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Systemic Management of Advanced Adrenocortical Carcinoma
Jeffery S. Russell1
Accepted: 16 July 2024 / Published online: 27 July 2024 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Opinion Statement
Adrenocortical cancer (ACC) is a rare and aggressive disease. Surgery has traditionally been the primary treatment for locally advanced disease with ongoing controversy around the optimal neoadjuvant and adjuvant treatment options. Unfortunately, local recurrence and the eventual development of metastatic disease is common and five-year survival rates are poor. While many trials have evaluated novel systemic agents to treat advanced adrenocortical cancer, only a few drugs have demon- strated any response at all. To date, only one drug, mitotane, is approved in the US for ACC and no regimen has clearly shown an increase in overall survival. In advanced metastatic or unresectable disease, data supports the first line regimen of EDP chemotherapy + mitotane as the primary treatment modality. In the second line, while data is limited, we would recommend consideration of immunotherapy using a PD(L)1 agent combined with a TKI/VEGF inhibitor or combination immunotherapy with PD1/CTLA-4 drugs. In all cases, we always prefer a clinical trial as available. This article reviews data from multiple studies evaluating novel systemic agents against ACC and discusses current systemic therapy combinations and ongoing clinical trials.
Keywords Adrenocortical Cancer . Adrenal Cancer . Systemic Therapy · Metastasis
Introduction
With an estimated incidence of approximately one case per million people, adrenocortical cancer (ACC) is a rare dis- ease in the US and across the world [1]. Often the disease is found incidentally, has a female preponderance, and can present at an advanced stage [2]. The innate biology of adre- nal cancers is complicated as some tumors secrete active hormones creating additional complicated medical issues for providers to manage in conjunction with a progressive malignancy. ACC is considered an aggressive cancer with high rates of recurrence after surgery and 5-year overall sur- vival rates of less than 50% [3].
Surgery is the mainstay of treatment for local disease with ongoing controversies around adjuvant radiation or adjuvant systemic therapy to improve outcomes [4]. Oligometastatic disease may be managed by surgery, radio-ablation, or by other means of local control often combined with systemic therapy.
Whether adrenal tumors are inherently resistan t to a variety of therapy types (chemotherapy, targeted therapy, or immunotherapy) or they can rapidly adapt to treatment pressures, no systemic treatment regimen has significantly demonstrated the ability to control the disease over the long term. Currently, only one drug is FDA approved in ACC and only one Phase 3 trial has shown a benefit with systemic therapy. While some tumors can be slow growing, intensive therapy may not be needed; conversely, fast growing tumors can be devastating to patients when not appropriately con- trolled. Improved systemic treatment strategies are needed, as well as a deeper understanding of the biology driving adrenocortical cancer, in order to improve outcomes for ACC patients.
Systemic Treatment Strategies: Neoadjuvant
An early case report from Rangel et al. described a patient with a primary left adrenocortical carcinoma with invasion into the inferior vena cava (IVC) with thrombus as well as invasion into neighboring organs [5]. While unresectable on presentation, this locally advanced ACC patient under- went salvage chemotherapy with etoposide, doxorubicin,
☒ Jeffery S. Russell jeffery.russell@hci.utah.edu
1 Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA
cisplatin, and mitotane for approximately six months. The patient was then able to undergo resection and no residual disease was found. Although the patient did develop pulmo- nary metastasis 18 months later, the patient was alive after 46 months with stable disease. As such, this study data sug- gested that neoadjuvant treatment for borderline resectable patients may be a potential therapy.
Previously, Kemp et al. performed a retrospective study of metastatic adrenal cancer patients with pulmonary metastasis who underwent pulmonary metastasectomy [6]. As no definitive treatment guidelines exist in the neoadju- vant or adjuvant setting for ACC management, their cohort contained a subset of patients that underwent neoadjuvant chemotherapy prior to pulmonary metastasectomy or adju- vant chemotherapy after surgery. Neither treatment had a significant impact on the long-term outcomes of patients.
