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The role of immune checkpoint inhibitor therapy in advanced adrenocortical carcinoma revisited: review of literature
E. P. Brabo1D . A. B. Moraes2D . L. V. Neto2DD
Received: 16 April 2020 / Accepted: 21 May 2020 @ Italian Society of Endocrinology (SIE) 2020
Abstract
Purpose Adrenocortical carcinoma (ACC) is a rare disease with few therapeutic options. There is an urgency of new effec- tive therapeutic options for these patients. The role of immune checkpoint inhibitors (ICI) in advanced ACC patients is still unclear.
Methods We conducted a MEDLINE search using the following string: adrenocortical carcinoma and immunotherapy or checkpoint inhibitors.
Results We found four case series comprising 10 patients, and four prospective studies totaling 115 patients. The response rate (RR) in the group of 10 patients was 1 complete response, 3 partial response (PR), 4 stable disease (SD), and 2 progres- sive disease (PD). The median progression-free survival (mPFS) ranged from 2 to 31 months and the median overall survival (mOS) ranged from 4.3 to 31 months. The results in the 115 patients from prospective trials was variable, the PR ranged from 6 to 23%, the SD ranged from 18 to 50% and overall disease control rate ranged from 30 to 64%. The mPFS reported varied from 1.8 to 2.6 months while the mOS varied from 10.6 to 24.9 months. There were five patients with sustained response for more than 24 months. The most common treatment-related adverse event (TRAE) was the increase in liver enzymes. No treatment-related deaths were reported. Better results in terms of RR and survival were observed in studies that used pembrolizumab. No predictive biomarker of response was found up to now.
Conclusion ICI, mainly pembrolizumab, is a potential therapeutic option, which is safe and associated with prolonged OS benefit, in selected patients with advanced ACC.
Keywords Immune checkpoint inhibitors . Immunotherapy · Adrenocortical carcinoma · Anti-programmed cell death
Introduction
Adrenocortical carcinoma (ACC) is a rare disease with few therapeutic options. Surgery for localized disease is the only chance of cure, but even these patients have a high recur- rence rate. The disease is very heterogeneous and even in
L. V. Neto
1 Oncology Unit and Neuroendocrine Section, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, 255 Professor Rodolpho Paulo Rocco Street, ground floor, University City, Rio de Janeiro, RJ 21941-913, Brazil
2 Department of Internal Medicine and Endocrine Unit, Medical School and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, 255 Professor Rodolpho Paulo Rocco Street, 9th floor, University City, Rio de Janeiro, RJ 21941-913, Brazil
the context of metastatic disease some patients may present long survival [1]. Clinical and pathological prognostic fac- tors such as stage, completeness of resection, Weiss Score, Ki67 labeling index, and functioning status are well known [2], but molecular ones are still waiting for clinical correla- tion and confirmation.
The treatment of metastatic disease is mainly based on mitotane, because of its inhibitory effect on adrenal steroido- genesis and cytotoxic effect on the tumor. The combination of mitotane and polychemotherapy with etoposide, doxoru- bicin and cisplatin (EDP) showed superior results in terms of overall survival over the control group, which combined mitotane and streptozocin [3]. The combination of mitotane and EDP is the standard treatment in many countries. We also have non-randomized data on the use of gemcitabine combined with capecitabine as second-line systemic treat- ment option [4, 5].
Local treatment of metastatic disease when feasible should also be performed and the therapeutic options include surgery, conventional radiotherapy, stereotactic ablative body radiotherapy (SABRT) or radiofrequency ablation [6]. A combination of systemic and local treatment may result in longer survival and benefit in selected patients. Recently, a report on the results of Lutetium treatment in ACC patients has shown promising results [7], and the results of a retro- spective study of cabozantinib warranted the phase II ongo- ing trial [8].
Based on few treatment options, widely variable thera- peutic response, lack of randomized trials and the rarity of ACC, there is an urgency of new effective therapeutic options for these patients. The treatment with immune checkpoint inhibitors (ICI) changed the therapeutic approach of many cancers. ICI is the standard first-line treatment for metastatic and localized melanoma [9, 10], and also for metastatic and locally advanced non-small cell lung cancer (NSCLC) [11, 12].
Therefore, taking all these considerations together, we reviewed all available published data on the use of ICI in advanced ACC patients.
