EJE OXFORD
Chemo-immunotherapy with cisplatin and nivolumab as second-line approach in metastatic adrenocortical carcinoma
Marta Laganà ( 1,21, Sara Rodella 1 1,21, Davide Lorenzo Bettini1,2, Andrea Esposito1,2, Andrea Abate1,3, Roberta Ambrosini1,4, Mariangela Tamburello1,3, Francesca Consoli2, Rita Tinti1,4, Stefano Calza5, Giovanni Casole1,6, Guido Alberto Massimo Tiberio 1,6, Sandra Sigala1,3, Alfredo Berruti1,2, Salvatore Grisanti1,2 ** and Deborah Cosentini1,2
1Adrenal Cancer Unit, ASST Spedali Civili, Brescia 25123, Italy
2Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Università degli Studi di Brescia, ASST Spedali Civili, Brescia 25123, Italy
3Department of Molecular & Translational Medicine, Section of Pharmacology, Università degli Studi di Brescia, Brescia 25123, Italy 4Radiology, ASST Spedali Civili, Piazzale Spedali Civili 1, Brescia 25123, Italy
5Unit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia 25123, Italy 6Surgery, Department of Clinical and Experimental Sciences, Università degli Studi di Brescia, ASST-Spedali Civili, Brescia 25123, Italy
*Corresponding author: Medical Oncology, ASST-Spedali Civili, Piazzale Spedali Civili 1, Brescia 25123, Italy. Email: salvatore.grisanti@unibs.it tM.L. and S.R. equally contributed and are co-primary authors.
S.G. and D.C. equally contributed and are co-senior authors.
Abstract
Context No effective therapies are available for patients with advanced adrenocortical carcinoma (ACC) progressing after standard therapy: EDP (etoposide, adriamycin, and cisplatin) and mitotane (EDP-M regimen). These patients have poor prognosis with a median life expectancy of 6-7 months. Immunotherapy in this setting is promising. Concomitant chemotherapy administration can enhance the efficacy of immunotherapy, as demonstrated in other malignancies.
Objective This retrospective study aims to explore the activity of a combination of cisplatin and nivolumab administered to patients with ACC who have previously undergone chemotherapy and mitotane treatment.
Patients and methods Cisplatin, 25 mg/m2 on day 1, and nivolumab, 240 mg on day 2, every 2 weeks, were administered to advanced/metastatic ACC with disease progression to EDP-M regimen plus/minus other chemotherapeutic regimens. The primary endpoint was the disease response according to RECIST. Secondary endpoints were clinical benefit, disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety.
Results Twenty-three patients were enrolled between January 2023 and March 2025. The median follow-up was 15.1 months. Eight patients [34.8% (95% CI, 15.3%-54.2%)] obtained a partial response and 4 patients (17.3%) a stable disease; therefore, 12 patients (52.2%) obtained a clinical benefit. The DCR after 6 months was obtained in 39.1% [95% CI, 19.7%-61.5%] of patients. The median PFS was 4.3 months [95% CI, 3.9-13.0], and the median OS was 18.9 months [95% CI, 15.8-not reached]. Chemo-immunotherapy combination was well tolerated, and most toxicities were limited to grade G1-2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria. One patient discontinued treatment after 1 cycle, due to grade 3 immune-related hepatitis.
Conclusion The combination of cisplatin and nivolumab is an active regimen in advanced, previously treated, ACC patients. The long survival achieved in this patient population with a poor prognosis is promising.
Keywords adrenocortical carcinoma, immunotherapy, chemotherapy, combination treatments, immunoresistance, neuroendocrine tumor
Significance
Adding chemotherapy to immunotherapy may be a viable strategy to overcome the intrinsic immunoresistance of adrenal cor- tical carcinoma (ACC), but it has never been explored in patients with this rare malignancy. In this single-center study in which 23 patients with previously pretreated metastatic ACC underwent the combination cisplatin + nivolumab, an objective response rate of 33% was achieved, and most importantly the median survival of the entire cohort was 19 months. Disease control has been achieved by 3 patients for 15 months or more. The results are promising and suggest that immunochemotherapy could be a po- tentially effective second-line treatment for patients with ACC.