More recently, Bednarski et al. evaluated a group of patients considered borderline resectable surgical cases in a retrospective study of advanced adrenocortical patients [7]. Fifty-three patients were considered as potential surgi- cal candidates. Thirty-eight patients went to immediate sur- gery and fifteen patients were identified as borderline resect- able cases and underwent neoadjuvant therapy with 80% receiving a combination of chemotherapy and mitotane, two patients mitotane alone, and one patient receiving chemo- therapy alone. Five of fifteen patients had a partial response to neoadjuvant treatment (33%); however, overall survival rates were similar between each group. In 2015, Dy et al. evaluated a retrospective cohort of 27 patients who under- went synchronous surgical resection for metastatic adrenal cancer [8]. Eight patients underwent neoadjuvant therapy and demonstrated a trend toward improved survival versus no prior neoadjuvant therapy. Adjuvant therapy after surgery also had a trend toward improved recurrence free survival at one year, but no significant improvement in overall survival.
Interestingly, in the pediatric setting, Lin et al. retrospec- tively reviewed cases of 49 children who underwent neoad- juvant treatment prior to surgical resection of adrenocorti- cal tumors [9]. Forty-four patients were identified with 33 moving to immediate surgical treatment and 7 patients who underwent neoadjuvant treatment with etoposide, doxo- rubicin, and cisplatin combination. Two partial responses (29%) were noted with the five additional patients having stable disease. Seventeen patients received the same chem- otherapy regimen as an adjuvant treatment after surgery. While responses were seen, it is unclear if data from a pedi- atric population can be directly applied to an adult ACC population.
While study data remains inconclusive in the neoadju- vant setting, given the above reports of approximately 30% response rates in patients treated with neoadjuvant chemo- therapy and mitotane combinations, a formal prospective trial is warranted.
Systemic Treatment Strategies: Adjuvant
The absolute benefit of systemic adjuvant treatments also remains unknown due to conflicting study reports. As mitotane has shown benefit in the metastatic setting, it has also been considered as a primary option in the adju- vant setting in disease with high-risk features (Ki67> 10%, Stage III disease, R1 resection). In 2007, Terzolo et al. performed a retrospective analysis of 177 adrenocortical carcinoma patients that underwent surgery and assessed responses in a mitotane treated group and an untreated control group [10]. Data indicated an improvement in recurrence free survival in the mitotane treated group com- pared to the untreated control group. However, in contrast, a retrospective study by Postelwait et al. in 2016 failed to find a significant improvement in recurrence free survival or in overall survival in high-risk resected ACC patients treated with adjuvant mitotane [11].
A published meta-analysis of 5 retrospective studies reporting on 1249 patients, however, did find a signifi- cant improvement in recurrence free survival and overall survival in post-surgical ACC patients receiving mitotane [12]. More recently, Terzolo et al. conducted a randomized phase 3 (the ADIUVO study) of low to intermediate risk post-surgical resection patients that were randomized to mitotane (target levels 14-20 mg/L) vs surveillance [13] **. Ninety-one patients were enrolled, and adverse events were as expected for mitotane treatment. Adjuvant mitotane did not significantly increase the 5-year recur- rence free survival in low to intermediate risk patients (79% vs 75%). The study was discontinued prematurely due to slow enrollment. However, with this new data, low to intermediate risk patients are unlikely to benefit from adjuvant mitotane treatment after surgical resection.
With respect to adjuvant chemotherapy, Kimpel et al. 2021 performed a retrospective case-controlled study of 31 patients undergoing platinum-based chemotherapy in the adjuvant setting [14]. Patients completed surgery and were stratified based on potential high-risk features [Resection status, Weiss score, Ki67]. Various platinum- based regimens were given, and most patients contin- ued oral mitotane. Median recurrence free survival was 20.5 months vs 9.1 months, significantly favoring the plati- num treated group. Adverse events were as expected for platinum-based therapy. However, a larger retrospective study conducted by Al-Asadi et al. evaluated 577 patients who underwent adrenalectomy for localized adrenal cancer [15]. 389 patients underwent adrenalectomy alone (67%) and 188 received adjuvant chemotherapy (33%). Analy- sis of data did not show any significant association with receiving adjuvant chemotherapy after surgical resection and overall survival. Currently, ADIUVO-2 is an ongoing
phase 3 trial looking at high risk post-surgical ACC patients being randomized to adjuvant mitotane versus a mitotane/chemotherapy combination (NCT03583710).