Literature review and results
We conducted a MEDLINE search using the following string: adrenocortical carcinoma and immunotherapy or checkpoint inhibitors. The search resulted in two published case series, two case reports and four clinical trials of ICI in advanced or metastatic ACC. We also reviewed the refer- ences cited in these papers to search for any missing cases or series. Preliminary results of the same study were not considered once the final report is published.
We found one phase Ib trial of avelumab [13], one phase II trial of nivolumab [14], two phase II trials of pembroli- zumab [15, 16], two retrospective case series of pembroli- zumab [17, 18], and two case reports [19, 20]. These papers comprised 125 patients treated with ICI reported up to March 2020.
The first case report was published in June 2018 and described a 58-years-old female patient with a cortisol- secreting metastatic ACC as part of Lynch syndrome due to a pathogenic mutation in MSH2. Three months after left adrenalectomy she developed liver metastasis; the first-line treatment was mitotane combined with pembrolizumab, but the patient developed progressive hepatic disease and died of fulminant liver failure [19].
The second case report was a letter in response to the case above; in this letter, the authors described a 29-year-old man with metastatic cortisol-secreting ACC, but his cortisol level was lower than that reported in the above-mentioned study. The patient received first-line therapy as in FIRM-act
study with the combination of EDP plus mitotane [3], which resulted in a progressive disease (PD). A second-line therapy with gemcitabine and capecitabine [4, 5] was introduced again with PD. His tumor presented with Mismatch Muta- tion Repair deficient (MMRd) when assessed by immu- nohistochemistry, and a third-line treatment was initiated with the combination of pembrolizumab and mitotane. The patient developed immune-related hepatotoxicity and ICI was interrupted. Pembrolizumab could be safely reintro- duced 3 months later. Six months after the reintroduction of ICI the patient was well with shrinking of all lesions on imaging studies [20].
The third report described two cases of heavily pretreated patients, both with high mutational burden (> 10 mutation/ megabase) detected by next-generation sequencing (NGS). One patient received pembrolizumab for 4 months, which was stopped because of grade 3 pneumonitis. The patient was followed up and had sustained complete response up to 14 months after the first dose of pembrolizumab. The other patient received pembrolizumab for five cycles and discon- tinued it because of disease progression, he was treated with local radiotherapy, mitotane and systemic chemotherapy without response and died of PD 8 months after stopping pembrolizumab [17].
The last report was a retrospective case series of six patients treated with pembrolizumab and mitotane. Three patients had cortisol-secreting tumors and three were non- functioning ones. All patients had metastatic disease and were previously treated with mitotane. Three patients also received chemotherapy along with mitotane as previous ther- apy. Two patients died of PD, one at 10 months after treat- ment discontinuation due to hepatitis. The other one died 2 months after treatment discontinuation, she had 19 months of stable disease (SD) before progression. There were four patients alive, two without evidence of disease, after local treatment for residual disease. Three patients are still on treatment and one discontinued pembrolizumab because of grade 2 pneumonitis but continued on mitotane therapy [18].
The first published trial was a phase Ib study of avelumab in fifty patients with metastatic ACC, previously treated with platinum-based chemotherapy. The primary endpoint was the overall response rate (ORR) using Response Evalua- tion Criteria In Solid Tumors (RECIST) (version 1.1) [21] and modified immune-related response criteria (irRECIST) [22]. Tumor assessment was performed every 6 weeks. Con- comitant mitotane use was allowed and 50% of the patients received the two drugs. Patients were heavily pretreated, 74% received 2 or more lines of systemic treatment. Partial response (PR) was observed in 3 patients (6%) and SD in 21 patients (42%), with a disease control rate (DCR) of 48%. Median progression-free survival (mPFS) was 2.6 months and median overall survival (mOS) was 10.6 months. The 1-year survival rate was 43%. A trend toward a greater
activity in patients with limited pretreatment and pro- grammed death ligand 1(PD-L1)-positive tumors was observed. No serum mitotane level and no mention of the functional status of the tumors were recorded [13].
The second trial was a phase II study of nivolumab in 10 patients with metastatic or locally advanced ACC, previ- ously treated or treatment naïve. The primary endpoint was the ORR using RECIST (version 1.1). Tumor assessment was performed every 8 weeks. At least one patient used concomitant mitotane. There were four functioning tumors (cortisol 2, aldosterone 1, and testosterone 1). There was an unconfirmed PR in one patient (10%) and SD in two patients (20%), with a DCR of 30%. The mPFS was 1.8 months and mOS was 21.2 months. The 6-month survival rate was 56%. The trial was stopped given the lack of confirmed PR in the first 10 patients [14].
