter study that tested the efficacy of adjuvant administration of mitotane versus observation in ACC patients with low/inter- mediate risk of relapse after radical surgery (i.e. stage I-III and Ki67 < 10%). The study was interrupted prematurely due to poor accrual and the results, which were presented at inter- national conferences, showed that patients meeting the elig- ibility criteria of this trial had a good prognosis and 75% of them were free from progression at 5 years with surgery alone and therefore potentially cured. In this patient group, the ADIUVO study did not demonstrate a clear advantage of adjuvant mitotane administration in terms of both relapse- free survival (RFS) and overall survival (OS) [58].
The first efficacy data of adjuvant chemotherapy plus mitotane in ACC patients with high risk of relapse were recently published by Kimpel et al. In this retrospective multicenter cohort study, the outcome of 31 ACC patients treated with adjuvant platinum-based chemotherapy after radical resection was compared with that of a similar group of patients, not addressed to adjuvant chemother- apy, carefully selected by applying a propensity score matching on a control cohort of 268 patients. Patients included in this study had ENSAT stage IV or R1 resection, large tumor thrombus in vena cava and/or Ki67 expressed in >30% of neoplastic cells. Fourteen patients in the che- motherapy group and 29 patients in the control group experienced recurrence. The hazard ratio (HR) for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). Chemotherapy treatment was well tolerated, only one patient experienced a Grade 3 event with febrile neutropenia and mucositis, but there were no Grade 4 or Grade 5 adverse effects [59]. The results of this trial strengthen the rationale of 2 randomized prospective clin- ical trials: ACACIA (NCT03723941) and ADIUVO2 (NCT03583710) recruiting ACC patients at high risk of
relapse after surgery (Ki67 ≥ 10%), who are randomized to receive either mitotane alone or mitotane associated with four cycles of cisplatin plus etoposide.
4. New therapies for patients with advanced/ metastatic ACC
4.1. Chemotherapy and radionuclide therapies
Recently, two clinical trials investigated the effects of temozo- lomide (TMZ) and cabazitaxel in ACC patients (Table 2), follow- ing the encouraging results of preclinical studies.
TMZ is an oral DNA-alkylating agent widely used in treat- ment of brain glioblastomas. The rationale for testing temo- zolomide in ACC patients derived from a preclinical study which evaluated the cytotoxic effects of this drug on ACC cells in vitro and showed that it caused a potent antitumor response with inhibition of cell growth, induction of apoptosis, and direct cytotoxic and cytostatic effects [60]. In a retrospective multicenter Italian trial, single-agent TMZ appeared to be active in the management of pretreated ACC patients obtaining an interesting disease response rate in 35.8% of patients. However, the observed progression-free survival (PFS) and OS were relatively short (3.5 and 7.2 months, respectively), suggesting a limited efficacy of this drug [61]. Noteworthy, TMZ obtained a long-lasting exceptional response as second-line approach in a young ACC patient with huge disease extent and poor performance status [62]. These data suggest that the drug may occasionally be very effective in ACC patients. MGMT methylation assessment could be used for response prediction, although this marker was not tested in the previously mentioned patient.
Cabazitaxel is a taxane that has been shown to be effective in MDR1 expressing tumors, such as ACC [63]. This rationale, together with the results of a recently published in vitro study by our group that has demonstrated that cabazitaxel is active in reducing ACC cell viability [35], led to testing this drug in the treatment of ACC patients. CabACC was a phase II trial recently conducted by our group with the aim of testing the activity of cabazitaxel as a second/third line in patients with metastatic ACC. The results of this study, recently published, showed that the drug was poorly effective, achieving only disease stabilizations in 9 out of 25 recruited patients. Median PFS and OS were short (1.5 and 6 months, respec- tively). On the basis of these disappointing results, cabazitaxel will not further developed in ACC patients [64].