Systemic Treatment Strategies: Metastatic/ Unresectable (Table 1)
Steroidogenesis Inhibition
Mitotane
Mitotane is a derivative of dichlorodiphenyldichloroeth- ane (DDD), an insecticide developed in the 1960s that was determined to have adrenolytic effects on test animals [16]. Early clinical trials in ACC were run in the 1960s and in 1973, Lubitz et al. published a data summary of studies using first line mitotane in 115 advanced or unresectable ACC patients [17]. Measurable disease response was noted in 61% of patients with an overall clinical response of 54%. Mean survival was 10.3 months in disease responders versus 2.4 months in non-responders. In patients with functional adrenocortical tumors, those that secrete glucocorticoids or other hormones, 85% showed decreased steroid excretion and improvement in clinical symptoms. Moderate toxic- ity was noted typically with gastrointestinal or neurologic adverse events and adverse events increased with escalating doses of mitotane.
More recently, Megerle et al. retrospectively studied 127 patients with advanced adrenocortical cancer using more modern imaging response techniques (RECIST v1.1) to determine responses to mitotane monotherapy [18]. Over- all response rate (ORR) was determined to be 20.5% with progression free survival (PFS) of 4.1 months and over- all survival (OS) of 18.5 months. Blood levels of mito- tane were predictive of response with those patients with levels > 14 mg/L had improved PFS and OS compared to patients below 14 mg/L.
Nevanimibe
Nevanimibe (ATR-101) was developed as an inhibitor of sterol O-acyltransferase 1 (SOAT1) and was shown in non- clinical studies to decrease steroidogenesis and induce apop- tosis in ACC cells [19]. Smith et al. conducted a phase 1 study of nevanimibe in 63 metastatic ACC patients who had failed prior first line therapy [20]. Only a few adverse events or drug limited toxicities were detected and the MTD could not be defined. Unfortunately, no significant responses were noted.
Chemotherapy
EDP + Mitotane
In 2012, Fassnacht et al. demonstrated that a first-line combination of chemotherapy and mitotane (EDP-M) had improved overall response rates and PFS compared to a regimen of streptozocin and mitotane [S-M] [21]. The FIRM-ACT trial was the first randomized study in ACC and enrolled 304 patients across multiple countries. EDP combination chemotherapy consisted of Etoposide 100 mg/ m2 IV d2-4, Doxorubicin 40 mg/m2 IV d1, and cisplatin 40 mg/m2 IV d3-4 and was given with oral mitotane taken daily and targeted to levels of 14-20 mg/L. While overall survival was not statistically different between the two arms, ORR was 23.2% (EPD-M) vs 9.2% (S-M) and PFS was sig- nificantly improved at 5.3 months (EDP-M) vs 2.0 months (S-M). There was a slightly higher rate of adverse events in the combination chemotherapy arm, mostly associated with high rates of bone marrow toxicity and infectious complica- tions. As the only phase 3 study to date to show clinical ben- efit, EDP-M has become the default first-line therapy option.
Other Chemotherapy Regimens
A first-line regimen of docetaxel and cisplatin every 3 weeks was explored in a phase 2 study of metastatic adrenocorti- cal carcinoma patients [22]. The overall response rate was 21% with neutropenia being the most common grade 3-4 events. Median PFS was 3 months and median overall sur- vival 12.5 months.
