Abstract
Background
Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma.
Objective
To investigate the clinical efficacy and safety of CABO monotherapy in ACC patients.
Design
Retrospective cohort study.
Setting
Three referral centers for ACC (Germany, United States).
Results
Sixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively.
Conclusion
CABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.
Keywords: adrenal cancer, ACC, cabozantinib, tyrosine kinase inhibitors
Adrenocortical carcinoma (ACC) is a rare and aggressive disease. In advanced stages, prognosis is variable (1–3), but median 5-year survival rate is below 15% in most series (4–8). Recently, the first international guidelines for the diagnosis and treatment of ACC were published (3). In localized stages, complete surgical resection is the treatment of choice and provides the only chance for cure. Mitotane is the only drug approved for treatment of advanced ACC and advocated by many centers as an adjuvant treatment as well (9–12). Based on the results of a large randomized phase 3 trial, the combination of etoposide, doxorubicin, and cisplatin with mitotane (13) is considered the current standard treatment in advanced stages, but only results in an objective response rate of 23% and disease stabilization in 35% of patients resulting in a progression-free survival (PFS) of only 5.1 months. Second-line therapies for ACC include gemcitabine-based regimens (14,15) and streptozotocin (16), which may lead to objective treatment response in a small proportion of patients. Similar to other solid malignancies, several tyrosine kinase inhibitors have been investigated in ACC, most of them with disappointing results (17–19). Thus, a phase 2 trial of sunitinib in refractory adrenocortical carcinoma (20) did not yield any signal of efficacy with a PFS of 83 days and median overall survival (OS) of 5.4 months. In line with a previous report (21), a negative correlation between mitotane plasma concentration and plasma concentrations of sunitinib and its active metabolite supported induction of cytochrome P450 3A4 by mitotane. CYP3A4 is involved in the metabolism of a large number of clinically used drugs (22) including tyrosine kinase inhibitors. Because cabozantinib (CABO) is also metabolized by CYP3A4 primarily to the N-oxide and a 77% decrease in CABO exposure (area under the curve0-inf) has been observed after administration of a strong CYP inducer (23), a comparable interaction appears to be conceivable.
CABO is a multityrosine kinase inhibitor targeting RET, c-Met, AXL, and vascular endothelial growth factor (VEGF) receptors and is approved for metastatic medullary thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma. Expression of hepatocyte growth factor and its target c-Met was demonstrated in human ACC tissue and down-regulation of c-Met impaired tumor growth in a xenograft model of ACC (24). Based on these data, CABO has been used in ACC patients seen in major referral centers after failing other treatments. Here, we report a case series of CABO-treated patients with advanced treated ACC from 3 referral centers in Germany and the United States.
Subjects and Methods
Study population
This retrospective study was part of the ENSAT registry study in Würzburg and Berlin (www.ensat.org/registry) and approved by the ethics committees/institutional review boards at all participating institutions (ethics committee at the University of Würzburg, institutional review board of MD Anderson Cancer Center PA12-0933). All patients provided written informed consent. Patients were identified and clinical parameters (e.g., sex, age at initial diagnosis, evidence of hormone excess, size of the primary tumor, tumor stage according to the ENSAT classification (6), Weiss score (25), Ki67 index (8,26), treatment details, end points) retrieved from the ENSAT registry and patient records. Inclusion criteria for the present study were histologic diagnosis of ACC, age ≥18 years, measurable disease at baseline. Follow-up was until November 15, 2019. Concomitant tumor therapy was an exclusion criterion.
Treatment evaluation
In all cases, treatment response was assessed by cross-sectional imaging in accordance with the Response Evaluation Criteria In Solid Tumors guideline, version 1.1 (27). Response was assessed locally following standard of care. Adverse drug effects were retrieved from patient records and graded according to the National Cancer Institute Common Toxicity Criteria, version 4.0. Adverse drug effects at least considered possibly treatment-related are reported in this study.