| Drug | Setting | Phase | Nº patients | Results | PFS months | OS months | Reference |
|---|---|---|---|---|---|---|---|
| Temozolomide | Advanced ACC progressing to EDP-M | Retrospective | 28 | 1 CR, 5 PR, 4 SD | 3.5 | 7.2 | [61] |
| Cabazitaxel | Advanced ACC progressing to EDP-M | II | 25 | 9 SD | 1.5 | 6 | [64] |
| 68Ga-DOTATOC and | Advanced ACC progressing to EDP-M | 2 | overall disease control of 4 and 12 months | na | na | [66] | |
| 177 Lu-DOTATATE | |||||||
| 123I-IMAZA and | Advanced ACC progressing to EDP-M | 13 | 2 PR, 3 SD | 14.3 in responder patients | 14.1 | [67] | |
| 131I-IMAZA |
ACC: adrenocortical carcinoma; CR: complete response; EDP-M: etoposide, doxorubicin, cisplatin + mitotane; OS: overall survival; PFS: progression free survival; PR: partial response, SD: stable disease
Theragnostics is a term derived from a combination of the words therapeutics and diagnostics. In this emerging field of medicine, drugs and/or techniques are uniquely combined to simultaneously or sequentially diagnose and treat medical conditions. The peptide receptor radionuclide therapy (PRRT) with the diagnostic tracers 68Ga-DOTATOC and the subse- quent therapeutic molecule 177Lu-DOTATATE is one of the first ‘theragnostic approach’ of targeting somatostatin recep- tors (SSTRs) in patients affected by neuroendocrine tumors. As SSTRs are expressed in more than 50% of ACC cells [45,65,66], this represents the rationale for testing this theragnostic approach in ACC patients. In a recently published experience involving 19 ACC patients with pretreated metastatic ACC, eight (42%) patients displayed radiometabolic uptake of any- grade intensity with focal and limited distribution, but two (11%) patients displayed strong uptake in multiple lesions. Both patients were addressed to PRRT with 177 Lu-DOTATATE and obtained an overall disease control lasting 4 and 12 months, respectively (Table 2) [66]. On the basis of these results, the PRRT with 177 Lu-DOTATATE deserves to be further tested in patients with ACC whose neoplasm strongly expresses somatostatin receptors.
123I-IMAZA scan is a diagnostic technique that uses a molecule (R-1-[1-(4-[123I] iodophenyl) ethyl]-1 H-imidazole- 5-carboxylic acid azetidinyl amide) that targets 11-B- hydroxylase and aldosterone synthase.
The diagnostic scan with 123I-IMAZA allows for the predic- tion of whether an ACC patient will benefit from 131I-IMAZA radionuclide therapy after determination of an individualized dose by dosimetry. In a single institution experience involving 69 ACC patients, 27 of them showed uptake of 123I-IMAZA in all known lesions. 13 patients were treated with 131I-IMAZA, in 12 patients follow-up was available, five patients revealed stable disease according to RECIST criteria. Median PFS was 14.3 months and median OS was 14.1 (Table 2) [67].
4.2. Targeted therapies
Several phase I-II trials evaluated the effects of molecular targeted drugs as second-line approaches in the management of ACC patients (Table 3).
One-third of ACCs overexpress epidermal growth factor receptor (EGFR) and EGFR molecular pathway has an impor- tant role in adrenal development and tumorigenesis [68]. The activity of EGFR inhibitors was tested in two prospec- tive clinical trials involving advanced pretreated ACC [69,70]. Two oral EGFR inhibitors, gefitinib and erlotinib, have been administered in 19 and 11 patients, respectively, either as monotherapy (gefitinib) or in combination with gemcitabine (erlotinib). Unfortunately, in both studies, no patients achieved partial remission of the disease. A minor response was obtained in only one patient receiving erlotinib plus gemcitabine who had the lowest expression of EGFR. This underlines the absent relationship between EGFR expression and efficacy of antineoplastic therapies containing EGFR inhibitors in ACC.