A combination of gemcitabine and 5FU/capecitabine was used in the second or third-line setting in a retrospective study of 28 patients [23]. Mitotane therapy was maintained during the chemotherapy. Two patients demonstrated objec- tive responses (one complete response [CR] and one partial response [PR]). Median PFS was 5.3 months and median overall survival was 9.8 months. Toxicities were tolerable with grade 3-4 cases of cytopenias or mucositis noted. Capecitabine and Bevacizumab have also been used as sal- vage therapy in ACC. Wortmann et al. reviewed 10 patients treated with capecitabine 950 mg d1-14 of 21 and bevaci- zumab 5 mg/kg q21 days and evaluated for response [24]. None of the patient s had an objective response and median survival was 4.1 months. In 2016, Kroiss et al. explored the use of trofosfamide as salvage therapy in refractory ACC [25]. Twenty-seven patients were evaluated and experi- enced mostly grade 1-2 adverse events such as dyspnea, loss of appetite, and fatigue with only two grade 3-4 events noted. Thirteen patients were evaluable for response, with no patients experiencing treatment response, but 23% had stable disease. In the study, median progression free sur- vival of 2.0 months and median progression free survival
| Study | Agent(s) | ORR (%) | PFS (months) | OS (months) | Study Type, # of patients |
|---|---|---|---|---|---|
| [1st Line] | |||||
| Steroidogenesis Inhibition | |||||
| Lubitz et al. 1973 | Mitotane alone | 54 | n/a | 10.3 | Retrospective, n=115 |
| Megerle et al. 2018 | Mitotane alone | 20.5 | 4.1 | 18.5 | Retrospective, n=127 |
| Combination Studies | |||||
| Fassnacht et al. 2012 | EDP-M vs | 23.2 | 5.2 | 14.8 | Phase 3, |
| S-M | 9.2 | 2.0 | 12.0 | n=304 | |
| Urup et al. 2013 | Cisplatin, Docetaxel | 21 | 3.0 | 12.5 | Phase 2, n=19 |
| Lerario et al. 2014 | Cixutumumab, Mitotane | 5 | 1.5 | n/a | Phase 2, n=20 |
| [2nd Line] | |||||
| Steroidogenesis Inhibitors | |||||
| Smith et al. 2020 | Nevanimibe (ATR-101) | 0 | n/a | n/a | Phase 1, n=63 |
| Chemotherapy | |||||
| Sperone et al. 2010 | Gemcitabine and 5FU/Capecitabine | 7 | 5.3 | 9.8 | Retrospective, n=28 |
| Wortmann et al. 2010 | Bevacizumab and Capecitabine | 0 | n/a | 4.1 | Retrospective, n=10 |
| Kroiss et al. 2016 | Trofosfamide | 0 | 2.0 | 6.6 | Retrospective, n=21 |
| Kroiss et al. 2018 | Thalidomide | 0 | 2.8 | 9.1 | Retrospective, n=27 |
| Cosentini et al. 2019 | Temozolomide | 21 | 3.5 | 7.2 | Retrospective, n=28 |
| Lagana et al. 2022 | Cabazitaxel | 0 | 1.5 | 6.0 | Phase 2, n=25 |
| Ferrero et al. 2013 | Oral Etoposide or Oral Cyclophosphamide | 20 | n/a | n/a | Retrospective, n=5 |
| Immunotherapy | |||||
| Liu-Chittenden et al. 2015 | IL-13/Exotoxin A | 0 | n/a | n/a | Phase 1, n=8 |
| Carnerio et al. 2019 | Nivolumab | 10 | 1.8 | n/a | Phase 2, n=10 |
| Le Tourneau et al. 2018 | Avelumab | 6 | 2.6 | 10.6 | Phase 1b, n=50 |
| Habra et al. 2019 | Pembrolizumab | 13 | n/a | n/a | Phase 2, n=16 |
| Raj et al. 2020 | Pembrolizumab | 23 | 2.1 | 24.9 | Phase 2, n=39 |
| Klein et al. 2021 | Ipilimumab / Nivolumab | 33 | n/a | n/a | Phase 2, n=6 |
