ENDOCRINE SOCIETY
OXFORD
Targeting 11-Beta Hydroxylase With [131]]IMAZA: A Novel Approach for the Treatment of Advanced Adrenocortical Carcinoma
Stefanie Hahner,1,* Philipp E. Hartrampf,2,*,OD Patrick W. Mihatsch,3 Marc Nauerz,2 Britta Heinze,1 Heribert Hänscheid,2 Carmina Teresa Fuß,1 Rudolf A. Werner,2 Christina Pamporaki, 4,[D Matthias Kroiss,1,5 Martin Fassnacht,1.[D Andreas K. Buck,2 and Andreas Schirbel2
1Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, Oberdürrbacher Straße 6, D-97080 Würzburg, Germany
2Department of Nuclear Medicine, University Hospital, University of Würzburg, Oberdürrbacher Straße 6, D-97080 Würzburg, Germany;
3Department of Diagnostic and Interventional Radiology, University Hospital, University of Würzburg, Oberdürrbacher Straße 6, D-97080 Würzburg, Germany
4Division of Endocrinology, Department of Internal Medicine III, University Hospital, University of Dresden, Fetscherstraße 74, D-01307 Dresden, Germany
5Department of Internal Medicine IV, University Hospital Munich, Ludwig-Maximilians-Universität München, Ziemssenstraße 5, D-80336 Munich, Germany
*S.H. and P.E.H. equally contributed.
Correspondence: Philipp E. Hartrampf, University Hospital Würzburg, Department of Nuclear Medicine, Oberdürrbacherstr. 6, D-97080 Würzburg. Email: Hartrampf_P@ukw.de.
Abstract
Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options. Theranostic approaches with adrenal specific radiotracers hold promise for improved diagnostics and treatment.
Objective: Here, we report a new theranostic approach to advanced ACC applying (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide ([123I]IMAZA) for diagnostic imaging and [13]]]IMAZA for radionuclide therapy.
Methods: Sixty-nine patients with nonresectable, metastatic ACCs were screened using a diagnostic [123IJIMAZA scan. Patients with significant uptake in all tumoral lesions were offered treatment with [13]]]IMAZA. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), and adverse effects were assessed by Common Toxicity Criteria (version 5.0).
Results: After screening, 13 patients were treated with a median of 25.7 GBq [131I]IMAZA (range 18.1-30.7 GBq). Five individuals received a second treatment course. Best response was a decrease in the RECIST target lesions of -26% in 2 patients. Five patients with disease stabil- ization experienced a median progression-free survival of 14.3 months (range 8.3-21.9). Median overall survival in all patients was 14.1 months (4.0-56.5) after therapy. Treatment was well tolerated, in other words no severe toxicities (CTCAE grade ≥3) were observed.
Conclusion: In patients with advanced ACC refractory to standard therapeutic regimens, [13] ]]IMAZA treatment was associated with disease stabilization and nonsignificant tumor size reduction in a significant patient fraction and only limited toxicities. High [131|]IMAZA-uptake in tumor lesions was observed in 38.5% of patients with advanced ACC, rendering [1311] IMAZA a potential treatment option in a limited, well-defined patient fraction. Further clinical trials will be necessary to evaluate the full potential of this novel theranostic approach.
Key Words: adrenocortical carcinoma, adrenal cancer, ACC, IMAZA, radionuclide therapy, 11-beta hydroxylase, CYP11B Abbreviations: [ 123I]IMAZA, (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide; ACC, adrenocortical carcinoma; CTCAE, Common Toxicity Criteria of the National Cancer Institute; PFS, progression-free survival; PRRT, peptide receptor radionuclide therapy; SOD, sum of diameter; SSTR, somatostatin receptor.
Adrenocortical carcinoma (ACC) is a rare malignancy with an overall poor prognosis (1, 2). Even after complete resection, disease recurrence is observed in 40% to 70% of patients (3). So far, pharmacological treatment options are of limited success (4, 5). Current standard treatment in nonresectable ACC consists of mitotane, which is the only approved drug (1, 6). Based on the results of a large phase 3 trial, mitotane is frequently combined with etoposide, doxorubicin, and cis- platin as first-line treatment (7). However, this combination
therapy only leads to an objective response rate of 23%, a progression-free survival (PFS) of 5.1 months and is associ- ated with significant toxicity. Thus, second- and third-line treatment options are needed in most patients. Radiation therapy has been shown to be of clinical utility both in an adjuvant and palliative setting, indicating radiation sensi- tivity of ACC (8-13). As a recent publication showed that ACC may express somatostatin receptors (SSTRs), a peptide receptor radionuclide therapy (PRRT) might be suitable but
only 1 case study reporting on 2 patients receiving [90Y] or [177Lu]DOTATOC therapy has been reported so far. An overall disease control lasting for 4 and 12 months was ob- served (14).