There were two phase II trials of pembrolizumab in patients with advanced ACC. One is a basket phase II trial that included 16 patients with metastatic disease treated in a single institution, 10 patients (63%) had received two or more previous lines of therapy. The primary endpoint was PFS at 6 months using RECIST or irRECIST. Tumor assessment was performed every 9 weeks. No concomitant use of mitotane was allowed. There were ten patients (63%) with functional tumors (cortisol and androgens alone or in combination). The PFS at 6 months was 36%, five out of 14 evaluable patients (1 lost to follow-up and one removed from the study because of toxicity). Considering 14 patients there were two PR and seven SD, an ORR of 14%. The clinical benefit rate was 57% (8/14), in one patient the SD last less than 4 months. The PD-L1 status, the microsatellite insta- bility (MSI) status and the tumor-infiltrating lymphocytes (TIL) were non-predictive factors for response [15, 23].
The other was a phase II pembrolizumab trial that enrolled 39 patients with metastatic or unresectable ACC. A pretreatment rate of 72% was observed. The primary endpoint was ORR according to RECIST. Tumor assess- ment was performed every 9 weeks. No concomitant use of mitotane was allowed. There were nine PR and seven SD with an ORR of 23% and a DCR of 52% excluding eight patients (21%) who were not evaluable due to clinical pro- gression at week 9. Important to note is that two patients in the PR group had pseudo-progression and the median time to response in these nine patients was 4.1 months. Two patients presented with mixed response. The mPFS was 2.1 months and the mOS was 24.9 months. The 2-year OS rate was 50%. There was no significant association between tumor PD-L1 status, Tumor Mutation Burden (TMB), TIL score, or somatic alterations and response. A trend toward homozygosity in nonresponding patients was observed [16].
A summary of these findings is shown in Tables 1 and 2.
Treatment-related adverse events (TRAE) were reported in all studies with a frequency of more than 80% in the
studies that combined checkpoint inhibitor with mitotane [13, 18-20]. The frequency of TRAE in the phase II trial of pembrolizumab [16] was 59%, concomitant mitotane use was not allowed in this trial. The Common Terminology Criteria for Adverse Events v4.0 (CTCAE 4.0) were used to graduate TRAE. No treatment-related deaths were reported. The four trials enrolled in total 115 patients, and the case reports and case series comprised other 10 patients. Treat- ment discontinuation due to a TRAE occurred in 10 patients, the proportion varied between trials from 5 [16] to 20% [14]. Hepatitis with elevated liver function tests (LFT) were the most commonly reported TRAE, even when concomitant mitotane was not allowed. Interestingly, all patients with objective response in the phase II pembrolizumab study [16] experienced elevated LFT ≥ grade 2. The summary of TRAE in 125 patients is listed in Table 3.
Discussion
Treatment with ICI changed cancer therapy, not only by the revolutionary action mechanism that is not directed to can- cer cell but also by their excellent results in some specific tumor types. There are very few reports of the effects of ICI in patients with ACC. Initial results were disappointing, and some authors have already listed at least four potential mechanisms of immune resistance in advanced ACC and proposed theoretical ways to overcome it [24, 25]. In this review, we made a critical analysis of the published data on the use of ICI in advanced ACC patients.
Advanced/metastatic ACC is a rare and heterogeneous disease. Some few patients may present with an insidious course of disease under the use of the adrenolytic drug mitotane [1]. Otherwise, some other patients may present with very aggressive disease refractory to all offered treat- ment. The majority of cases will rest in between these two extremes. More than half of the patients have functioning tumors and the most commonly secreted hormone is cortisol. Hypercortisolism per se is associated with a worse prognosis and patients can suffer a very morbid condition with many metabolic complications [2].