| Targeted Therapy | |||||
| Haluska et al. 2010 | IGF-R1 Ab | 0 | n/a | n/a | Phase 1, n=14 |
| Naing et al. 2013 | IGF-R1 Ab | 0 | n/a | n/a | Phase 1, n=26 |
| Fassnacht et al. 2015 | IGF-R1 oral vs | 0 | n/a | 10.8 | Phase 3, n=139 |
| Placebo | 11.9 | ||||
| Kroiss et al. 2012 | Sunitinib | 0 | 2.8 | 5.4 | Phase 2, n=29 |
| O'Sullivan et al. 2014 | Axitinib | 0 | 5.5 | 13.7 | Phase 2, n=13 |
| Kroiss et al. 2020 | Cabozantinib | 19 | 4.0 | 14.5 | Retrospective, n= 16 |
| Combination Studies | |||||
| Halperin D. et al. 2014 | Imatinib, Dacarbazine, Capecitabine | 17 | 8.8 | n/a | Phase 1, n=6 |
| Study | Agent(s) | ORR (%) | PFS (months) | OS (months) | Study Type, # of patients |
|---|---|---|---|---|---|
| Berrutti et al. 2012 | Paclitaxel/ Sorafenib | 0 | n/a | n/a | Phase 2, n=9 |
| Bedrose et al. 2020 Radioisotopes | Pembrolizumab/ Lenvatinib | 25 | 5.5 | n/a | Retrospective, n=8 |
| Hahner et al. 2012 | [131-Metomidate | 9 | 14 | 13 | Phase 1, n=11 |
| Grisanti et al. 2020 | Lu177-DOTATOC | n/a | n/a | n/a | Case reports, n=2 |
*ORR overall response rate, PFS progression free survival, OS overall survival
of 6.6 months were noted. A later study by Kroiss et al. used thalidomide in refractory adrenocortical cancer cases [26]. Twenty-seven patients were enrolled and treated with thalidomide. No objective responses were noted, PFS was 2.8 months and median OS was 9.1 months. Mild side effects of fatigue or GI distress were noted. Cosentini et al. evalu- ated the activity of temozolomide in refractory ACC cases [27]. A retrospective evaluation of twenty-eight patients treated with temozolomide 200 mg/m2 daily for 5 days for a 28-day cycle. Temozolomide was well tolerated with grade 1-2 toxicity events. ORR was noted to be 21% with median PFS of 3.5 months and overall survival of 7.2 months. Cabazitaxel was evaluated as a second- or third-line therapy in ACC [28]. Lagana et al. performed a phase 2 trial with 25 patients enrolled. No patients had an objective response, but stable disease was noted in 36% of patients. Median PFS was 1.5 months and median overall survival was 6.0 months. The regimen was tolerated well with grade 3 nausea and anemia noted.
An interesting study by Ferrero et al. demonstrated that low dose, metronomic chemotherapy in refractory ACC demonstrated a few responses in heavily pretreated patients with indolent disease [29]. Oral regimens of etoposide (50 mg daily) or cyclophosphamide (50 mg daily) in com- bination with mitotane were studied in a small group of 5 patients that progressed on a prior gemcitabine/capecitabine regimen. One partial response and one stable disease were noted. Overall, the drugs were well tolerated.
Immunotherapy
A novel phase 1 study was performed in metastatic ACC patients using a combination of IL-13 and a truncated form of Pseudomonas exotoxin A [30]. Eight patients were enrolled and the MTD was identified. No objective responses were noted, and safety was as expected. A limitation related to the study may have been the development of neutralizing antibodies against the exotoxin.