Introduction
Adrenocortical carcinoma (ACC) is an extremely rare disease with an estimated annual incidence of .5-2 new cases per million population per year.1
Surgery is the only therapeutic approach that offers patients a chance of cure, and it is the mainstay of therapy.
For patients with metastatic disease who are not eligible for surgery, systemic treatment consists of either mitotane alone2 or mitotane in combination with etoposide, doxorubicin, and cis- platin (EDP-M) chemotherapy.1,3
Although some patients may achieve a complete pathological response with EDP-M chemotherapy, only a minority of them ob- tain long-term disease control.4 According to the FIRM-ACT study, in fact, 25% of patients who underwent EDP-M experi- enced no progression after 12 months of treatment, and 15% of patients remained alive after 5 years.5
To date, there are no effective treatments for patients pro- gressing after first-line therapy. Some studies have evaluated the efficacy of second-line chemotherapy regimens, such as the combination of gemcitabine and capecitabine,6 temozolo- mide,7 or cabazitaxel monotherapy,8 but the results have been unsatisfactory.
Disappointing results have also been obtained with target ther- apies such as antiangiogenetic drugs: sunitinib9 and axitinib10 and insulin-like growth factor-1 inhibitors either alone11,12 or in com- bination with mechanistic target of rapamycin inhibitors.13 A re- cent small phase II study with cabozantinib resulted in potentially interesting results.14 Nevertheless, confirmation is ne- cessary for the observed progression-free survival (PFS) of 6 months and overall survival (OS) of 24 months.
The results of immunotherapy appear to be more promising. A recent meta-analysis of published studies, including 250 pa- tients, showed that, although this treatment modality achieved an objective response rate (ORR) of only 14%, and a median PFS of just 2.8 months, the median OS was 14 months. This latter finding is encouraging, as it is approximately twice that reported for the great majority of the second-line therapies mentioned above.15
Advanced adrenocortical carcinoma is not considered an immunologically “hot tumor” due to several mechanisms.16 In many types of cancer, chemotherapy has been combined with immunotherapy to overcome the immunosuppressive “cold” tumor microenvironment,17 often with significant re- sults, and this approach has become a therapeutic standard, 18,19
The use of chemo-immunotherapy has yet to be tested in the treatment of patients with ACC.
This paper presents the findings of a retrospective analysis that evaluated the activity and efficacy of a combination of cis- platin and nivolumab in metastatic ACC with progressive disease (PD) to EDP-M.
Patients and methods
Study design and patient population
This monocentric observational retrospective study was conducted on consecutive patients with advanced ACC who underwent che- mo-immunotherapy with cisplatin and nivolumab between January 2023 and March 2025 at the Medical Oncology Unit of the ASST-Spedali Civili, Università degli Studi di Brescia, Italy. Patients were given chemo-immunotherapy as their next treat- ment option after the standard treatment of EDP-M chemotherapy.
Patients were addressed to chemo-immunotherapy if they had histologically proven locally advanced or metastatic ACC not suitable for surgery (stage III-IV), age of 18 years or older, radiologically measurable disease according to RECIST 1.1 cri- teria, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, adequate hematologic and biochemical function, and no history of other malignancies. (Detailed inclusion and exclu- sion criteria are provided in the Appendix).
The study was approved by the Ethical Review Board of ASST-Spedali Civili in Brescia (protocol number: NP6521) and was designed and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. Written consent was ob- tained from each patient.
Treatment administered
The chemo-immunotherapy regimen consisted of cisplatin, which was administered intravenously at a dose of 25 mg/m2 on day 1 of each cycle, and nivolumab at a dose of 240 mg given intravenously at day 2. One cycle of the regimen was defined as a 2-week interval. Mitotane treatment was maintained associated with glucocorticoid replacement.
Nivolumab was purchased as an off-label drug from the ASST-Spedali Civili in Brescia.