The angiogenetic pathway of vascular-endothelial growth factor (VEGF) is another possible target for molecular therapies in ACC patients, as heparinase-1 (HPA-1), VEGF, and vascular- endothelial growth factor receptor-2 (VEGFR-2) are signifi- cantly elevated in these patient’s serum and in tissue samples [71]. The anti-angiogenetic monoclonal antibody bevacizumab has been tested in association with oral capecitabine in a small phase II trial. The results were disappointing since no patient experienced disease response [72]. Sorafenib was studied in association with metronomic paclitaxel, as a second/third line in advanced ACC; the trial was prematurely interrupted, as tumor progression was observed in all patients [73]. No objec- tive responses according to RECIST criteria were obtained with the use of axitinib, a potent selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, in advanced pre-treated ACC patients [74], while sunitinib in the same setting showed a negligible
| Target | Drug | Setting | Phase | Nº patients | Results | PFS months | OS months | Reference |
|---|---|---|---|---|---|---|---|---|
| EGFR | Gefitinib | Advanced pretreated ACC | II | 19 | No disease response | na | na | [69] |
| EGFR | Erlotinib + gemcitabine | Advanced pretreated ACC | II | 10 | 1 minor response | na | na | [70] |
| Angiogenesis | Bevacizumab + capecitabine | Advanced pretreated ACC | II | 10 | No disease response | 1.96 | 4.13 | [72] |
| Angiogenesis | Sunitinib | Advanced pretreated ACC | II | 36 | 5 patients SD > 4 months | 2.8 | 5.4 | [75] |
| Angiogenesis | Sorafenib + weekly paclitaxel | Advanced pretreated ACC | II | 10 | No disease response | na | na | [73] |
| Angiogenesis | Axitinib | Advanced pretreated ACC | II | 13 | No disease response | 5.48 | > 13.7 | [74] |
| Angiogenesis | Cabozantinib | Advanced pretreated ACC | Retrospective | 16 | 3 PR, 5 SD | 3.73 | 13.53 | [76] |
| IGF-1 R | Figitumumab | Advanced pretreated ACC | I/II | 14 | 8 patients SD ≥ 3 months | na | na | [77] |
| IGF-1 R + mTOR | Cixutumumab + Temsirolimus | Advanced pretreated ACC | II | 26 | 11 patients SD > 6 months | na | na | [78] |
| IGF-1 R | Linsitinib | Advanced pretreated ACC | III | 139 | no differences between the therapy arm and the placebo one | 1.47 | 10.77 | [39] |
| Immune modulators | Thalidomide | Mitotane - pretreated ACC | Retrospective | 27 | 2 SD | 2.61 | 8.49 | [80] |
ACC: adrenocortical carcinoma; EGFR: receptor of the epidermal growth factor; IGF-1 R: type 1 receptor of the insulin-like growth factor; mTOR: mammalian target of rapamycin; OS: overall survival; PFS: progression free survival; PR: partial response; SD: stable disease
activity, i.e. 14% of disease stabilization and no responses [75]. Most interesting results, among angiogenesis inhibitors, were obtained from cabozantinib, a TKI inhibitor targeting c-Met, VEGFR-2, AXL, and RET. This molecule obtained three objective responses and three stable diseases in 16 pretreated ACC patients [76]. These results provided the rationale for the design of phase II trials that is still recruiting (NCT03612232).