Le Tourneau et al. evaluated a subset of the JAVE- LIN solid tumor trial that enrolled refractory metastatic
adrenocortical cancer [31]. Fifty patients were treated with avelumab and mitotane treatment could be continued simultaneously. ORR was 6% with progression free sur- vival of 2.6 months and overall survival of 10.6 months. Two patients developed grade 3 immune related adverse events. While PDL1 expression in ACC is heterogeneous, high PDL1 expression in ACC subsets was noted to be associated with longer disease-free survival [32]. Carneiro et al. published a small phase 2 study with nivolumab in metastatic ACC patients in 2019 [33]. Ten patients with metastatic ACC who had previously been treated with first line platinum-based chemotherapy with or without mitotane or patients who had declined first line therapy were enrolled. The study notes one unconfirmed partial response, with median PFS of 1.8 months. Side effects were tolerable and as expected with single agent immune therapy. Habra et al. conducted a single-center phase 2 clinical trial of pembrolizumab in refractory adrenocorti- cal carcinoma patients [34]. Sixteen patients were enrolled and were treated with every 3 week pembrolizumab. ORR was determined to be 13%. Responses were independent of PDL1 status, microsatellite instability, or hormonal func- tion of the tumor. Side effects occurred at a low rate. Simi- larly, Raj et al. evaluated a cohort of thirty-nine patients with ACC and treated with every 3 week pembrolizumab [35] *. Objective response was 23%. Median progression free survival was 2.1 months and medical overall survival was 24.9 months. 13% of patients experienced grade 3-4 adverse events. In 2021, Klein et al. released data from CA209-538, a trial evaluating rare tumors, which included a subgroup analysis of patients with advanced adrenal cancer treated with combination immunotherapy agents, ipilimumab and nivolumab [36] **. Patients received ipili- mumab at 1 mg/kg IV q3 weeks × 4 doses with nivolumab at 3 mg/kg IV × 4 doses and then maintenance nivolumab 3 mg/kg IV q2 weeks until progression or toxicity. Six ACC patients were enrolled with two patients demon- strating partial responses (33%). Sixty-seven percent of patients experienced grade 3-4 toxicities on trial.
Targeted Therapy
Insulin-Like Growth Factor 1 Receptor (IGFR)
Insulin-like growth factor (IGF) overexpression and acti- vation of IGFR/mTOR pathways are common findings in adrenocortical cancer [37, 38]. Several strategies have been developed to target this signaling and survival pathway. Haluska et al. used the anti-IGF-1R antibody, figitumumab, in patients with refractory adrenal cancer in a phase 1 study [39]. Fourteen patients were enrolled with mild treatment related toxicities including hyperglycemia, nausea, fatigue, and anorexia. No objective responses were noted, but 57% had stable disease. In 2013, Naing et al. use a combination of IFG-1R antibody (cixutumumab) combined with the mTOR inhibitor temsirolimus in patients with advanced adrenocor- tical carcinoma [40]. Twenty-six patients were enrolled on weekly IV treatments of cixutumumab and temsirolimus. No objective responses were noted, but stable disease was seen in> 40% of patients. Toxicities were mostly commonly grade 1-2 with mucositis, thrombocytopenia, hypertriglyc- eridemia, and hyperglycemia being most common. A further study looked at the combination of cixutumumab and mito- tane as a first line therapy [41]. Lerario et al. enrolled twenty patients in a phase 2 single arm study, but the study was terminated due to slow accrual and limited efficacy. One par- tial response was noted for an ORR of 5%. Median PFS was determined to be 1.5 months. Toxicities were as expected for the drug combination. Linsitinib was developed as an oral inhibitor to IFG-1R and the insulin receptor. Initial studies of linsitinib indicated an appropriate safety profile and some preliminary evidence of anti-tumor activity [42]. Fassnacht et al. enrolled 139 advanced ACC patients in a phase 3 study and were randomized to Linsitinib or placebo [43]. No dif- ference in overall survival was noted. Side effects were mod- est and as expected.
VEGFİ/TKIs
In 2012, Kroiss et al. used sunitinib a multi-kinase inhibi- tor in refractory ACC patients [44]. Thirty-eight patients were enrolled with 29 available for evaluation. No objective responses were noted, but PFS was noted at 2.8 months and median overall survival was 5.4 months. The majority of adverse events were grade 1-2. O’Sullivan et al. conducted a phase 2 trial of refractory ACC patients using axitinib, a potent VEGFR inhibitor [45]. Thirteen patients were enrolled. No tumor responses were noted, but median PFS was determined to be 5.5 months with median overall sur- vival of 13.7 months. All patients experienced grade 1-2 toxicity with 77% experienc ed grade 3-4 events. Cabozan- tinib is an inhibitor of c-MET, VEFR2, RET, and AXL and is FDA approved in thyroid cancer, renal cancer, and liver
cancer. Kroiss et al. performed a retrospective analysis of 16 patients with progressive ACC treated with cabozantinib without concurrent mitotane [46] *. Nineteen percent of patients had a response, median PFS was 4.0 months and median OS was 14.5 months. Side effects were consistent with the known safety profile of cabozantinib.