The radiotracers [11C]metomidate and [123I]iodometomidate ([123IJIMTO) selectively bind to the adrenal specific enzymes 11-beta-hydroxylase (CYP11B1) and aldosterone syn- thase (CYP11B2) and have been shown to accumulate in adrenocortical carcinoma tissue (15-18). Taking advantage of this high adrenocortical avidity, a theranostic concept was introduced employing [123IJIMTO for molecular imaging and [131I]IMTO for radionuclide therapy (19).
Treatment of ACC with [13]]]IMTO demonstrated fa- vorable tolerability and clinically meaningful responses in a small series of 11 patients with advanced ACC. Disease control for ≥5 months with a median PFS of 14 months was achieved in 54% of the patients (19). From a general perspective, success of radionuclide therapy depends on the intratumoral expression of the target enzymes, radiosensitivity of the tumor tissue, and retention of the radiotracer in the tumor lesions.
Rapid metabolic inactivation of [123IJIMTO in vivo led us to the assumption that a compound with higher metabolic stability might improve and prolong target binding and con- secutively result in higher tumor doses. Such a compound was recently developed by replacing the methyl ester in [123]] IMTO by a carboxylic amide: (R)-1-[1-(4-[123I]iodophenyl) ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide ([123]] IMAZA) (20).
In preclinical studies, IMAZA showed similarly high avidity to the target enzymes CYP11B1 and CYP11B2, higher meta- bolic stability and sustained uptake in the target tissue. In first-in-human investigations, [123IJIMAZA provided higher tumor to background ratios than [123IJIMTO and a faster clearance from nontarget tissues. The rapid clearance resulted in lower doses to both the whole body and the bone marrow, which enables administration of very high therapeutic activ- ities in case of endoradiotherapy (20).
We here report our experience with [131IJIMAZA treatment in a series of patients with advanced ACC.
Patients and Methods
Radiolabeling
The radiosynthesis of [13]]]IMAZA followed the same protocol (https://sci-att.com/grp/) as already published (20) and was performed by a GRP module (Scintomics GmbH, Fürstenfeldbruck, Germany) inside a well-ventilated lead cell.
Patient Selection and Administration of [13]]]IMAZA
Between December 2014 and June 2019, 69 patients with nonresectable ACC and metastatic disease were screened for specific retention of [123IJIMAZA in preknown tumor manifestation sites. Target uptake was visualized by single photon emission computed tomography (SPECT)/computed tomography (CT) after intravenous administration of about 185 MBq of [123IJIMAZA. Thirteen patients showed intense uptake in all ACC lesions and were considered suitable for treatment with [131I]IMAZA by an interdisciplinary tumor board. All patients had measurable target lesions as defined by response evaluation criteria in solid tumors (RECIST ver- sion 1.1) (21). Patient characteristics are described in Table 1.
[131I]IMAZA dosimetry and treatment were performed after individual decision making based on §13.2b of the German Pharmaceuticals Act.
Based on the first 7 treatments, the maximum administrable therapeutic activity was assessed by dosimetry with ~75 MBq of [131IJIMAZA. Whole-body planar images were acquired 5 minutes as well as 1, 4, 24, 48, and 72 to 120 hours after injec- tion. Imaging was performed with concurrent acquisition of a standard activity for quality control. In parallel, blood samples were taken to quantify the activity concentration in the periph- eral blood. Activity time functions and residence times were de- duced, and the specific radiation absorbed dose to the blood was determined as recommended (22). In the absence of major [131]]IMAZA accumulation in nonadrenocortical tissue, blood was considered as a surrogate of the actual critical organ at risk, namely the bone marrow. The maximal tolerable activity was calculated aiming for a bone marrow dose of 2 Gy. For the later treatments, the maximal tolerable activity was estimated based on the activity kinetics measured after [123I]IMAZA.