Treatment was continued until disease progression, consent withdrawal, and unacceptable toxicity. Cisplatin was planned to be discontinued in case of grade 3-4 toxicities, worsening renal function particularly in patients with a single kidney, and upon reaching a cumulative dose of 600 mg, beyond which the risk of neurotoxicity significantly increases. In the absence of disease progression, nivolumab was continued for a maximum of 2 years.
| Total patients, n | 23 |
|---|---|
| Sex, n (%) | |
| Male | 7 (30.4) |
| Female | 16 (69.6) |
| Age, years | 49 (32-69) |
| ECOG PS, n (%) | |
| 0 | 19 (82.6) |
| 1 | 4 (17.4) |
| Clinical presentation, n (%) | |
| Hormone symptoms | 6 (26.1) |
| Mass symptoms | 9 (39.1) |
| Incidentaloma | 8 (34.8) |
| Hormone secretion at diagnosis, n (%) | |
| No secretions | 14 (60.9) |
| Cortisol excess | 7 (30.4) |
| Androgens excess | 2 (8.7) |
| ENSAT stage at diagnosis, n (%) | |
| II | 9 (39.1) |
| III | 10 (43.5) |
| IV | 4 (17.4) |
| Previous surgery, n (%) | |
| No | 3 (13.0) |
| Yes | 20 (87.0) |
| Resection status, n (%) | |
| R0 | 15 (65.2) |
| R1 | 4 (17.4) |
| RX | 1 (4.3) |
| Adjuvant treatment, n (%) | |
| Mitotane | 18 (78.3) |
| EP plus mitotane | 2 (8.7) |
| No adjuvant treatment | 3 (13.0) |
| RFS, months | 8.7 (2-34.7) |
| First-line metastatic treatment, n (%) | |
| EDP-M | 22 (95.7) |
| Cisplatin only | 1 (4.3) |
| Best response to first-line therapy, n (%) | |
| PR | 6 (26.1) |
| SD | 12 (52.2) |
| PD | 5 (21.7) |
| Median number of first-line chemotherapy | 5 (2-7) |
| cycles | |
| Second-line metastatic treatment, n (%) | |
| Temozolomide | 4 (17.4) |
| Gemcitabine plus capecitabine | 1 (4.3) |
| Third-line metastatic treatment, n (%) | |
| Temozolomide | 1 (4.3) |
| Gemcitabine plus capecitabine | 2 (8.7) |
| N of chemotherapy lines, n | |
| 1 | 18 (78.3) |
| 2 | 2 (8.7) |
| 3 | 3 (13.0) |
| Time between end of EDP and start of | 7.5 (.9-57.4) |
| CIS-NIVO | |
| Mitotane in advanced setting, n (%) | 21 (91.3) |
| (continued) |
| Table 1 Continued | |
|---|---|
| Total patients, n | 23 |
| Mitotane levels at the start of CIS-NIVO, n (%) | |
| <14 mg/L | 13 (56.5) |
| >14 mg/L and <20 mg/L | 8 (34.8) |
| Median mitotane level at start of treatment (mg/L) | 12.8 (3.4-18.9) |
| Cortisol hypersecretion before CIS-NIVO, n (%) | 3 (13.0) |
Abbreviations: CIS-NIVO, cisplatin-nivolumab; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EDP-M, etoposide, doxorubicin, and cisplatin plus mitotane; ENSAT stage, European Network for the Study of Adrenal Tumours staging system; EP, etoposide-cisplatin; n, number; PD, progression disease; PR, partial response; RFS, relapse-free survival; SD, stable disease.
Premedication and antiemetic prophylaxis were recommended as per institutional guidelines.
Adverse events (AEs) were monitored throughout the study and reported using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.
Physical examination, performance status, and routine labora- tory tests were evaluated at baseline and during the combination treatment every 2 weeks, while mitotane plasma levels were evaluated at baseline and then every 2 months. All patients underwent an endocrine workup prior to starting therapy. Disease restaging by computed tomography (CT) scan was per- formed approximately every 12 weeks until disease progression or patient drop-out from the study. Disease response was as- sessed according to RECIST criteria (version 1.1).20
Patients who experienced progression but continued to bene- fit clinically as determined by the treating investigator stayed on therapy for another 8 weeks until radiological confirmation of progression. Once the study treatment was interrupted due to disease progression, the patients were followed for survival.