EGFR Inhibition
Epidermal Growth Factor Receptor (EGFR) was found to be highly expressed (>90%) in adrenocortical patients and suggested the use of anti-EGFR agents to target ACC [47]. In 2008, a small study of 10 patients previously treated for metastatic adrenocortical cancer used a combination of the EGFR-inhibitor erlotinib and gemcitabine as a salvage ther- apy [48]. One minor response was described with a mean survival rate of 5.5 months. Toxicities were as expected. Previous use of erlotinib has been in cancers with mutated EGFR; in contrast, ACC demonstrates high surface expres- sion, but not necessarily mutation, thus, erlotinib may not have been the correct agent to target EGFR overexpression. Agents targeting the surface expression of EGFR may have more efficacy and should be further studied.
Combination Therapy
Combination therapy has become the standard for many tumors in the last few years. TKI therapy has shown some activity in adrenal cancer as discussed above and immuno- therapy checkpoint responses are more varied. However, by combining therapies, the tumor can be attacked by different modalities of killing and may help overcome resistance.
Towards this end, Berruti et al. conducted a phase 2 trial of weekly paclitaxel and sorafenib in refractory ACC patients [49]. Nine patients were eligible for evaluation, but due to tumor progression at the first assessment the trial was stopped with no responses noted. Treatment was well tolerated with expected side effects. In 2014, Halperin et al. developed a phase 1 clinical trial in endocrine malignancies using a combination of imatinib, dacarbazine, and capecit- abine as combination therapy [50]. One of six ACC patients had a partial response with PFS of 8.8 months. Toxicities included fatigue, edema, and dyspnea. More recently, Bed- rose et al. described a retrospective study of eight heavily pretreated metastatic ACC patients treated with a combina- tion of pembrolizumab and lenvatinib [51] **. This included patients with prior TKI or immune checkpoint therapy. Two of eight patients demonstrated a partial response for an ORR of 25%. Median progression free survival was 5.5 months and overall survival was not reported. Adverse events occurred as expected.
| NCT Identifier | Agent(s) | Status |
|---|---|---|
| NCT06066333 | Radiation, Pembrolizumab | Recruiting |
| NCT06006013 | Cabozantinib, Atezolizumab | Not yet recruiting |
| NCT05634577 | Pembrolizumab, Mitotane | Recruiting |
| NCT04318730 | Camrelizumab (PD1), Apatinib | Recruiting |
| NCT06041516 | ADCT-701 | Not yet recruiting |
| NCT06141369 | Individualized mRNA vaccine | Recruiting |
| NCT03746431 | [225Ac]-FPI-1434 | Recruiting |
*Reviewed on 4/8/24
Radioisotopes
Radiolabeled Metomidate has been used for adrenocorti- cal imaging for several years. I123-Metomidate appears to have high radiotracer uptake in primary and metastatic sites in adrenocortical patients. Hahner et al. developed an [131-Metomidate agent to target metastatic ACC lesions [52]. Forty-nine patients were evaluated by I123-Metomidate with thirteen patients exhibiting high radiotracer uptake within tumors. Eleven ACC patients underwent treatment with I131-Metomidate. One partial response (9%) was noted and median PFS was 14 months and median overall survival was 13 months. Adverse events were limited to grade 1-2 and primarily noted as bone marrow changes.
Previous preclinical studies have also demonstrated high levels of expression of somatostatin receptors in adreno- cortical cancer [53]. Grisanti et al. evaluated uptake of Gallium-68 (Ga 68)-DOTATOC, a somatostatin analog, in nineteen patients and found two patients with clinically significant uptake at sites of metastatic disease [54]. One patient received Lu177-DOTATOC with a partial response and stable disease for 12 months. The second patient received Lu177-DOTATOC with 4.0 months of disease sta- bilization and an improvement in clinical symptoms.
Miscellaneous Agents
Other single patient case reports or small case series of vari- ous drugs can be found in the literature and have suggested some response with modest toxicity, but these agents need to be vetted in larger, prospective trials.