IGF pathway is one of the most promising targets for future pharmacotherapy in ACC patients. Genetic alterations in this pathway were observed in most of ACCs; in particular, IGF-2 overexpression is observed in more than 85% of cases [38,68]. Inhibition of this molecular pathway was associated with rele- vant cytotoxicity on ACC cells in preclinical studies [40]. A phase I/II trial studied the effects of figitumumab on che- motherapy-refractory ACCs. Fifty-seven percent of patients had stable disease and hyperglycemia was the most common adverse effect [77]. A subsequent trial investigated the effects of cixutumumab combined with the mTOR inhibitor temsiro- limus on advanced pretreated ACCs. Almost half patients experienced stability of disease for at least 6 months during the trial, suggesting that the combination of IGF and mTOR inhibitors can be a good option for future ACC therapy [78]. These promising results of IGFR inhibitors in small phase II studies are in contrast with the results of a prospective multi- center multinational phase III study which tested the efficacy of linsitinib, a potent, oral small molecule inhibitor of both IGF- 1 R and the insulin receptor, versus placebo in patients with advanced, heavily pretreated ACC [39]. In this trial, the experi- mental drug failed to demonstrate superiority over placebo both in terms of PFS and OS. These results suggest that the IGF pathway, as a target of specific targeted therapies, deserves to be further explored in clinical trials. However, mitotane is a strong inducer of CYP3A4, a hepatic enzyme involved in the catabolismof several small molecules in use in medical oncology, and has a long half-life, remaining in the circulation in significant concentrations even weeks after its suspension. These characteristics can probably hinder the eva- luation of the efficacy of small molecular targeted therapies in pretreated ACC patients. In this sense, monoclonal antibodies against IGFR are not affected by mitotane concentrations and would be preferred in future trials.
Thalidomide has anti-inflammatory and anti-angiogenetic effects, and is used in cancer treatment, in particular in
management of multiple myeloma [79]. Its effect on mitotane- pretreated ACCs was studied in a retrospective trial published in 2019, showing poor results with only 7.5% of stable diseases and no RECIST radiological response [80].
4.3. Immunotherapy
Compared to targeted therapy, the studies that tested immu- notherapy with check point inhibitors (ICIs) seem to have obtained better results in terms of disease control in patients with metastatic ACC. As can be seen from the Table 4, seven phase I/II studies and one retrospective study have been published. The drugs used were PD-1 (programmed death protein 1) inhibitors in seven studies including pembrolizu- mab used in four studies [81-84] and nivolumab in three studies [85-87]. In one study, the drug used was the PDL-1 inhibitor avelumab [88]. In two studies, nivolumab was asso- ciated with the CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitor ipilimumab [86,87]. In one study, immunotherapy (pembrolizumab) was associated with a targeted therapy: len- vatinib a multiple antiangiogenetic inhibitor against the VEGFR1, VEGFR2, and VEGFR3 kinases [84].
Comparing the studies with immunotherapy with those that tested targeted therapies (Table 3), it seems that ICIs have obtained a greater number of objective remissions and disease stabilization, the PFS data does not seem to differ while the overall survival seems to favor immunotherapy. Certainly, such indirect comparisons are of limited value, how- ever it is clear that the results of immunotherapy in patients with ACC, although encouraging, are overall lower than those obtained by this therapeutic strategy in other neoplasms, in which immune check point inhibitors have been approved for clinical use.
Ongoing clinical trials involving ACC patients (Table 5) are testing combinations of inhibitory check points with targeted therapies or the double inhibition CTLA4 and PD-1, which was proven effective in other neoplasms [89].
Pathophysiological pathways involved in ACC onset and progression, such as ß-catenin gene activation, TP53 muta- tions are also mechanisms of resistance to immunotherapy [90,91]. Moreover, glucocorticoids hypersecretion in the major- ity of ACC patients contributes to generate an immunosup- pressive microenvironment [92,93]. Therefore, the future of