Patients received 1 g of sodium perchlorate orally for thy- roid blockade 30 minutes in advance of each administra- tion of radiolabeled [123I]IMAZA. Both potassium iodide and perchlorate were used for blocking thyroidal uptake during therapy. Also, antiemetic drugs (dimenhydrinate or ondansetron) were administered. Up to 30 GBq of [131]] IMAZA, dissolved in 10 mL of ethanol/phosphate-buffered saline (PBS) 40/60, was administered with the help of an in- fusion pump and an intravenous catheter. To prevent pain during injection, the tracer was diluted immediately before infusion with saline solution using a 3-way valve attached to the indwelling cannula. Finally, the whole infusion system was flushed with 50 mL of saline containing 5% ethanol.
During inpatient treatment, activity kinetics were meas- ured to verify the results of pretherapeutic dosimetry. Besides whole-body retention measurements with a survey meter at 2 m distance after each treatment, blood samples were drawn during 5 treatments.
To assess kinetics in tumor lesions and to calculate ab- sorbed tumor doses, planar whole-body scanning was per- formed 2 to 4 days after therapy (as soon as the radioactivity level was below 1 GBq). Most patients also received a SPECT/ CT scan before discharge.
Evaluation of Toxicity and Tumor Response
Documentation of patient history, physical examination, and performance status were included in the baseline evaluation. A full blood cell count, serum chemistry profile, and tomo- graphic imaging (chest and abdominal CT or whole-body fludeoxyglucose positron emission tomography (FDG-PET)/ CT and/or magnetic resonance imaging scans) were collected as part of the clinical routine. Acute drug-related adverse events and toxicities were evaluated during hospitalization by daily visits. For evaluation of subacute drug-related ad- verse events and toxicities (especially bone marrow and kidney function) data of serum chemistry and full blood cell counts were sent to our department at 2-weekly intervals for the first 3 months. For longer follow-up, patients either pre- sented at our department or medical records from outpatient specialists were evaluated. Drug-related adverse events and toxicities were evaluated according to the Common Toxicity Criteria of the National Cancer Institute (CTCAE version 5.0) (23). For response monitoring, repetitive FDG-PET/CT imaging was performed in median every 4 months (2.7-7.8)
| Patient | Sex | Age | Hormone production | Sites of tumor manifestation | Time from surgery of ACC to IMAZA therapy (months) | Previous surgical treatments (n) | External radiation therapy | systemic Previous therapies (n) | Systemic therapies | Mitotane within 4 months before 1st IMAZA therapy | systemic Subsequent therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | f | 73 | Cor, Est, And | LR, LI, LU, LN, ST | 56 | 1 | No | 2 | M, EDP | No | — |
| 2 | m | 72 | Est, | LU, SK | 18 | 1 | Yes | 2 | S, M | Yesª 0.2 | - |
| 3 | f | 58 | Cor, Ald | LR, LU, ST | 33 | 2 | Yes | 3 | EDP, M, S | Yesª 14.8 | G/C |
| 4 | f | 73 | Cor | LR, LU | 20 | 1 | Yes | 1 | M | No | S, Entrectinib |
| 5 | f | 66 | Cor | LU, ST | 35 | 2 | Yes | 1 | M | Yes ª19.1 | M |
| 6 | f | 61 | unknown | LR, LI, LU | 19 | 2 | No | 3 | EDP-M, T, G/C | No | S, EDP |
| 7 | f | 31 | Cor, And | LI, LU, LN, ST | 25 | 1 | Yes | 4 | EDP, M, G/C, S, | No | n/a |
| 8 | f | 53 | Cor | LU, LN, ST | 174 | 9 | Yes | 5 | M, S, C/E, G/C, IMTO | Yesª 19.2 | Nivolumab, M, Endoxan/ MTX |
| 9 | f | 72 | no | LR, LU, ST | 44 | 1 | No | 5 | M, C/E, D, N, G/C, | No | S |
| 10 | f | 55 | unknown | LR, LU, LI, LN, SP | 61 | 2 | No | 3 | M, C, G/C, | Yesb | unknown |
| 11 | f | 35 | unknown | LI, LN, ST | 37 | 3 | Yes | 4 | M, D+C, adriamycin+etoposide, G/C, | No | unknown |
| 12 | f | 70 | Cor, Ald | LI, SK | 13 | 1 | Yes | 3 | M, G/C, IMTO, | Yesª 16.4 | — |
| 13 | f | 65 | Cor, And | LR, LI, ST | 41 | 2 | No | 1 | M | No | unknown |
Abbreviations: f, female; m, male; Cor, cortisol; Ald, aldosterone; And, androgens; Est, estrogens; LR, local recurrence; LI, liver; LU, lung; LN, lymph nodes; SK, skeleton; SP, spleen; ST, other soft tissue; EDP, etoposide; doxorubicin; cisplatin; M, mitotane; EDP-M, etoposide, doxorubicin, cisplatin, and mitotane; T, thalidomide; G/C, gemcitabine/capecitabine; S, streptozotocin; D, docetaxel; N, navelbine; C, cisplatin; C/E, carboplatin/etoposide; IMTO, [131IJIMTO. “Last available mitotane value (mg/L).