Endpoints and statistical analysis
The primary endpoint of our study was the ORR according to RECIST 1.1 criteria. Secondary endpoints were clinical benefit rate (CBR), de- fined as the proportion of patients attaining a complete, partial, and stable disease (SD); disease control rate (DCR), defined as the pro- portion of patients attaining an objective response or disease stabil- ization as the best overall response lasting 6 months; PFS, defined as time from treatment initiation to progression by RECIST or death from any cause, or date of the last disease assessment in case of nonprogressing patients; OS, defined as time elapsing from treat- ment start to death for any causes or date of last follow-up; and drug combination safety according to NCI-CTCAE criteria.
Survival curves were calculated with the Kaplan-Meier estima- tor. Statistical analysis was performed with SPSS software (ver- sion 24.0, IBM Corp., Armonk, NY, USA).
Results
Patients characteristics
A total of 23 consecutive patients with advanced ACC, meeting the eligibility criteria, entered the study during the enrollment period. Their characteristics are summarized in Table 1.
The median follow-up for the cohort was 15.1 months [inter- quartile range (IQR), 7.3-20.1].
Women prevailed over males (69.6% vs 30.4%), and the me- dian age was 49 years [range, 32-69].
Seven patients had cortisol-producing ACCs (30.4%) and 2 had androgen-producing ones (8.7%) at first diagnosis, and the re- maining 14 (60.9%) patients had non-hormone-producing tumors. Prior to the initiation of chemo-immunotherapy, 3 pa- tients (13.0%) presented with hypercortisolism and clinical fea- tures of Cushing’s syndrome despite ongoing treatment with mitotane. They were additionally treated with metyrapone at doses ranging from 750 to 1500 mg/day.
Twenty patients (87.0%) had previously undergone adrenalec- tomy, with 14 (60.1%) performed via laparotomy and 6 (26.1%) via laparoscopy. Three patients (13.0%) were metastatic at first diagnosis. Eighteen patients (78.3%) received adjuvant mitotane after surgery, 2 patients (8.7%) received adjuvant therapy with etoposide-cisplatin (EP) plus mitotane as part of the ACACIA trial (NCT00058090), while 3 patients (13.0%) did not undergo any ad- juvant treatment. The median relapse-free survival (mRFS) of the entire cohort was 8.7 months [range, 2.0-34.7].
All patients included had a radiologically PD before starting the cisplatin plus nivolumab regimen. Twenty-two patients (95.7%) had undergone first-line chemotherapy with the EDP-M regimen, while the remaining patients underwent cisplatin monotherapy due to contraindication to polychemotherapy. The median number of first-line chemotherapy cycles was 5 [range, 2-7]. Six patients (26.1%) had achieved a partial response (PR) to first-line chemotherapy, 12 (52.2%) had a SD, and 5 pa- tients (21.7%) underwent disease progression. Overall, 18 pa- tients (78.3%) received first-line chemotherapy before starting treatment with cisplatin and nivolumab. Two patients (8.7%) re- ceived second-line chemotherapy, and 3 patients (13.0%) re- ceived third-line chemotherapy with temozolomide in monotherapy or the combination gemcitabine plus capecitabine.
The median time between the end of first-line treatment with EDP and the initiation of chemo-immunotherapy combination was 7.5 months [range, .9-57.4].
Treatment administered and toxicity
Table 2 shows the number of cycles of cisplatin and nivolumab administered and the reason for their suspension. The median number of cisplatin cycles was 8 [range, 4-22]. The reasons for discontinuation of this drug were disease progression in 14 pa- tients (60.9%) and neurotoxicity in 6 patients (26.1%). The pa- tients who stopped cisplatin therapy for reasons other than disease progression continued nivolumab administration for up to 2 years. Nivolumab was administered for a median number of 9 cycles [range, 4-39].
Chemo-immunotherapy combination was interrupted due to radiological disease progression in 16 patients (69.6%) and for completion of the 2 years in 1 patient. Six patients were still on treatment at the last follow-up date (Table 2).