| Type of therapy | Drug | Setting | Phase | Nº patients | Results | PFS months | OS months | Reference |
|---|---|---|---|---|---|---|---|---|
| ICI (PD-1) | Pembrolizumab | Metastatic pretreated ACC | II | 16 | 2 PR, 7 SD | na | na | [83] |
| ICI (PD-1) | Pembrolizumab | Advanced ACC | II | 39 | 9 PR, 7 SD | 2.1 | 24.9 | [81] |
| ICI (PD-1) | Pembrolizumab | Advanced rare cancers, | II | 127 15 | 2 PR, 6 SD | na | na | [82] |
| including ACC | ACC | |||||||
| ICI (PD-1) + TKI | Pembrolizumab + Lenvatinib | Metastatic pretreated ACC | Retrospective | 8 | 2 PR, 1 SD | 5.5 | na | [84] |
| ICI (PD-1) | Nivolumab | Metastatic ACC | II | 10 | 1 unconfirmed PR, 2 SD | 1.8 | 21.2 | [85] |
| ICI (PDL-1) | Avelumab | Metastatic pretreated ACC | Ib | 50 | 3 PR, 21 SD | 2.6 | 10.6 | [88] |
| ICI (PD-1 + CTLA-4) | Nivolumab + Ipilimumab | Advanced rare genitourinary cancers, including ACC | II | 57 16 ACC | 1 PR, 7 SD | na | na | [86] |
| ICI (PD-1 + CTLA-4) | Nivolumab + Ipilimumab | Advanced pretreated ACC | II | 6 | 2 PR, 2 SD | na | na | [87] |
ACC: adrenocortical carcinoma; CTLA4: cytotoxic T-lymphocyte antigen 4; ICI: immune check-point inhibitors; OS: overall survival; PD-1: programmed death protein 1; PDL-1: ligand of programmed death protein 1; PFS: progression free survival; PR: partial response; SD: stable disease; TKI: tyrosine-kinase inhibitors
| Type of therapy | Drug | Setting | Phase | Status | Reference |
|---|---|---|---|---|---|
| Cancer vaccine ICI (PD-1) + antiglucocorticoid | Nivolumab + EO2401 Pembrolizumab + Relacorilant | Advanced unresectable or metastatic ACC Advanced unresectable or metastatic ACC, hormonally active | I/II I | Recruiting Recruiting | NCT04187404 NCT04373265 |
| ICI (PD-1) + TKI | Camrelizumab + Apatinib | Pretreated advanced unresectable or metastatic ACC | II | Not yet recruiting | NCT04318730 |
| ICI (PD-1 + CTLA-4) | Nivolumab + Ipilimumab | Advanced unresectable or metastatic rare tumors, including ACC | II | Recruiting | NCT02834013 |
ACC: adrenocortical carcinoma; CTLA4: cytotoxic T-lymphocyte antigen 4; ICI: immune check-point inhibitors; PD-1: programmed death protein 1; TKI: tyrosine-kinase inhibitors
ACC resistance to immunotherapy
WNT/ß-catenin pathway
Glucocorticoids hypersecretion
TP53 pathway
FH535
IWR-1
Metyrapone
Osilodrostat
PNU-74654
Relacorilant
AZD1775
immunotherapy in ACC is the adoption of therapeutic strate- gies that overcome the intrinsic resistance of this disease to immunotherapeutic drugs. It could be obtained combining immune check point inhibitors with molecular agents target- ing the mentioned pathways, such as WEE1 inhibitors (AZD1775) targeting TP53 [94] or Wnt/beta catenin inhibitors, namely, FH535, PNU-74654, or IWR-1 [95]. Anti-glucocorticoids, such as metyrapone [96], osilodrostat [97], or relacorilant [98], could also be useful to overcome ACC’s intrinsic immuno- resistance (Figure 1).
Chimeric antigen receptor T-cell therapy (CAR-T) targeting specific driver proteins represent the present and future of immunotherapy in the management of cancer patients. This strategy has been developed and actually in use in the man- agement of hematologic malignancies, non-Hodgkin lym- phoma in particular. Several trials involving patients with solid tumors are currently under way. Since Wnt/ß-catenin is one of the most frequently altered pathways in ACC, CAR-T directed against molecules involved in this pathway, that obtained interesting preclinical results in the management of hepatocellular carcinoma [99], could be a possible option also for ACC patients and deserve to be tested in phase I/II studies.
4.4. Bone health
About 7-10% of metastatic ACC have bone metastases [5]. A recent multicenter, multinational, retrospective study showed that bone metastases in ACC patients are associated
with high risk of adverse skeletal-related events, such as frac- tures and spinal cord compression [100]. Moreover, a retrospective cohort study, conducted in two reference cen- ters in Italy and France, which recruited ACC patients without bone metastases, revealed a high frequency of vertebra frac- tures associated with mitotane therapy plus/minus EDP [101]. These data suggest adopting appropriate preventive mea- sures, such as the prescription of bone resorption inhibitors (bisphosphonates and denosumab), in order to prevent adverse skeletal related events in ACC patients who are receiv- ing standard systemic therapy irrespective to the presence or not of bone metastases.