Ongoing Trials (Table 2)
A review of ongoing or future trials at clinicaltrials.gov shows a small number of trials potentially available for advanced adrenocortical cancer. Most trials are looking at combination agents, but a few novel agents such as an anti- body-drug conjugate, an individualized mRNA vaccine, and
a new radioisotope are under investigation. Enrolling in an ACC trial is difficult, both due to low numbers of patients and complex geographic distribution of patients. Future tri- als will likely require cooperative group studies to find a critical mass of patients for appropriate analysis. From a review of studies in Table 1 and the described outcomes, futures studies will likely be a combination of triple or quad therapy (i.e. mitotane, chemotherapy, TKIs, and/or immu- notherapy). Balancing clinically significant responses with limiting adverse events will be critical to find novel strate- gies for ACC patients.
Summary and Future Directions
Adrenocortical cancer is an aggressive tumor with a high risk of recurrence. Reviewing the data above, many therapies have been used to slow the growth of adrenocortical cancer, but with limited results. Unfortunately, conflicting data is also a common theme in ACC studies. Across a spectrum of therapeutic agents, tumors appear to be relatively resistant to steroidogenesis inhibitors, chemotherapy, targeted therapy, and immunotherapy. EDP-M remains as the first-line stand- ard for those patients who can tolerate treatment. For the most part, the presented trials have several consistent limi- tations including: small numbers of patients enrolled, lim- ited case reports or case series, or retrospective studies. In addition, the prospective phase 1 and 2 studies have limited enrollment. In general, trials for rare diseases are difficult and are best managed through multi-site enrollment to pool resources and allow for improved data assessment.
Combination chemotherapy with mitotane was the first established phase 3 proven therapy for metastatic adreno- cortical carcinoma. New standard regimens in treating ACC will likely be based on combinations of existing drugs or arise from novel agents being tested in clinical trial develop- ment. We encourage all providers and patients to take advan- tage of clinical trials as available.
Key References
· M. Terzolo et al., “Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADI- UVO): an international, multicentre, open-label, ran- domised, phase 3 trial and observational study,“Lancet Diabetes Endocrinol, vol. 11, no. 10, pp. 720-730, Oct 2023, https://doi.org/10.1016/S2213-8587(23)00193-6.
o This study is of major importance as it demonstrated in a radomized phase 3 study that for low risk ACC patients there is no apparent benefit with adjuvant mitotane.
· N. Raj et al., “PD-1 Blockade in Advanced Adrenocorti- cal Carcinoma,” J Clin Oncol, vol. 38, no. 1, pp. 71-80, Jan 1 2020, https://doi.org/10.1200/JCO.19.01586.
o This study is of importance as it is the largest phase 2 study of single agent PD1 in ACC that demonstrated a response.
· O. Klein et al., “Combination immunotherapy with ipili- mumab and nivolumab in patients with advanced adreno- cortical carcinoma: a subgroup analysis of CA209-538,” Oncoimmunology, vol. 10, no. 1, p. 1908771, Apr 12 2021, https://doi.org/10.1080/2162402X.2021.1908771.
o This study is of major importance as it demonstrated an objective response rate with ipilimumab and nivolumab in advanced ACC patients.
· M. Kroiss et al., “Objective Response and Prolonged Disease Control of Advanced Adrenocortical Carcinoma with Cabozantinib,” J Clin Endocrinol Metab, vol. 105, no. 5, pp. 1461-8, May 1 2020, https://doi.org/10.1210/ clinem/dgz318.
o This study is of importance as it was the first study to suggest an objective response in ACC patients treated with cabozantinib.
· S. Bedrose et al., “Combined lenvatinib and pembroli- zumab as salvage therapy in advanced adrenal cortical carcinoma,” J Immunother Cancer, vol. 8, no. 2, Jul 2020, https://doi.org/10.1136/jitc-2020-001009.
o This study is of major importance as it demonstrated objective response in pretreated ACC patients with a combination of lenvatinib and pembrolizumab.
Acknowledgements None
Author Contributions J.S.R .: literature research and main manuscript writing.
Funding This work is non-funded.
Data Availability No datasets were generated or analysed during the current study.
Declarations
Conflict of Interest The authors declare no competing interests.
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.
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