The treatment was well tolerated. As depicted in Table 3, all patients had an AE of any grade; however, they were mild (G1 and G2) in most of them. The most common AEs were chemo- therapy related, such as asthenia in 14 of patients (60.9%),
| No. of cycles | Reason of withdrawal |
|---|---|
| 4 CIS-NIVO | Disease progression |
| 4 CIS-NIVO | Ongoing treatment |
| 5 CIS-NIVO | Disease progression |
| 5 CIS-NIVO | Disease progression |
| 5 CIS-NIVO | Disease progression |
| 5 CIS-NIVO | Disease progression and G3 hepatic toxicity |
| 5 CIS-NIVO +5 NIVO maintenance | Ongoing treatment. The patient is continuing platinum-free therapy due to neurotoxicity and renal toxicity |
| 6 CIS-NIVO | Disease progression |
| 6 CIS-NIVO +1 NIVO maintenance | Ongoing treatment. The patient is continuing platinum-free therapy due to mucositis |
| 7 CIS-NIVO | Disease progression |
| 7 CIS-NIVO | Disease progression |
| 8 CIS-NIVO | Disease progression. The patient underwent surgery |
| 8 CIS-NIVO | Ongoing treatment |
| 11 CIS-NIVO | Disease progression |
| 11 CIS-NIVO | Disease progression. The patient underwent surgery |
| 11 CIS-NIVO +10 NIVO maintenance | Ongoing treatment. The patient is continuing platinum-free therapy due to neurotoxicity |
| 11 CIS-NIVO +3 NIVO maintenance | Disease progression. Cisplatin had been discontinued due to neurotoxicity |
| 12 CIS-NIVO +1 NIVO maintenance | Disease oligoprogression. The patient underwent TACE on progressive liver lesions |
| 12 CIS-NIVO +4 NIVO maintenance | Disease progression. Cisplatin had been discontinued due to neurotoxicity |
| 14 CIS-NIVO +13 NIVO maintenance | Ongoing treatment. The patient is continuing platinum-free therapy due to neurotoxicity |
| 17 CIS-NIVO 18 CIS-NIVO +4 NIVO maintenance | Disease progression Disease oligoprogression. The PD lesion in psoas muscle was surgically removed |
| 22 CIS-NIVO +17 NIVO maintenance | Completion of 2 years of treatment |
Abbreviation: CIS-NIVO, cisplatin-nivolumab.
nausea in 11 (47.8%), and paraesthesia in 7 (30.4%). While im- munotherapy adverse effects occurred in a very small number of patients, they were mostly oral mucositis in 6 patients (26.1%) and rash in 2 (8.7%). Only 1 patient had G3 liver toxicity after 5 nivolumab administrations, leading to permanent treat- ment discontinuation also due to concomitant disease progres- sion, and 2 patients (8.7%) presented an oral mucositis G3 requiring a temporary suspension.
| All grades | G1 | G2 | G3 | |
|---|---|---|---|---|
| Asthenia | 14 (60.9%) | 8 (34.8%) | 6 (26.1%) | |
| Nausea | 11 (47.8%) | 7 (30.4%) | 4 (17.4%) | |
| Diarrhea | 5 (21.7%) | 5 (21.7%) | ||
| Constipation | 3 (13.0%) | 3 (13.0%) | ||
| Oral dysesthesia | 4 (17.4%) | 3 (13.0%) | 1 (4.3%) | |
| Dysgeusia | 4 (17.4%) | 4 (17.4%) | ||
| Palmar-plantar erythrodysesthesia syndrome | 2 (8.7%) | 1 (4.3%) | 1 (4.3%) | |
| Paresthesia (neurotoxicity) | 7 (30.4%) | 1 (4.3%) | 6 (26.1%) | |
| Mucositis | 6 (26.1%) | 4 (17.4%) | 2 (8.7%) | |
| Erythema | 2 (8.7%) | 2 (8.7%) | ||
| Thyroiditis | 1 (4.3%) | 1 (4.3%) | ||
| Hepatitis | 1 (4.3%) | 1 (4.3%) |
Abbreviation: CIS-NIVO, cisplatin-nivolumab.