Very few randomized studies on treatment options are available. The results of these studies must be interpreted with caution because of differences in patient populations. The standard first-line treatment is mitotane with poly- chemotherapy according to the FIRM-ACT trial [3]. Very few studies on second-line chemotherapy are published with modest activity [4, 5]. An inhibitor of the insulin-like growth factor (ILGF), linsitinib, was compared to placebo in a recent phase III trial. Unfortunately, the trial was negative; linsitinib fails to show benefit over placebo in patients with advanced ACC. Interestingly patients in the placebo group had a mOS of 11 months (356 days). The authors comment
| N Age | Female | Functioning tumor | Lynch syn- drome | MSI | PD-L1 | Prior palliative treatment | Con- comitant mitotane | ≥ Two lines of previous therapy | mPFS (months) | mOS | (months) Outcome | Final status | Follow- up time (months) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case report [19] | 1 58 | Yes | Yes (cortisol, androgens) | Yes | Yes | <1% | No | Yes | No | NR | 4.3 | PD | Dead | 4.3 |
| Case report [20] | 1 29 | No | Yes (cortisol) | No | Yes | 1% | Yes | Yes | Yes | NR | 9 | PR | Alive | 9 |
| Case series | 1 40 | Yes | NR | NR | Yesb 10% | Yes | No | Yes | 26 | 26 | CR | Aliveb | 26 | |
| [17] | 1 28 | No | NR | NR | No NR | Yes | No | Yes | 2 | 10 | PD | Dead | 10 | |
| Case series | 1 24 | Yes | No | Yes | Yes NR | Yes | Yes | No | 24 | 24 | PR | Alive | 24 | |
| [18] | 1 44 | Yes | No | No | No NR | Yes | Yes | Yes | 31 | 31 | PR | Alive | 31 | |
| 1 54 | Yes | Yes (cortisol, androgens) | Yes | I NR | Yes | Yes | No | 19 | 21 | SD | Dead | 21 | ||
| 1 29 | Yes | Yes (cortisol, androgens) | No | No | NR | Yes | Yes | Yes | 8 | 16 | SD | Dead | 16 | |
| 1 46 | Yes | No | No | No | NR | Yes | Yes | Yes | 26 | 26 | SD | Aliveb | 26 | |
| 1 65 | Yes | Yes (cortisol) | No | No | NR | Yes | Yes | No | 11 | 16 | SD | Alive | 16 | |
All patients had disease stage IV. All deaths were caused by disease progression
MSI presence of microsatellite instability, PD-L1 expression in % of programmed death ligand 1, mPFS median progression free survival; mOS median overall survival, NR not reported, PD progressive disease, PR partial response, CR complete response, SD stable disease, I indeterminate
ªSomatic mutation in MSH2 gene
b Alive without evidence of disease after local treatment
| N Age | Female | Func- tion- ing | Lynch syn- drome | MSI | PD-L1 | Stage IV | Prior sys- temic | Con- comitant mitotane | ≥ Two lines of previ- | Primary end point | mPFS (months) | mOS (months) | Assessment of response (weeks) | PR | SD | DCR | mFollow- up (months) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| tumor | treat- ment | ous | ||||||||||||||||
| ther- apy | ||||||||||||||||||
| Phase Ib avelumab [13] | 50 50 (2-71) | 52% | NR | NR | NR | 30% ≥ 1% | 100% | 100% | 50% | 74% | ORR | 2.6 | 10.6 | 6 (RECIST) | 6% | 42% | 48% | 16.5 |
| Phase II | 10 57 (31- | 70% | 40% | NR | 0/5 | 60% ≥1% | 100% | 80% | Yes (at | 30% | ORR | 1.8 | 21.2 | 8 (RECIST) | 10%b | 20% | 30% | 4.5 |
| nivolumab [14] | 67) | tested | least one patient)ª | |||||||||||||||
| Phase II basket pembroli- zumab [15] | 16 48 (31- 78) | 50% | 63% | NR | 1/14 tested | 0% | 100% | 100% | No | 62.5% | PFS at 6 months | NR | NR | 9 (RECIST + irRE- CIST) | 14% (2/14) | 50% (7/14) | 64% (9/14) | NR |