Plasma concentrations of cabozantinib
As an exploratory analysis, CABO plasma concentrations were determined in patients after at least 15 days of treatment, which corresponds to the time point at which steady state is expected (28). The liquid chromatography-tandem mass spectometry method was validated and fulfilled criteria of US Food and Drug Administration and European Medicines Agency guidelines on bioanalytical method validation. CABO was detected by electron-spray ionisation (ESI) + in multiple reaction monitoring mode (m/z 502.2→391.4 for CABO and m/z 506.0→391.4 for internal standard CABO-d4). The lower limit of quantitation was 6 ng/mL (S/N > 200) and the assay dynamic range was 6 to 1000 ng/mL. Intra-day accuracy and precision ranged from 99% to 112% (95% to 118% for lower limit of quantitation) and 1.8% to 9.5% for 5 quality control levels (6 ng/mL, 18 ng/mL, 54 ng/mL, 440 ng/mL, and 740 ng/mL). Inter-day accuracy and precision ranged from 106% to 111% and 6% to 12%. All other required parameters were validated and met acceptance criteria. Quantification was performed by peak area (10-point calibration) using Analyst software (version 1.6.3 MD) with linear regression, origin excluded, and 1/conc2 weighting.
Statistical analysis
PFS and OS were defined as the interval between treatment initiation with CABO and the date at which imaging documented progressive disease or death from any cause, respectively. In cases with ongoing PFS (n = 1) and OS (4, lost to follow-up: 2) at the time of analysis, survival was censored at the date of last follow-up. Survival curves were constructed using the Kaplan-Meier method. Continuous variables are presented as the median and range. GraphPad Prism 6.0 software (GraphPad Software Inc., San Diego, California, USA) was used for statistical calculations.
Results
Patient characteristics
Sixteen patients (13 female, 87%) treated with CABO between 2014 and 2019 in 2 German centers (Würzburg, Berlin; Germany) and at the MD Anderson Cancer Center (Houston, Texas; USA) fulfilled the inclusion criteria and were included in the analysis (Table 1 and detailed supplementary file available in a digital research material repository) (29). Clinical or biochemical hormone excess was present at primary diagnosis in 13/16 patients (81%). Primary tumor was resected in 14/16 (88%) patients. All but 1 received prior therapy with mitotane (94%). Ten patients had received at least 3 prior systemic therapies in addition to mitotane and 1 patient had refused any cytostatic chemotherapy and mitotane. Eight patients had surgery for metastases, 3 were treated with radiofrequency ablation or selective internal radiation therapy and 7 received palliative radiation therapy for metastases. The median interval between initiation of CABO and the initial diagnosis of ACC was 37.0 months (range, 5.2 to 115.4 months; Table 1).
Table 1.
Characteristics of ACC Patients Treated With CABO
| Characteristic | Number (%) of Patients or Median (Range) |
|---|---|
| Number of patients | 16 |
| Female sex | 13 (81) |
| Age at initial diagnosis (y) | 42 (18–66) |
| Primary tumor size at initial diagnosis (cm, n = 14) | 9.5 (5.8–23.8) |
| ENSAT tumor stage at initial diagnosis | |
| II | 8 |
| III | 4 |
| IV | 4 |
| Main endocrine activity at initial diagnosis | |
| Glucocorticoids | 8 (50) |
| Sex hormones | 4 (25) |
| Glucocorticoid and androgens | 1 (6) |
| None | 3 (19) |
| Histopathology | |
| Ki67 (n = 13) | |
| <10% | 3 |
| 10%–19% | 2 |
| ≥20% | 8 |
| Weiss score (n = 9) | 6 (4–7) |
| Therapy before treatment with cabozantinib | |
| Surgery of primary tumor | 14 (87) |
| EBRT of tumor bed | 3 (19) |
| Surgery for local/distant recurrence | 8 (50) |
| EBRT in advanced disease | 7 (44) |
| Mitotane | |
| Previous mitotane treatment | 15 (94) |
| Last plasma concentration before cabozantinib (n = 12) | 1.6 (0–10.5) |
| Time interval from last mitotane plasma concentration to treatment with cabozantinib (months, n = 12) | 3.3 (0–70) |
| Documented mitotane plasma concentration ≤2 mg/L (n = 12) | 7 (44) |
| Cytotoxic chemotherapy | |
| Etoposide, doxorubicin, cisplatin | 12 (75) |
| Other platinum containing | 2 (13) |
| Streptozotocin | 8 (50) |
| Gemcitabine/capecitabine | 11 (69) |
| Other systemic treatment or clinical trial | 6 (38) |
| Number of systemic therapies (except mitotane) | 3 (0–11) |
ACC, adrenocortical carcinoma; CABO, cabozantinib; EBRT, external beam radiation therapy.