bLast mitotane value not available.
Tumor response was assessed using RECIST criteria (version 1.1) (21).
Statistical Analyses
Statistical analyses were performed using GraphPad Prism ver- sion 9.0.2 for Windows (GraphPad Software, San Diego, CA, USA). Descriptive data are presented as median and range in parentheses. Survival times were analyzed with the Kaplan- Meier method. Overall survival (OS) was calculated starting with the date of the first [13]]]IMAZA therapy. Comparison between subgroups was performed using the Mann-Whitney U-test. A P value of <. 05 was considered statistically significant. Since the presented study is of retrospective character and there- fore exploratory, a sample size analysis was not performed.
Results
Screening With [123]]IMAZA
In the [123I]IMAZA screening scan, 34 of 69 patients showed [123I]IMAZA uptake in known tumorous lesions. Of these, 7 patients showed a heterogeneous uptake pattern (not all lesions showed sufficient uptake) and were not considered for [13]]]IMAZA therapy. Of the remaining 27 patients with [123IJIMAZA uptake, 14 were offered an alternative treatment due to rapid tumor progression (5 patients), un- promising dosimetry data (4 patients), or the decision of an
interdisciplinary tumor conference (5 patients). Thirty-five patients showed no relevant uptake in tumor lesions after visual evaluation. Figure 1 shows the patient recruitment process.
Patients Receiving Treatment
In total, 13 patients (12 females, 1 male) with advanced disease were treated with a median administered activity of 25.2 GBq (range 18.1-30.1 GBq) of [13]]]IMAZA. Five pa- tients with favorable biodistribution and disease stabilization received a second treatment course with [13]]]IMAZA and a median activity of 26.0 GBq (range 24.0-30.7 GBq).
All patients had received primary surgical treatment and 8 patients had received external radiation therapy for local con- trol of metastatic lesions. Median time from initial surgery to [13]]]IMAZA therapy was 35 months (range 13-174 months). Progressive disease after a median number of 3 drug regi- mens (range 2-5) was documented before initiation of [131]] IMAZA therapy in all patients. All patients had received mitotane either as monotherapy or in combination with etoposide, doxorubicin, and cisplatin. At the time of [131]] IMAZA therapy, 3 patients were still receiving mitotane (pa- tients 5 and 8, both with last mitotane plasma concentration before treatment at 19 mg/L) or had stopped only a few days before (patient 12, last plasma concentration before therapy at 16 mg/L).
Screening
Patients with [123|]IMAZA screening scan (n = 69)
. No relevant uptake in the tumour lesions (n = 35)
Patients with [1231]IMAZA uptake in screening scan (n = 34)
Eligibility
· Heterogeneous [123]]IMAZA uptake (n = 7)
· Clinical progress before therapy start (n = 5)
. Unpromising dosimetry data (n = 4)
. Decision for another therapy by tumour board (n = 5)
Analysis
Patients with [131|]IMAZA treatment (n = 13)
Table 1 further outlines the characteristics of the study co- hort, including hormonal activity, sites of metastases and pre- vious therapies.