| Phase II pem- brolizumab [16] | 39 62 (19- 87) | 62% | NR | 2/33 tested | 6/38 tested | 21% ≥ 1% | NR | 72% | No | NR | ORR | 2.1 | 24.9 | 9 (RECIST) | 23% | 18% | 52% | 17.8 (5.4- 34.7) |
MSI presence of microsatellite instability, PD-L1 programmed death ligand 1, mPFS median progression-free survival, mOS median Overall survival, PR partial response, SD stable disease, DCR disease control rate, mFollow-up median follow-up time, ORR overall response rate, RECIST response evaluation criteria in solid tumors, irRECIST immune-related RECIST, NR not reported
aOne patient cited that used concomitant mitotane
bUnconfirmed
| Adverse event | With mitotane N=33ª No. of patients (%) | Without mitotane N=92b No. of patients (%) | Total N=125 | ||
|---|---|---|---|---|---|
| All grades | Grades 3/4 | All grades | Grades 3/4 | ||
| Hepatitis | 13 (39) | 6 (18) | 22 (24) | 7 (8) | 35 (28) |
| Fatigue | 9 (27) | 18 (20) | 27 (22) | ||
| Nausea/vomiting | 14 (42) | 1 (3) | 12 (13) | 26 (20) | |
| Hypothyroidism | 3 (9) | 9 (10) | 12 (10) | ||
| Diarrhea | 7 (21) | 1 (3) | 4 (4) | 1 (1) | 11(9) |
| Rash | 3 (9) | 8 (9) | 11 (9) | ||
| Pruritus | 2 (6) | 7 (8) | 9 (7) | ||
| Chills | 3 (9) | 5 (5) | 1 (1) | 8 (6) | |
| Pyrexia | 5 (15) | 3 (3) | 8 (6) | ||
| Pneumonitis | 1 (3) | 6 (6) | 5 (5) | 7 (6) | |
| Mouth sores | 1 (3) | 1 (3) | 5 (5) | 6 (5) | |
| Infusion-related reaction | 1 (3) | 5 (5) | 6 (5) | ||
| Anemia | 1 (3) | 1 (3) | 4 (4) | 5 (4) | |
| Decreased appetite | 2 (6) | 3 (3) | 5 (4) | ||
| Hypophosphatemia | 1 (3) | 3 (3) | 2 (2) | 4 (3) | |
| Adrenal insufficiency | 2 (6) | 1 (3) | 2 (2) | 4 (3) | |
| Hypocalcemia | 4 (4) | 1 (1) | 4 (3) | ||
| Edema | 4 (4) | 4 (3) | |||
| Increased alkaline phosphatase | 4 (4) | 4 (3) | |||
| Asthenia | 3 (9) | 1 (1) | 4 (3) | ||
| Lymphopenia | 1 (3) | 1 (3) | 2 (2) | 3 (2) | |
| Dry skin | 3 (3) | 3 (2) | |||
| Dehydration | 2 (6) | 1 (1) | 1 (1) | 3(2) | |
| Back pain | 3 (9) | 3 (2) | |||
| Hypokalemia | 2 (2) | 2 (2) | 2 (2) | ||
| Headaches | 2 (6) | 2 (2) | |||
| Neuropathy | 2 (6) | 2 (2) | |||
| Rectal bleeding | 2 (6) | 2 (2) | |||
| Hyperpigmentation | 2 (2) | 2 (2) | |||
| Hypoalbuminemia | 2 (2) | 2 (2) | |||
| Increased creatinine | 2 (2) | 2 (2) | |||
| Hypomagnesemia | 1 (1) | 1 (1) | 1 (1) | ||
Additional grade 1-2 adverse events with one patient each included arthralgia, myalgia, thrombocytopenia, neutropenia, hyperglycemia, hyponatremia, pain, libido decreased, malaise, hyperthyroidism, constipation, duodenitis, alopecia, skin and subcutaneous tissue disorder, dry eyes, conjunctivitis, and dizziness
a2 patients in case reports +6 patients in case series and 25 patients in phase Ib avelumab trial b39 patients in phase II pembrolizumab trial + 16 patients in the other phase II pembrolizumab trial + 25 patients in phase Ib avelumab trial + 10 patients in phase II nivolumab trial (at least 1 patient received con- comitant mitotane) +2 patients in case series
that they might have selected patients with indolent disease. Unfortunately, there is no information regarding treatment after progression [26]. A comparison of response rates and disease control rates of the above-mentioned studies and the ICI trials in advanced ACC is shown in Fig. 1.