Previous mitotane therapy
Mitotane had been discontinued (never received: 1 patient) in all patients before CABO treatment (29). Mitotane plasma concentration was ≤2 mg/L in 7 patients, in 3 patients with unavailable mitotane plasma concentrations, transitory mitotane treatment had been stopped for adverse drug reactions 21, 70, and 93 months before CABO treatment and in 3 additional cases with documented mitotane plasma concentration >2 mg/L more than 12 months had elapsed since the last measurement. There were 2 patients in whom mitotane plasma concentrations of 5.9 mg/L and 3.4 mg/L were documented within 1 month before CABO.
Treatment administered
CABO was given in capsules (marketed as Cometriq for the treatment of medullary thyroid carcinoma) to 13 patients treated between 2014 and 2018 and in tablets (available as Cabometyx for renal cell and hepatocellular carcinoma) to 3 patients treated from 2018. Initial dosage was 60 mg in 11, 100 mg in 2, and 140 mg, 40 mg, and 20 mg in 1 patient each. In 2 patients, dosage was increased to 140 mg, and in 5 patients from 60 mg to 80 mg. One patient received a maximal dose of 120 mg. Dose reductions and interruptions were considered necessary for management of toxicities in 5 patients (Table 2).
Table 2.
CABO Treatment Administered
| Interval between the initial diagnosis and cabozantinib initiation (m) | 37 (5.2–115) |
| Age at cabozantinib initiation (y) | 47.3 (21–71) |
| CABO dose at treatment initiation (mg) | 60 (20–140) |
| Maximum cabozantinib dose (mg) | 80 (60–140) |
| CABO formulation: capsules/tablets | 13 (81) / 3 (19) |
| Cases with dose interruption/dose reduction for adverse events | 5 (31%) |
CABO, cabozantinib.
Plasma concentrations of cabozantinib
In 5 patients, random plasma samples were available for analysis of CABO plasma concentration after a median of 84 days (range, 19 to 292) with consecutive samples being available in 2 patients. Steady-state concentrations of CABO are expected to be reached on day 15 (30). Median plasma concentration of CABO was 616 ng/mL (range, 223 to 1040). The patient with the lowest CABO plasma concentration had a mitotane concentration of 3.4 mg/L before CABO treatment.
Treatment response
The median interval between treatment initiation and first staging (n = 13) was 10.6 weeks (range, 6.0 to 13.9 weeks).
Best response to treatment was partial response in 3 patients (Fig. 1), stable disease in 5 patients, whereas 8 patients experienced progressive disease with 3 of them having clinically progressive disease (death after 5.6, 6.9, and 13 weeks). The estimated median PFS was 16.2 weeks (range, 2.8 to 61 weeks; Fig. 3A) with 3 patients still on drug at the time of analysis (2 treated beyond progression). A PFS of >16 weeks was observed in 8 patients. At the time of data cutoff (November 15, 2019), 10 patients are deceased and median OS is 58 weeks (range, 5.6 to 83.1 weeks, Fig. 3B).
Figure 1.
FDG-PET-CT of a 51-year-old patient with metastatic ACC (A) at baseline and (B) 3 months after treatment initiation with CABO shows evidence of pronounced metabolic response of the primary tumor and both lung and liver metastases. ACC, adrenocortical carcinoma; CABO, cabozantinib; FDG-PET-CT, fluorodeoxyglucose positron emission tomography computed tomography.
Figure 3.
(A) Progression-free and (B) overall survival of patients treated with CABO. CABO, cabozantinib.
Treatment-emergent adverse events
Retrospective information about tolerability was available in 15 patients (94%), 1 patient was deceased after less than 7 weeks on CABO resulting from tumor progression. Adverse events of any grade were observed in 15 patients (Table 3). Sixty-three adverse events were grade 1 and 2 and consistent with the known safety profile of CABO. There were 3 grade 3 events with hypertension and pulmonary embolism. Hypertension occurred at a dose of 140 mg CABO and was treated with dose interruption and dose reduction. Dose was later established at 20 and 40 mg every other day and hypertension treated with beta blocker, calcium channel blocker, and angiotensin-converting enzyme inhibitor. Thrombosis and pulmonary embolism occurred after 113 days of CABO treatment and was treated with dose interruption and direct oral anticoagulant; later, low-molecular-weight heparin was chosen. Computed tomography showed signs of pulmonary infarction subsequently, which resolved during follow-up imaging with cavernous residual lesions. CABO was resumed and continued. The patient died while on the drug because of sepsis, which was unrelated to CABO treatment. In 1 case, we observed grade 3 neutropenia associated with grade 2 lymphopenia and grade 1 thrombopenia and treated with dose interruption.