Dosimetry
Activities in total body were well fitted by mono- or biexponential decay functions for 13 treatments with a median residence time of 10.2 hours (range 6.6-29 hours). Median specific blood absorbed dose to the blood was 0.04 Gy per GBq of [13]]]IMAZA administered (range 0.04-0.06 Gy/GBq). Total blood dose was estimated for 7 treatments and ranged between 1.1 and 1.7 Gy. The distribution pattern indicated that the blood absorbed dose can be used as a conservative estimate for the radiation absorbed dose to the red marrow. Calculated doses for a single tumor lesion ranged between 6.4 and remarkable 265 Gy (24) ..
Adverse Effects of [13]]]IMAZA Treatment
Median time of hospitalization was 6.5 days (range 4-15) according to the German Radiation Protection Regulation. No severe acute adverse effects due to [131IJIMAZA were ob- served after therapy. The treatment was well tolerated by all patients. A single patient reported nausea and vomiting a few days after therapy. Another patient reported reduced sense of taste. One patient developed diarrhea during hospitalization and another patient had fever. One patient developed hypo- kalemia due to aldosterone excess.
As documented for treatment with [131IJIMTO, a transient suppression of the bone marrow could be observed after radionuclide therapy with a maximum suppression after ap- proximately 6 weeks. In our cohort, no toxicities above grade 2 were reported in the first follow-up visit 3 months after therapy. Only mild anemia (grade 1: 1 patient, grade 2: 2 pa- tients) occurred. No blood transfusions were needed. Kidney function assessed by estimation of glomerular filtration rate with the modification of diet in renal disease (MDRD) formula was not affected by [131IJIMAZA (Table 2, Fig. 2).
Antitumor Efficacy of [13]]]IMAZA Treatment
In 12 out of 13 patients, at least 1 imaging follow-up was available, whereas 1 patient was lost to follow-up due to
| Acute | Grade 1/2 | Grade 3/4 |
|---|---|---|
| Nausea | 1 | — |
| Reduced sense of taste | 1 | — |
| Diarrhea | 1 | — |
| Hypokalemia due to aldosterone excess | 1 | — |
| Subacute | ||
| Anemia | 3 | — |
| Leukopenia | — | — |
| Thrombocytopenia | — | — |
| Kidney disfunction | — | — |
100
80
60
Change in %
40
20
0
-20
-40
Hemoglobine Leukocytes
Platelets
Erythrocytes Creatinine
further treatment abroad (Table 3). Response assessment using RECIST 1.1 criteria in follow-up CT scans after a me- dian of every 4 months (2.7-7.8) for best response revealed stable disease in 5 out of 12 patients (median change in sum of diameters [SODs] -16 mm, range -26 to -11 mm) and progressive disease in 7 out of 12 patients, respectively (me- dian change in SOD 30 mm, range: +3 to +150 mm) (Table 3, and Figs. 3 and 4). In addition, 2 patients with stable target lesions were classified as progressive disease because of the presence of new tumor lesions at follow-up. Median PFS of the whole cohort was 4.1 months (range 0.2-21.9), while PFS in 5 patients with disease stabilization was 14.3 months (range 8.3-21.9) and in patients with a progressive disease as best response only 3.2 months, respectively (range 0.2-4.4). Regarding overall survival, the median survival in our cohort was 14.1 months (range 4-56.5) (Fig. 5).
No significant differences were detected between patients with disease stabilization (n = 5) and patients with progres- sive disease (n = 7) regarding age at [131IJIMAZA treatment, time from initial surgery, number of therapy lines, and the number of tumor sites.
Discussion
We here report on the safety and efficacy of a novel radio- nuclide based therapy with the radiopharmaceutical [131]] IMAZA in a series of patients with advanced ACC. The
| Patient | Best response | Response at last follow-up | Baseline SOD (mm) | Best response SOD (mm) | Progression-free survival (months) | Overall survival after [131]] IMAZA treatment (months) |
|---|---|---|---|---|---|---|
| 1 | SD | PD | 120 | 94 | 21.9 | 30 |
| 2 | PD | PD | 30 | 40 | 3.0 | 4 |
| 3 | PD | PD | 53 | 203 | 4.4 | 12.8 |
| 4 | SD | PD | 72 | 53 | 12.8 | 33 |
| 5 | PD | PD | 26 | 56 | 3.4 | 11 |
| 6 | SD | PD | 113 | 102 | 8.3 | 15 |
| 7 | PD | PD | 109 | 159 | 0.2 | 13.2 |
| 8 | SD | PD | 42 | 31 | 17.9 | 56.5 |
| 9 | SD | PD | 104 | 88 | 14.3 | 18.2 |
| 10 | PD | PD | 156 | 178 | 3.7 | 29 |
| 11 | PD | PD | 261 | 258 | 2.7 | 8 |
| 12 | PD | PD | 114 | 156 | 3.2 | 9.9 |
| 13 | l.t.f.u. | — | — | — | — | — |
Abbreviations: SOD, sum of diameters; PD, progressive disease; SD, stable disease; l.t.f.u., lost to follow-up.