Three out of the four trials of ICI in advanced ACC have ORR as primary end point, and the measurement tool was RECIST. The increase in bi-dimensional measure of a target lesion may exclude some patients who are actually
benefiting from treatment. The best example of this was in the neoadjuvant nivolumab trial in non-small cell lung can- cer (NSCLC). In this trial, a patient with enlarging tumor in chest computed tomography after two doses of nivolumab, actually had a complete pathological response in surgical resection specimen [27]. Then a new model for reporting pathological response to immunotherapy was suggested later [28]. A recent report of “nodal flare” was associated with ICI therapy in NSCLC [29]. In real-life resection/biopsy of
EDP+mitotane N=127 [3]
Streptozocin+mitotane N=125 [3]
Linsitinib* N=90 [26]
Placebo* N=49 [26]
Gencitabine+capecitabine N=28 [4]
Gencitabine+capecitabine N=145 [5]
Avelumab N=50 [13]
Nivolumab N=10 [14]
Pembrolizumab+mitotane N=6 [18]
Pembrolizumab N=16 [15]
Pembrolizumab N=39 [16]
0
10
20
30
40
50
60
70
80
90
100
(%)
Complete response * Partial response % Stable disease ” Progressive disease
EDP - Etoposide, Doxorubicin, cisplatin; * data extracted from figure 4, ref [26]
the enlarging metastatic site is not always feasible, that is why some trials allowed the continuation of treatment in patients who derived clinical benefit albeit with PD in imag- ing exams. Thus, a modified tool was developed to assess the response in ICI treatment, the irRECIST. The major dif- ference to RECIST is that a confirmation of progression is needed after 4 months of documentation of progression on imaging exams. In lung cancer and melanoma, the meta- bolic imaging with fluoro-deoxy glycose positron emission tomography (FDG-PET) showed promising results as a tool to predict response to ICI therapy [30]. The case series from Brazil showed a very interesting case of a patient with advanced ACC who presented with complete metabolic response on FDG-PET after pembrolizumab therapy [17]. There are new promising data for radiomics in the evaluation of response to ICI therapy [31, 32]. Indeed, the best tool to identify the patient who is driven true benefit from the ICI treatment is not yet available.
The pembrolizumab phase II trial reported that the median time to response was 4.1 months (range 1.7-10.5 months) [16]. The mPFS of all the trials revisited was shorter than 4.1 months. Authors assigned the short PFS to the fact that patients who progress do it early. Actually, in the pembroli- zumab phase II trial, two of the nine patients (22%) with par- tial response had pseudo-progression. In this trial, treatment beyond progression was allowed whether the patient-derived clinical benefit. Otherwise, these patients could have been classified as PD and excluded from the study. In the ave- lumab trial, one patient also experienced a pseudo-progres- sion. Two other patients had mixed response, one received local therapy to the progressive site and turned out to be without evidence of disease. We must keep in mind that individualization is imperative, and we must allow patients who are not deteriorating and are doing well, to continue ICI treatment because response could be seen even up to 10 months after the beginning of therapy [16].
The immune infiltration of the tumor bed after ICI therapy may be misdiagnosed as a progressive disease by conventional imaging [27]. A delay in response up to 10.5 months was reported in the pembrolizumab phase II trial [16]. These two important considerations must be pondered when interpreting mPFS in ICI therapy trials. We cannot even exclude antitumor immune activation beyond progression, which is a feasible basis for pseudo- progression. The mPFS might not appropriately capture the true benefit of the treatment. The mOS is a more relia- ble end point to the benefits of ICI therapy in solid tumors.
In the opposite situation of pseudo-progression is the hyperprogressive disease (HPD). This tumor flare-up phenomenon is associated with a poorer outcome. The pathophysiology of HPD is controversial and not yet fully understood. The most feasible basis for HPD is an immune-related adverse event. The early switch to cyto- toxic therapy may counteract the deleterious flare-up. Phy- sicians who take care of cancer patients undergoing ICI therapy must promptly recognize and manage the HPD [33].
Treatment with ICI was continued until disease progres- sion or toxicity in the case series and in the case reports. One patient had the pembrolizumab safely reintroduced 3 months after grade 4 liver elevation tests [20]. In the case series that combined ICI and mitotane, there were patients using pembrolizumab for a median of 18.5 months (range 8-31). In the prospective trials, the duration of treatment was quite variable; in the pembrolizumab phase II trial, there was a pre-specified 24-month duration of treatment [16]. There were five patients alive with response for more than 2 years, one patient in the avelumab trial, one patient in the pembrolizumab basket trial and three in the pembrolizumab phase II trial. Of note, some patients experienced sustained response after a short treatment course, even after only one dose of ICI [17, 20]. Based on these results there is no estab- lished duration of treatment. We still do not know if patients who benefit could be treated with less than 6 months or up to 2 years or even until a benefit is still observed. That question will probably remain unanswered because of the rarity of the disease and the paucity of trials exploring ICI in ACC.