5. Conclusions
Several compounds have demonstrated cytotoxic activities against ACC in a preclinical setting; however, they often failed to confirm their efficacy when evaluated in clinical trials. In a heterogeneous tumor such as ACC, the use of multiple preclinical models, which can represent different aspects of the disease, is thus mandatory. Unfortunately, up to now, many studies report results obtained only with the NCI- H295R cell line (and eventually SW13 cells, that however do not express ACC biomarkers [102]). Pathophysiological limita- tions of this worldwide used model are now emerging [29,103-105] underlying the importance of the development of other cellular models of ACC, with molecular characteristics different from those already available, that could guarantee
more robust preclinical results and that could be more easily translatable into the clinic.
Strategies to improve the efficacy of current available therapies in the treatment of ACC should be implemented in two different setting: adjuvant and metastatic.
The results of the ADIUVO trial recently presented show that the referent drug for this disease, mitotane, substantially failed to demonstrate efficacy in reducing disease relapse rate, in patients with low-intermediate risk [58]. It should be noted, however, that these patients represent a subset with a relatively good prognosis, the great majority of them being potentially cured by surgery alone. So, the role of adjuvant mitotane is currently confined in patients at high risk of relapse, who represent about two-third of ACC patients.
As regard patients with advanced metastatic disease, the standard therapy still remains mitotane either alone or com- bined with chemotherapy. Other modern targeted therapies or immunotherapy drugs failed to demonstrate a substantial activity so far (Table 3, Table 4).
Targeted therapy had been administered in patients heav- ily pretreated with mitotane and this could represent an hin- drance, as mitotane is a potent stimulator of CYP3A4 which is involved in the metabolism of several drugs [8]. Because of its long elimination half-life and its great volume of distribution, mitotane’s effects can last for several weeks after the disconti- nuation of the therapy [106].
Among all the molecular-targeted agents tested in ACC, cabozantinib seems to be the more promising one and we are waiting for results of the still ongoing prospective trial (NCT03612232) [76].
An indirect comparison between trial results, which tested targeted therapy or immunotherapy, seems to show a potentially greater benefit of immunotherapy and therefore this strategy deserves to be further tested in the management of ACC. Moreover, immune check point inhibitors do not interfere with mitotane, and this should be an interesting point to keep in consideration.
Theragnostics represents the present and the future of med- ical oncology and could be also a possible option in the manage- ment of ACC patients. Small clinical trials demonstrated activity only in a limited subset of patients, but the advantage of ther- agnostic approach is the possibility to carefully select patients that could obtain the greater effect of the therapy.
6. Expert opinion
The management of ACC is challenging, since patients radi- cally resected are generally at high risk of relapse and the efficacy of systemic therapy in patient with advanced meta- static disease is limited.
Radically resected ACC patients are generally considered at high risk of relapse. However, ADIUVO trial has demonstrated that there is a group of patients, characterized by stage I-III, Ki67 < 10% and R0 disease, that have a low-intermediate risk of relapse and are potentially cured by surgery alone [58].
Future strategies are to intensify efforts in adjuvant setting with the aim to prevent disease recurrence and reducing the risk of death. In this respect, high-risk patients should be included in adjuvant trials ongoing worldwide with
chemotherapy plus mitotane (ADIUVO2 - NCT03583710 and ACACIA - NCT03723941). Of course, if a new drug will demon- strate to be efficacious in advanced disease, the subsequent step should be to test this compound in adjuvant setting.