300
250
200
Change in target lesions (SOD) in %
150
120
100
80
60
40-
20
0
-20
-40
3
5
7
12
2
10*
11*
6
9
1
8
4
Patient No.
highly specific uptake in the target tissue enabled treat- ment with only minimal adverse effects. In general, transient bone marrow suppression is considered to be the most im- portant and dose limiting toxicity. From radioiodine therapy in thyroid cancer and from [13]]]IMTO therapy in ACC it is known that an absorbed dose to the blood of less than 2 Gy of radiation is safe, making repeated radiotherapies feasible. Treatments with [13]]]IMAZA did not exceed a total blood dose of 1.7 Gy. In our study, no CTCAE grade III or IV events with need of medical intervention (eg, transfusion of plate- lets or administration of growth factors) were observed. This stands in contrast to many cytotoxic treatments. As long-term follow-up is rare, long-term toxicity cannot be excluded with certainty, but, in our opinion, the potential benefit of [13]]] IMAZA radionuclide therapy outweighs the potential risks of bone marrow suppression.
After therapy, 7 out of 13 patients presented stable target lesions. Disease stabilization according to RECIST 1.1 cri- teria was achieved in 5 patients (42%). Median PFS was 4.1 months for the whole cohort and median overall survival was 14.1 months. For patients with disease stabilization, me- dian PFS was 14.3 months. Remarkably, even after experi- encing progressive disease following 5 different systemic antitumor treatments, a disease stabilization with reduction of target lesions by 15% and 26% was observed in 2 patients (nos. 8 and 9). Based on our preclinical analyses (20) and the imaging results obtained in patients evaluated with [131]] IMAZA, our hypothesis was that treatment results might be superior to treatment with [131IJIMTO. In fact, our results are comparable with those obtained with [131IJIMTO. Similarly, overall survival in our study cohort was 14.1 months, com- pared with 13 months in the [13]]]IMTO-treated cohort (19). This finding suggests that tumor sensitivity to radiation could be more a more relevant factor for treatment efficacy than the residence time of the radiopharmaceutical.
For [131IJIMTO treatment, interruption of mitotane treat- ment before therapy was considered necessary (19), as it is known that mitotane can attenuate the uptake of [11C] metomidate in adrenocortical tissue (25). To date, the effect of mitotane in attenuating the uptake of [131IJIMAZA remains unclear. In this study, no standard assessment of mitotane levels was performed. Six patients were on active mitotane treatment or had received mitotane within 4 months before receiving [131IJIMAZA therapy. All 6 patients still showed a high tracer uptake. Of note, a higher proportion of patients showing stable disease at first follow-up was notable in the group of patients without recent mitotane treatment war- ranting assessment in a larger cohort. Despite the combination of different chemotherapies, such as etoposide, doxorubicin, cisplatin, and mitotane, which has been established as first- line systemic therapy of metastatic ACC with a median PFS of 5 months and a median overall survival of approximately 15 months (7), prognosis of advanced stage ACC still remains poor and novel treatments are urgently needed.
In the last years some other approaches for salvage therapy with controversial results were introduced. Several attempts
a
d
f
i
b
e
g
j
C
h
FDG baseline
1st therapy
2.5 months
5 months
2nd therapy
14 months
Overall survival
100
Probability of Survival (%)
80
60
40
20
0
0
10
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Months
to target tyrosine kinases have failed including trials with sunitinib, linsitinib, or axitinib (26-28), but we recently found promising responses to cabozantinib (29). Whereas immune checkpoint inhibitors have revolutionized treatment of many cancer entities, initial studies of different inhibitors in ACC were heterogeneous with only selected patients benefiting from treatment (30-34). A recent case study in 2 patients showed that PRRT with [90Y] or [177Lu]DOTATOC was as- sociated with an overall disease control of 4 and 12 months, respectively (14).