All trials of ICI in advanced ACC included patients with Eastern Cooperative Oncology Group (ECOG) of 0 or 1. The exception was the nivolumab trial that included two patients with ECOG 2 and 3, one patient for each. Considering that the total number of patients in these trials is 115, two patients correspond to 1.7% of the total. This is a clear selec- tion bias because they excluded very symptomatic patients who usually have more advanced disease and a greater tumor burden. We must keep it in mind before extrapolating the results to real-life patients. In the two largest trials, we have no specific information about the functionality of the tumors. This should be considered another selection bias because as
previously mentioned hypercortisolism is associated with worse prognosis. Another prognostic factor that is lacking in the trials is the Ki-67 labeling index.
In the case series that combined ICI with mitotane, the two observed deaths occurred in patients with cortisol secreting tumors. In the nivolumab trial, all patients with hormone-producing tumors experienced PD. In the pem- brolizumab basket trial, a higher proportion of PD was also observed in patients with cortisol-secreting ACC. It is possible that cortisol excess might compromise antitumor immune response [34, 35]. The study population from the reviewed studies was too small and no significance could be observed. The functional status of the tumors should not be omitted, otherwise we cannot exclude selection bias.
An association between previous chemotherapy and response to ICI was suggested in the pembrolizumab phase II trial [16]. An inverse association was suggested in the avelumab trial [13]. For NSCLC, a distinct study compared biopsy and surgical specimens before and after neoadjuvant chemotherapy. The authors demonstrated that chemotherapy was associated with an increase in the expression of PD-L1 and with activation of specific immune response mecha- nisms [36]. This may be the potential basis of the successful synergism observed with the association of chemotherapy and pembrolizumab in NSCLC [11]. The synergism between ICI and chemotherapy was also observed in other tumor types such as breast, head and neck, and small cell lung cancer [37-42]. The association of ICI with chemotherapy in ACC patients may be a reasonable question for future clinical trials in this disease.
The association of ICI with the backbone ACC drug mitotane was safe and feasible in studies in which this combination was used. Caution is recommended and close monitoring of liver function tests is mandatory. Mitotane serum levels were reported in the case series that used this combination, the values for each patient ranged from 0 µg/ mL up to 25.60 µg/mL [18]. We have neither biological basis nor randomized data for the observed synergism. The results presented in the case series that combined mitotane and ICI are very promising since all patients derived clinical ben- efit. This can be observed in Fig. 1. The association of ICI therapy and mitotane is another reasonable question to be addressed in future clinical trials of ICI in ACC.
Previous favorable results of pembrolizumab in patients whose tumors have the presence of microsatellite instability (MSI) [43] lead to the hypothesis of the same association in patients with ACC. The responses were observed indepen- dently of the microsatellite status in all studies. The excep- tion was the phase II pembrolizumab trial, in which a trend toward better results in patients with MSI was noted. For patients who harbor MSI tumors, the PR and SD rates were 33.3% and 33.3% each. These rates in patients with micro- satellite stable tumors were 22% and 15% for PR and SD,
respectively. These results suggest that pembrolizumab has activity even in patients with microsatellite stable tumors, and this population should not be denied the benefit of pembrolizumab. The authors recommend that all patients with advanced ACC have the microsatellite status tested. Regarding the method of determining the MSI status of a tumor, there is a report of a patient whose tumor presented with microsatellite stable by immunohistochemistry but had Mismatch Repair Deficient (MMR-D) status at NGS [16].
The expression of PD-L1 in cancer cells and the presence of TIL were tested in all trials except the avelumab trial that does not mention TIL testing. The results were disappoint- ing in terms of the predictive potential of response to ICI of these factors. Notably, the proportion of PD-L1 expres- sion was quite variable, with a range from no patient up to 21% of the patients tested. This heterogeneity of results may reflect differences in the studied populations. Also, we can- not exclude differences in the accuracy of the method used, as each trial used a different antibody for the immunohisto- chemistry analysis of PD-L1.