Modern concept of adjuvant therapy suggests that patients to be addressed to a specific treatment should be selected not only on prognostic parameters but also on the basis of pre- dictive factors. Currently, the only predictive factor for mito- tane efficacy is the achievement and maintenance over time of mitotane levels within the so-called therapeutic range [11]. Future research should be oriented to search, on tumor sam- ple or on circulating DNA, molecular predictive factors of mitotane efficacy in adjuvant setting and the results of some gene expression such as ribonucleotide reductase large sub- unit (RRM1) need to be validated prospectively [107].
Novel therapies in advanced disease failed to demonstrate a substantial efficacy. This could be possible due to: 1) tested drugs were not efficacious, this implies that new drugs and new targets are needed to be explored, 2) heavily pretreated patients with mitotane plus chemotherapy could be an inade- quate setting to test new drugs, in particular targeted therapies.
These points underline the importance as well of having multiple preclinical experimental models for a heterogeneous disease such as ACC, which could success- fully allow an effective translation of preclinical results into clinic effectiveness.
Since no efficacious drugs have been introduced so far, the current strategy for the management of ACC patients is to use at best the available standard therapies (i.e. EDP plus mito- tane). A general oncologic rule is that cancer patients benefit from the delivery of full-dose chemotherapy; reducing the delivery of full chemotherapy dose intensity through treat- ment delays, dose reduction, or early termination of cancer treatment may increase the risk for recurrence and death. EDP- M is quite toxic, but ACC patients are often young and can tolerate full doses. Early tumor progression according to RECIST criteria may not necessarily mean treatment inefficacy and a combination of RECIST and CHOI criteria could provide a more reliable way to assess disease response and progres- sion [15,108]. Another interesting point for future research could be implementing strategies aiming to improve the effi- cacy of available standard therapy by adding new drugs. In this respect, combination of chemotherapy plus immunother- apy, that have demonstrated to be efficacious in other neo- plasm, such as lung and breast cancer [109,110], could be interesting to be studied also in ACC.
As regards immunotherapy, it is well known that adreno- cortical carcinoma is often antigenic but not immunogenic, due to intrinsic immune resistance linked to the activation of p53 and Wnt/Bcatenin pathway and to the cortisol hyperse- cretion that could characterize some kind of ACCs [91]. Strategies to overcome the intrinsic immune resistance of this disease need to be implemented.
Theragnostics is another important future strategy with the advantage of selecting patients who could benefit of the proposed treatment. Further studies exploring currently avail- able radioligands as well as new radioligands should be imple- mented in future.
Abbreviations
ACC: adrenocortical carcinoma
CAR-T: chimeric antigen receptor T-cell therapy
CDK: cyclin dependent kinase
CTLA4: cytotoxic T-lymphocyte antigen 4 DDT: dichlorodiphenyltrichloroethane EDP: etoposide, doxorubicin, cisplatin
EGFR: receptor of epidermal growth factor HPA-1: heparinase-1
HR: hazard ratio
ICI: immune checkpoint inhibitor
IGF: insulin-like growth factor
IGFR: receptor of insulin-like growth factor
mTOR: mammalian target of rapamycin
OS: overall survival
PD-1: programmed death protein 1
PDL-1: ligand of programmed death protein 1
PFS: progression free survival
PS: performance status PRRT: peptide receptor radionuclide therapy
RFA: radio-frequency ablation RFS: relapse free survival
RRM1: ribonucleotide reductase large subunit
SSTRs: somatostatin receptors
TACE: trans-arterial chemoembolization
TILs: tumor infiltrating lymphocytes
TKI: tyrosine kinases inhibitor
TMB: tumor mutation burden
TMZ: temozolomide
VEGF: vascular-endothelial growth factor
VEGFR: receptor of vascular-endothelial growth factor
Funding
This paper was funded by F.I.R.M. (Fondazione Internazionale di Ricerca in Medicina), Cremona, Italy.
Declaration of interest
A Berruti received honoraria for advisory and public speech from Novartis- AAA, Janssen, Bayer, Astellas, Amgen and research grants for ACC research from Janssen and Sanofi. S Sigala received research grants for preclinical studies from Novartis and Pharmamar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
ORCID
Andrea Abate ID http://orcid.org/0000-0002-0835-0916
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