Treatment efficacy
Treatment response obtained is depicted in Table S1.
No patients attained a complete response according to RECIST 1.1. Eight patients achieved a PR with an ORR of 34.8% [95% CI, 15.3%-54.2%]; 4 (17.4%) had a SD, and 11 (47.8%) had a PD as the best response to treatment. A clinical benefit was obtained in 12 patients (52.2%) (Figure 1A).
Nine patients maintained the SD or response for 6 months, re- sulting in a DCR after 6 months of 39.1% [95% CI, 19.7%-61.5%] (Figure 1B).
The 3 patients with Cushing’s syndrome despite ongoing mito- tane therapy promptly started metyrapone treatment before and during cisplatin and nivolumab. Of these, 2 exhibited disease progression as their best response and subsequently died, while 1 patient achieved a partial response.
Notably, a patient had a dramatic response (68% reduction in overall tumor size according to RECIST 1.1 criteria and 90% re- duction of the hepatic target lesion) after cisplatin plus nivolu- mab. The therapy continued for the planned duration of 2 years without any signs of progression, and the disease was free from progression at the last follow-up, 28 months after the beginning of treatment (Figure S1). This patient had previously experienced recurrence of the disease to the liver after only 6 months after surgery despite receiving adjuvant mitotane and chemotherapy (cisplatin plus etoposide). Moreover, first-line chemotherapy with EDP-M, second-line therapy with temozolo- mide, and third-line with gemcitabine plus capecitabine for ad- vanced disease were totally ineffective.
Fifteen patients underwent disease progression, and the me- dian PFS was 4.3 months [95% CI, 3.9-13.0] (Figure 2A). Six pa- tients died, and the median OS was 18.9 months [95% CI, 15.8-not reached] (Figure 2B).
Four patients were addressed to cytoreductive surgery after chemo-immunotherapy, and 3 of them were currently free from progression after 3, 3, and 7 months, respectively. The re- maining patient underwent lung and liver progression after 7 months. Interestingly, 1 of these patients before starting che- mo-immunotherapy had a large pelvic mass that was associated with abdominal ascites, which needed frequent evacuative
paracentesis. The restaging CT scan showed a progression of pel- vic mass after 8 cycles of therapy, despite an increase in the nec- rotic component. However, the ascites had disappeared completely, so the patient could be radically resected of the vo- luminous pelvic mass (Figure S2).
Moreover, 1 patient was given locoregional treatments on metastatic lesions after oligo disease progression after 22 treat- ment cycles, which were liver transarterial chemoembolization (TACE) and muscle metastasis cryoablation.
The 6-month interval after the end of a previous treatment with a cisplatin-containing regimen is regarded as a valuable cut-off to detect malignancies that may be sensitive to a cisplatin rechallenge.21 To explore the potential contribution of cisplatin rechallenge to the efficacy of cisplatin + nivolumab immunoche- motherapy, we assessed the patients’ outcome by stratifying them based on the 6-month cut-off from the end of EDP-M to the beginning of cisplatin + nivolumab. No difference was found between the 2 groups in terms of either PFS and OS (Figure S3).