Table 3.
Treatment Emergent Adverse Events Considered at Least Possibly Related to CABO Treatment
| CTCAE Class | Grade 1 | Grade 2 | Grade 3 |
|---|---|---|---|
| Blood and lymphatic system | |||
| Neutrophils decreased | 1 | ||
| Lymphocytes decreased | 1 | ||
| Thrombocytes decreased | 1 | ||
| Cardiovascular | |||
| Hypertension | 1 | 1 | |
| Thromboembolism | 2 | 1 | |
| Skin | |||
| Hair loss | 1 | ||
| Hair discoloration | 3 | ||
| Perionychitis | 1 | ||
| Hand-foot-syndrome | 2 | ||
| Rash | 3 | 1 | |
| Itching | 1 | ||
| Hyperhidrosis | 1 | ||
| Gastrointestinal | |||
| Dry mouth | 1 | 1 | |
| Dysgeusia | 1 | ||
| Mucositis | 2 | 1 | |
| Acid reflux | 1 | ||
| Nausea | 3 | 2 | |
| Diarrhea | 1 | 5 | |
| Constipation | 1 | ||
| Bloating | 1 | ||
| Elevated liver enzymes | 2 | ||
| Pulmonary | |||
| Dyspnea | 1 | 1 | |
| Cough | 1 | ||
| Kidney | |||
| Proteinuria | 1 | ||
| Neuromuscular | |||
| Dizziness | 1 | ||
| Muscle cramps | 1 | ||
| Psychic | |||
| Depression | 2 | ||
| General | |||
| Malaise | 1 | ||
| Weight loss | 3 | 1 | |
| Fatigue | 7 | 1 | |
| Pain | 2 |
CABO, cabozantinib; CTCAE, Common Terminology Criteria for Adverse Events.
Discussion
The development of novel drugs and treatment concepts over the past few years has little changed the therapeutic landscape in ACC with mitotane alone (12) or in combination with platinum-containing chemotherapy (13) remaining the mainstays of treatment in advanced disease. Even with aggressive treatment, PFS was only 5 months.
The present study assessed the efficacy and tolerability CABO in patients with advanced ACC. Most patients were heavily pretreated including mitotane in all except 1 patient. Mitotane had been discontinued in all patients before CABO. Two patients had partial response and we observed stable disease in 6 at first tumor evaluation. Although 50% of patients had tumor progression, this result compares favorably with other treatments. Importantly, at 4 months evaluation, one-half of patients lived progression free.
Adverse events were consistent with the known safety profile of CABO but underreporting of adverse events is likely (especially for low grade adverse events) outside of a clinical trial. Most severe adverse events were grade 3 hypertension, pulmonary embolism, and neutropenia, which were treated by temporary dose interruptions and standard treatment. Patients with ACC, particularly with glucocorticoid excess, are at an increased risk of thromboembolic events.
No association of mitotane plasma concentration and response was observed. Because platinum-containing chemotherapy had been administered in 13 patients and steroid excess was reported in 13/15 patients with this information available, we were unable to study the impact of hormone secretion and previous chemotherapy regimens on response.
In 5 patients, we had the opportunity to quantify CABO in plasma samples (Fig. 2). In the 2 patients with stable disease and 1 patient with partial response, plasma concentrations of CABO were within the expected range of plasma concentrations at steady state. The small number of samples and cases as well as the random time interval between last administration and plasma sampling precludes any conclusion as to how previous mitotane therapy might affect plasma concentrations of CABO. In a single case with mitotane plasma concentration of 3.4 mg/L before CABO, a relatively low CABO plasma concentration was observed (28). However, we cannot exclude dose interruptions or reductions that may have occurred, especially because the patient died before the first tumor evaluation.
Figure 2.
