A Durable Response With the Combination of Nivolumab and Cabozantinib in a Patient With Metastatic Paraganglioma: A Case Report and Review of the Current Literature

Economides, Minas P.; Shah, Amishi Yogesh; Jiménez, Camilo; Habra, Mouhammed Amir; Desai, Monica Dandona; Campbell, Matthew T.

doi:10.3389/fendo.2020.594264

Cited by 13 publications

(4 citation statements)

References 42 publications

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“…Combining cabozantinib with nivolumab was associated with a PR, disease stabilization, the disappearance of the symptoms of catecholamine excess, and an acceptable toxicity, and the clinical benefits of this combined therapy lasted for 22 months. This case report suggests that cabozantinib could have induced some degree of tumor vascular normalization that facilitated the activation of the immune system [73].…”

Section: Does Immunotherapy With Checkpoint Inhibitors Work For Mppgl?mentioning

confidence: 78%

Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Jiménez

Armaiz-Peña

Dahia

et al. 2022

Cancers

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Adrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials.

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Section: Does Immunotherapy With Checkpoint Inhibitors Work For Mppgl?mentioning

confidence: 78%

Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Jiménez

Armaiz-Peña

Dahia

et al. 2022

Cancers

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“…Recently developed ICI may offer new therapeutic opportunities for this disease. In fact, a first clinical trial revealed that some patients with metastatic PPGL gained a moderated but, in some cases, durable clinical benefit when treated with pembrolizumab [ 16 , 37 ]. Knowledge of CTL tumor infiltration and PD‐L1 expression levels in PPGL are the basis for ICI‐based therapies.…”

Section: Discussionmentioning

confidence: 99%

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

Celada

Cubiella

San-Juan-Guardado

et al. 2022

The Journal of Pathology

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Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia‐inducible factor 2 (HIF2)‐mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death‐ligand 1 (PD‐L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD‐L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD‐L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD‐L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD‐L1 and CD8 expression was lower in norepinephrine than epinephrine‐secreting PPGL. This in silico analysis also revealed the low PD‐L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α‐coding gene, EPAS1, which, together with SDH‐mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…In fact, in the literature, there is a case report of a 32-year-old male patient suffering from an advanced metastatic paraganglioma, showing a progressive disease when enrolled in a CBZ-based trial as a monotherapy treatment. Nonetheless, he showed prolonged disease control with a significant tumour reduction and decrease in metastatic burden when enrolled in the study by Apolo (started on CBZ plus nivolumab) [ 61 , 62 ]. A phase II clinical trial on CBZ in monotherapy is now recruiting patients with unresectable metastatic paraganglioma or pheochromocytoma (Table 3 - https://clinicaltrials.gov ).…”

Section: Thyroid Cancersmentioning

confidence: 99%

Cabozantinib for different endocrine tumours: killing two birds with one stone. A systematic review of the literature

Zago,

Galluzzo,

Pradella

et al. 2023

Endocrine

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Purpose Cabozantinib is an oral multi-tyrosine kinase inhibitor (TKI) that has been approved in Europe for advanced renal cell carcinoma, hepatocellular carcinoma, locally advanced and metastatic medullary thyroid carcinoma (MTC) and radioiodine-refractory differentiated thyroid cancer. Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous malignant neuroendocrine tumour that usually presents in sun-exposed skin areas of immunosuppressed patients. Conflicting data exist about cabozantinib for MCC and this TKI is currently under investigation in several onco-endocrine frameworks. Methods We herein report a case of an 83-year-old man who was diagnosed with MCC during the treatment of an advanced metastatic MTC. The diagnosis of MCC was established based on clinical, histopathologic evaluation and immunohistochemistry. A systematic review of the literature on cabozantinib use for advanced endocrine and neuroendocrine tumours has been performed. Results The patient was initially treated with surgery and adjuvant radiotherapy. Cabozantinib was therefore started to control both MTC and MCC. After 24 months, no sign of local or metastatic MCC relapse was evidenced. Conclusion Promising data on cabozantinib treatment for endocrine and neuroendocrine neoplasms is recently emerging in the literature. In our clinical case, we reported that, besides the good response for the MTC, cabozantinib also seems to effectively control metastatic MCC, along with efficient surgery and adjuvant radiotherapy. Further investigations are needed to determine the efficacy and safety of cabozantinib in MCC patients and in off-label endocrine tumours.

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A Durable Response With the Combination of Nivolumab and Cabozantinib in a Patient With Metastatic Paraganglioma: A Case Report and Review of the Current Literature

Cited by 13 publications

References 42 publications

Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

Cabozantinib for different endocrine tumours: killing two birds with one stone. A systematic review of the literature

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