Discussion
This retrospective single-center study showed that a chemo- immunotherapy combination with cisplatin plus nivolumab, ad- ministered as a second/third line in patients with metastatic ACC was active. The ORR of 35% and clinical benefit obtained in 52% of patients were relevant as they appeared superior to the results obtained by chemotherapy, target therapy, and immunotherapy alone administered in the same setting.6-14 In addition, the re- sponse was durable since 39% of patients were free from pro- gression after 6 months. In particular, a patient has achieved remarkable tumor shrinkage after a few months of therapy. He completed the maximum expected 2-year duration of chemo-im- munotherapy without developing progression and was still free from progression after 6 months of treatment interruption. Because the disease was resistant to 2 previous lines of treat- ment for advanced disease, the result obtained with cisplatin and nivolumab in this patient was extraordinary. It is known that patients with ACC may develop hypercortisolism, which can hinder the efficacy of immunotherapy.16 In this study, 3
A
90%
80%
Partial response
70%
Stable disease
Progressive disease
60%
50%
40%
30%
20%
10%
0%
-10%
-20%
-30%
-40%
-50%
-60%
-70%
-80%
B
Cushing’s syndrome
Cushing’s syndrome
I
Cushing’s syndrome
Partial response
Stable disease
Progressive disease
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
duration of the treatment
FU time after treatment completation
| death
patients developed Cushing’s syndrome despite being on mito- tane therapy. They were immediately treated with full doses of metyrapone; 2 of them had a disease progression as the best re- sponse and subsequently died, while 1 had a partial response to therapy. These results indicate that Cushing’s syndrome may not be a deterrent to immunotherapy due to the availability of powerful steroidogenesis inhibitors such as metyrapone.22 22
Overall, the median PFS of 4.3 months of patients included in this study was relatively short, although it was superior to that obtained by immunotherapy administered alone. However, the most significant result of this study was the relatively low propor- tion of death after a median follow-up of 15 months. Although during the study course 15 patients underwent progression, only 6 of them died, so the median OS was about 19 months.
A
100%
B
100%
75%
75%
Survival Probability
Survival Probability
50%
50%
25%
25%
0%
0%
0
5
10
15
20
25
30
0
5
10
15
20
25
30
Time
Time
At Risk 23
10
5
3
1
1
0
At Risk 23
17
12
9
3
1
0
Events
0
11
15
17
17
17
17
Events
0
2
2
4
6
6
6
This study’s survival data is of great interest because it is not only much better than the survival achieved with chemotherapy and tar- get therapy administered as a second line in patients with metastat- ic ACC6-13 but appears superior to the median survival of 14 months obtained with EDP-M in the first metastatic line.5 These data suggest that the combination cisplatin plus nivolumab was efficacious, and the efficacy seems to be maintained beyond progression. After dis- ease progression to cisplatin and nivolumab, 3 patients underwent debulking surgery, but they did not experience any further progres- sion after 3, 3, and 7 months, respectively. Notably, 1 of these patients had a pelvic lesion, which increased in size after treatment; however, the mass was associated with ascites, which disappeared after chemo-immunotherapy allowing surgery feasible despite dis- ease progression according to RECST 1.1 criteria. Therefore, in this patient, the overall response has been progression, but the dis- appearance of ascites that made surgery feasible identifies a favor- able result of chemo-immunotherapy. Another patient received local regional therapies for oligoprogression, and the disease did not further progress after 7 months. Taken together, these data sug- gest that this regimen may have made the disease more indolent, leading to a positive effect on OS.
Disparities between PFS and OS have already been observed in immunotherapy studies that involved patients with metastatic disease from other histologies.23,24
It is noteworthy that the survival of patients enrolled in this study is higher than the 14 months of survival obtained with immunother- apy alone. Although this observation, which is based on an indirect comparison, should be taken with caution, these data suggest that the combination with chemotherapy may improve the efficacy of immunotherapy, as demonstrated in other neoplasms. 18,19
In general, the present study’s results indicate that combining an immune check point inhibitor with another antineoplastic drug is a way for overcoming the intrinsic immunoresistance of ACC. Along with the results obtained in renal cell carcinoma with the combination of immunotherapy and an antiangiogenetic drug, a prospective phase II study conducted in China tested the
combination of camrelizumab and apatinib as second line in 21 patients with advanced ACC. The results were exceptionally good with objective remission rates of 53%, a 13-month PFS, and a 21-month OS.25 Recently, a study conducted across mul- tiple centers in Spain has published the results of a combination of atezolizumab (a PDL-1 inhibitor) and cabozantinib in 24 pa- tients with pretreated advanced ACC. The ORRs (8%), mPFS (2.9 months), and mOS (13.5 months) did not appear to be better than what was expected solely from immunotherapy.26 Based on these conflicting results, the efficacy of combining immuno- therapy with antiangiogenetic drugs requires confirmation.