Plasma concentrations of CABO in 4 patients with available samples. The shaded area is the expected 95% confidence interval of steady-state concentration in a mixed population of male and female patients with 60 mg CABO tablets (mean: straight line). Identification of individual patients given, in brackets: sex, mitotane plasma concentration prior CABO, best response. *Mitotane had been discontinued for 21 months and **93 months before CABO. CABO, cabozantinib.
Objective response compared with frequently used second-line regimens such as gemcitabine/capecitabine (14,15) and streptozotocin (16) is exceptional, although significant responses were seen in few patients and prolonged disease stabilization observed in others. Few studies have reported disease stabilization of 4 months or longer in a substantial proportion of patients with refractory ACC. Results of immunotherapy are heterogeneous. Clinical trials with avelumab (31), nivolumab (32), and 1 study of pembrolizumab in unselected populations of ACC patients (33) were disappointing. One large phase 2 study showed remarkable response to pembrolizumab in 9/39 patients of which 2 had known Lynch syndrome (34). This is in line with similar reports that germ line mutations that lead to impaired DNA mismatch repair predict response to immunotherapy in ACC (35). It is presently unclear which markers may predict response in ACC cases not affected by Lynch syndrome. A clinical trial with small molecule drugs in a similar setting of advanced ACC reported a median PFS and OS of 2.8 and 5.4 months (20), a phase 2 trial of sorafenib was prematurely terminated when progression was observed in all evaluable patients after 8 weeks (17). In a phase 3 trial of linsitinib monotherapy, median PFS was 44 days and OS 10.6 months (36).
Heterogeneity of treatment response to immunotherapy has stimulated the search for response markers at tissue level, which was unfortunately unsuccessful. Extensive neo-angiogenesis as a hallmark of tumor growth has attracted attention also in ACC. Because of the high expression of VEGF and receptor 2 in ACC tumor cell lines (37,38), prospective phase 2 clinical trials have been conducted using the multityrosine kinase inhibitors sunitinib and sorafenib (17,20). However, results were disappointing and are partly supposed to be related to accelerated metabolism of tyrosine kinase inhibitors through induction of cytochrome P450 3A4 by mitotane (21,22).
Hepatocyte growth factor receptor c-Met was shown to be overexpressed and activated in ACC. Antagonizing c-Met signaling by RNA interference and treatment with CABO, an inhibitor of VEGF receptor 2, AXL, and c-Met resulted in growth delay in xenograft models (24).
Our experience with CABO seems more favorable compared with other multityrosine kinase inhibitor studies in ACC, which failed to demonstrate objective response (17,20). It must be considered that this study may suffer from some selection bias for tumors with more indolent course because of the requirement of low mitotane plasma concentration before initiation of CABO. We did not have the opportunity to study potential tissue markers of treatment response, which remains to be investigated prospectively. Nevertheless, the results compare favorably with trofosfamide (39) and thalidomide (40), which were considered ineffective and suggests CABO to be active as a treatment of ACC.
Given the overall tolerable safety profile of CABO with manageable toxicity, these retrospective results encourage prospective evaluation of CABO. Accordingly, 2 phase 2 clinical trials with CABO are recruiting in the United States (NCT03370718) and Germany (NCT03612232) in patients with ACC. Both clinical trials mandate discontinuation of mitotane before CABO treatment and exclude patients with a plasma mitotane concentration >2 mg/L.
In the absence of effective treatment options in advanced ACC, CABO holds some promise as a novel treatment option.
Acknowledgments
The authors thank Michaela Haaf for maintaining the ENSAT registry and biobank at the University Hospital Würzburg and Sabine Kendl for supporting mass spectrometry measurements of cabozantinib.
Financial Support: This study was supported in part by the Deutsche Forschungsgemeinschaft (DFG) project number 314061271—TRR 205 to M.K. and M.F. and a research grant from the Hector Stiftung II gGmbH to O.Sch.
Glossary
Abbreviations
- ACC
adrenocortical carcinoma
- CABO
cabozantinib
- OS
overall survival
- PFS
progression-free survival
- VEGF
vascular endothelial growth factor
Additional Information
Disclosure Summary: M.K. received travel cost reimbursement, speaker honoraria, and research support from Ipsen Pharma GmbH. C.J. has received research support from Progenics and Exelixis.
Data Availability
All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.