Other potential biomarkers were suggested in the trials. Of note, a potential role of homozygosity in non-respond- ers was observed in the pembrolizumab phase II trial [16]. Another interesting finding was observed in the nivolumab phase II trial. The peripheral blood flow cytometry immu- nophenotypic analysis showed a significant decrease in the percentage of CD3 +CD56- cell, natural killer T cells (NKT cells) in all patients after 6 weeks of treatment [14].
Better results were observed with the anti-PD1 drug pem- brolizumab, alone or in combination with mitotane. The results of the anti-PD-L1 drug avelumab were less attractive. A recent study tested tissue samples from 34 ACC patients for PD-L1 and PD-L2 (programmed death ligand 2). A sig- nificant difference in expression of the ligands was shown: 44% expressed PD-L2 whereas only 3% expressed PD-L1 [44]. This is a hypothesis-generated result and next studies should attempt to incorporate testing of PD-L2 expression in their design.
At the moment of the preparation of this manuscript, there are six trials exploring the role of ICI therapy in ACC. Three of them with the combination of ipilimumab and nivolumab, one combining nivolumab and a vaccine, one of pembrolizumab and another one with a combination of an anti PD1, camrelizumab and apatinib. These data are dis- played in Table 4.
A recent study reported a successful patient-derived xen- ograft in a humanized mouse model of ACC for the study of mechanisms and biomarkers of response to immuno- therapy [45]. The authors showed tumor growth inhibition and increase in CD8+ T cells, a surrogate of response in preclinical models and clinical studies [46-48].
The toxicity profile of ICI in advanced ACC patients was quite different from the previously reported for other tumors,
| Drug | Tumorª | Phase | N | Status | NCT identificationb |
|---|---|---|---|---|---|
| Camrelizumab + apatinib | ACC | II | 43 | Not yet recruiting | NCT04318730 |
| EO2401 + nivolumab | ACC | I | 72 | Not yet recruiting | NCT04187404 |
| Ipilimumab + nivolumab | Rare genitourinary tumors | II | 57 | Recruiting | NCT03333616 |
| IPI-549 + nivolumab | Advanced cancers | I | 220 | Recruiting | NCT02637531 |
| Pembrolizumab | Rare tumors | II | 225 | Recruiting | NCT02721732 |
| Ipilimumab + nivolumab | Rare tumors | II | 818 | Recruiting“ | NCT02834013 |
ACC adrenocortical carcinoma, N number of patients
ªTrials of others tumor types with ACC
bNCT National Clinical Trials
“ACC cohort is closed
especially for elevated liver enzymes, data are shown in Table 3. Nevertheless, no treatment-related death was reported and even patients with liver toxicity could have the ICI drug safely reintroduced. The second most commonly observed grade 3/4 TRAE was pneumonitis with resulting permanent treatment discontinuation. Of note, some patients with TRAE experienced sustained response even after inter- ruption of treatment.
Notwithstanding the rarity of ACC, the results of impor- tant trials of ICI treatment were reported in this patient pop- ulation in the last year. The most exciting results are the long mOS, observed in the largest phase II pembrolizumab trial [16]. The nivolumab trial was closed and the mOS of the avelumab trial was close to the observed in chemotherapy trials, as very well discussed in an editorial published in 2019 [49]. Many unanswered questions remain: which will be the best partner? Chemotherapy, mitotane or both? What is the best sequence of treatment? ICI as the first line or after failure of the first and the second line? We have basis to believe that previous chemotherapy may induce a propitious microenvironment to ICI antitumor efficacy [36].
A provocative study title “Immunotherapy failure in adrenocortical cancer: where next?” was chosen by the authors in mention to a previous similar title regarding mitotane in 1993. Mitotane showed to be the backbone of ACC treatment. The authors of the 2018 study hope that ICI has the same relevance in the treatment of ACC patients as mitotane has [24]. Actually, in 2019, the pembrolizumab phase II studies were published and pleased us with a very promising new hope.
In conclusion, ICI therapy showed long-term benefit in mOS in highly selected patients with advanced ACC, espe- cially the anti-PD1 pembrolizumab. Unfortunately, we have no prospective validated biomarker of response, but some potential candidates. ICI, mainly pembrolizumab, is a poten- tial therapeutic option, because it is safe, well-tolerated and efficacious in patients with advanced ACC.
Funding This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval The approval by the Institutional Review Board is not applicable because the study is a review of the literature.
Informed consent There were no individual’s person data requiring consent for publication.
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