Overall, cisplatin plus nivolumab treatment was well tolerated, and there was no unexpected toxicity compared to what is com- monly observed with the administration of the 2 individual drugs. Certainly, the administration of cisplatin is encumbered by neur- opathy, which is related to the cumulative dose administered. This is why, in 6 nonprogressing patients requiring prolonged therapy, cisplatin was discontinued and treatment continued with nivolumab only. Immunotherapy resulted in the discontinu- ation of only 1 patient due to autoimmune hepatitis. The reason why cisplatin was chosen as the cytotoxic drug to be combined with nivolumab is that it is the most effective chemotherapy for treating ACC. Rechallenging cisplatin-containing regimens in pa- tients who have been treated with EDP-M has been demonstrated to recruit disease responses.27 Therefore, we could not exclude that some of the positive results obtained in this study may be at- tributable to the efficacy of cisplatin rechallenge, especially when a long time has elapsed since the administration of EDP-M.
However, the absence of an advantage in terms of PFS and OS of the group of patients with platinum-free interval greater than 6 months compared to their counterpart suggests that platinum resistance did not have a detrimental contribution on the effi- cacy of the combination regimen.
The strength of this study is that the patients enrolled were con- secutive and all managed in a single reference center for this very rare disease. The retrospective nature is the main limitation.
In conclusion, the results of this study show that the combin- ation of chemotherapy with immunotherapy is efficacious in the management of patients with metastatic ACC and has the poten- tiality to become the standard second-line therapy. These data need to be confirmed in a prospective study.
Acknowledgments
We thank CreativeLab ASD, school of dance, Livorno, Italy, https:// www.facebook.com/creativelabasd in memory of Serena Mazzoni, Fratelli Cattaneo snc in memory of Silvia Cattaneo, Mrs Serena Ambrogini in memory of her son Guido Cioni, Fondazione Internazionale di Ricerca in Medicina (F.I.R.M.) ONLUS, Cremona (Italy), for supporting research against adrenal cortical carcinoma at our institute.
Authors’ contributions
Marta Laganà (Investigation [equal], Supervision [equal], Validation [equal], Writing-original draft [equal]), Sara Rodella (Data curation [equal], Formal analysis [equal], Methodology [equal], Writing- original draft [equal]), Davide Lorenzo Bettini (Data curation [equal], Investigation [equal], Validation [equal]), Andrea Esposito (Investigation [equal], Validation [equal]), Andrea Abate (Methodology [equal], Software [equal], Validation [equal]), Roberta Ambrosini (Software [equal], Validation [equal]), Mariangela Tamburello (Methodology [equal], Validation [equal]), Francesca Consoli (Investigation [equal], Validation [equal]), Rita Tinti (Software [equal], Validation [equal]), Stefano Calza (Methodology [equal], Software [equal], Supervision [equal]), Giovanni Casole (Validation [equal]), Guido Alberto Massimo Tiberio (Supervision [equal], Validation [equal]), Sandra Sigala (Investigation [equal], Methodology [equal], Supervision [equal], Validation [equal]), Alfredo Berruti (Investigation [equal], Supervision [equal], Validation [equal], Writing-original draft [equal]), Salvatore Grisanti (Investigation [equal], Supervision [equal], Validation [equal]), and Deborah Cosentini (Data curation [equal], Investigation [equal], Methodology [equal], Validation [equal])
Supplementary material
Supplementary material is available at European Journal of Endocrinology online.
Conflict of interest: A.B. has received fees for advisory board and pub- lic speaking from Merck Sharp and Dome, ESTEVE, and RECORDATI and research funding from REGENERON. S.G. has received fees for advisory board from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dome, Novartis, Pfizer, Regeneron, Roche, and Takeda. D.C., M.L., S.R., D.L.B., A.E., A.A., R.A., M.T., F.C., R.T., S.C. G.C., G.A.M.T., and S.S. have no conflicts of interest to declare.
Funding
This research was funded in part by AIRC (Associazione Italiana per la Ricerca contro il Cancro), IG23009 (PI: A.B.) and IG27233 (PI: S.S.).
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