As ACC is a very heterogeneous disease and several trials demonstrated that a “one fits all” approach is not promising it might be necessary to tailor treatment to specific targets and/or combine different treatment options to simultaneously attack this aggressive tumor from different angles (35). [131]] IMAZA radionuclide therapy may be 1 component of this in- dividualized therapeutic approach in future. It might further be interesting to assess the potential of [13]]]IMAZA at earlier stages of the disease or in an adjuvant setting in those patients exhibiting high and sustained tracer uptake in their primary
tumor preoperatively. This, however, warrants evaluation in future prospective studies.
A very important difference between [131IJIMAZA treat- ment and conventional cancer therapies is the approach with a “tailor-made” therapy for patients, which signifi- cantly exhibits the target structure. This target structure can be made visible by scintigraphy with [123IJIMAZA following the theranostic idea. Unfortunately, the number of patients eligible for [13]]]IMAZA treatment as a therapeutic option and the final number of treated patients was low with only 13 (19% of scanned patients). Accordingly, the percentage of screened patients which showed a benefit (disease stabil- ization in target lesions) was also very low with ~10%. For future research projects, it still remains to identify the charac- teristics required for successful [13]]]IMAZA treatment to im- plement an individually adjusted therapy of ACC. In our small cohort it was not possible to detect significant predictors for treatment response after [131I]IMAZA, so for now, it is recom- mended to only consider patients showing a high radiotracer uptake in all tumor lesions, ensuring sufficient tumor doses under [131IJIMAZA treatment. In addition, patients with very rapidly progressing disease might not be suitable candidates for radionuclide therapy, as it takes a certain amount of time to fully deliver the radiation dose to the tumor cell compart- ment. We also assume that the low number of treatable pa- tients might be due to the poor differentiation of advanced ACC where the target enzymes CYP11B1/2 are no longer ex- pressed. So, further optimization of the chemical structures of [131I]IMAZA or [13]]]IMTO does not seem promising. Instead, new approaches targeting other steroidogenic enzymes which are expressed more frequently, might prove useful.
Our study has several limitations: First, treatment and follow-up were not completely standardized and the treat- ment was performed on a compassionate use base according to §13.2b of the German Pharmaceuticals Act. According to our internal standards, restagings were planned every 3 months, but we had also patients from other German cities and European countries with some deviations in restaging intervals. However, the imaging data were sufficient for re- sponse evaluation according to RECIST 1.1 criteria. Also,
data concerning possible adverse events was registered on a regular basis. Second, the study group was heterogeneous as it consisted mostly of patients with late-stage disease that had received different previous treatments at different cen- ters. Third, the number of treatments and therefore the cu- mulative activity differed in this study. Five patients received 2 cycles and tended to show a longer overall survival (at least 15 months) than the patients receiving only 1 cycle. The pos- sibility remains, that an additional therapeutic cycle could have improved the overall survival for these patients, too.
Conclusion
Targeted radionuclide therapy with [131IJIMAZA shows rele- vant antitumor activity in a fraction of patients with advanced and heavily pretreated, refractory ACC. First-in-man use does not suggest a clinical advantage over the previously proposed compound [131IJIMTO. Further evaluation in prospective clin- ical trials is necessary to fully discover the therapeutic poten- tial of this novel compound.
Acknowledgments
We thank Paola Loli, Massimo Terzolo, Wiebke Arlt, Michael O’Reilly, and Marcin Motyka for their clinical collaboration and inclusion of patients.
Funding
This work was supported by the IZKF Würzburg (grant no. F-365 to A.S. and S.H., and Z-02/85 to P.H.) and the German Research Foundation (DFG), project number 314061271 (CRC/Transregio 205 “The Adrenal: Central Relay in Health and Disease” and DFG AL 203/1-1).
Competing Interests
A.S. and S.H. filed a patent application WO/2014/048568 for IMAZA. All other authors declare no potential conflicts of interest.
Ethical Approval
All findings, data acquisition and processing in this study comply with the ethical standards laid down in the latest Declaration of Helsinki as well as with the statutes of the Ethics Committee of the University of Würzburg (waiver of the ethics committee: 20200916 02).
Consent for Publication
Not applicable.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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