An overview of the clinical use of cabozantinib in the treatment of advanced non-clear-cell renal cell carcinoma (NCCRCC)

D’Angelo, Alberto; Bagby, Stefan; Pierro, Giulia Di; Chirra, Martina; Nobili, Stefania; Mini, Enrico; Villari, Donata; Roviello, Giandomenico

doi:10.1016/j.critrevonc.2020.102921

Cited by 9 publications

(7 citation statements)

References 42 publications

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“…Cabozantinib is an oral small-molecule inhibitor of tyrosine kinases (TKI) including c-MET that leads to a significantly longer progression-free and overall survival in patients with metastatic RCC (mRCC) that have progressed after VEGFR-targeted therapies [ 3 , 12 , 13 ]. Pretherapeutic prediction of treatment response to therapy with TKIs like cabozantinib in mRCC patients is highly desirable for the individualization of patient management and improvement of therapeutic outcomes in mRCC patients.…”

Section: Introductionmentioning

confidence: 99%

68Ga-EMP-100 PET/CT—a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma—first in-human biodistribution and imaging results

Mittlmeier

Todica

Gildehaus

et al. 2021

Eur J Nucl Med Mol Imaging

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Background 68Ga-EMP-100 is a novel positron emission tomography (PET) ligand that directly targets tumoral c-MET expression. Upregulation of the receptor tyrosin kinase c-MET in renal cell carcinoma (RCC) is correlated with overall survival in metastatic disease (mRCC). Clinicopathological staging of c-MET expression could improve patient management prior to systemic therapy with for instance inhibitors targeting c-MET such as cabozantinib. We present the first in-human data of 68Ga-EMP-100 in mRCC patients evaluating uptake characteristics in metastases and primary RCC. Methods Twelve patients with mRCC prior to anticipated cabozantinib therapy underwent 68Ga-EMP-100 PET/CT imaging. We compared the biodistribution in normal organs and tumor uptake of mRCC lesions by standard uptake value (SUVmean) and SUVmax measurements. Additionally, metastatic sites on PET were compared to contrast-enhanced computed tomography (CT) and the respective, quantitative PET parameters were assessed and then compared inter- and intra-individually. Results Overall, 87 tumor lesions were analyzed. Of these, 68/87 (79.3%) were visually rated c-MET-positive comprising a median SUVmax of 4.35 and SUVmean of 2.52. Comparing different tumor sites, the highest uptake intensity was found in tumor burden at the primary site (SUVmax 9.05 (4.86–29.16)), followed by bone metastases (SUVmax 5.56 (0.97–15.85)), and lymph node metastases (SUVmax 3.90 (2.13–6.28)) and visceral metastases (SUVmax 3.82 (0.11–16.18)). The occurrence of visually PET-negative lesions (20.7%) was distributed heterogeneously on an intra- and inter-individual level; the largest proportion of PET-negative metastatic lesions were lung and liver metastases. The highest physiological 68Ga-EMP-100 accumulation besides the urinary bladder content was seen in the kidneys, followed by moderate uptake in the liver and the spleen, whereas significantly lower uptake intensity was observed in the pancreas and the intestines. Conclusion Targeting c-MET expression, 68Ga-EMP-100 shows distinctly elevated uptake in mRCC patients with partially high inter- and intra-individual differences comprising both c-MET-positive and c-MET-negative lesions. Our first clinical results warrant further systemic studies investigating the clinical use of 68Ga-EMP-100 as a biomarker in mRCC patients.

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Section: Introductionmentioning

confidence: 99%

68Ga-EMP-100 PET/CT—a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma—first in-human biodistribution and imaging results

Mittlmeier

Todica

Gildehaus

et al. 2021

Eur J Nucl Med Mol Imaging

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“…The multi-kinase inhibitor cabozantinib, which has demonstrated activity against ALX, KIT, MET, RET, ROS1, VEGFR2 and TIE2 [88], and is already approved for the treatment of medullary thyroid and renal cell carcinoma [89][90][91], has been administered by Drilon et al in a phase II study enrolling lung cancer patients [75]. Within the aforementioned clinical trial, a daily dose of 60 mg cabozantinib showed efficacy (in terms of imaging and symptoms) in a young female non-smoker harbouring D2033N-ROS1 genomic alteration who acquired resistance to crizotinib.…”

Section: Cabozantinibmentioning

confidence: 99%

Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies

D’Angelo

Sobhani

Chapman

et al. 2020

Cancers

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The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.

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“…It displays a potent inhibitory activity against VEGFR2, MET, AXL, and other RTKs such as RET, KIT, and Tie2 that are involved in cancer development and progression. 12 , 13 Targeting these RTKs inhibits angiogenesis, tubule formation, tumor cell migration, and induces apoptosis of endothelial and tumor cells. Cabozantinib is approved for the treatment of medullary thyroid cancer, advanced renal cell carcinomas with an intermediate or poor risk and after prior VEGF-targeted therapy, and hepatocellular carcinomas previously treated with sorafenib.…”

Section: Introductionmentioning

confidence: 99%

Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma

Hagege

Sâada-Bouzid

Rastoin

et al. 2022

Cell Reports Medicine

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An overview of the clinical use of cabozantinib in the treatment of advanced non-clear-cell renal cell carcinoma (NCCRCC)

Cited by 9 publications

References 42 publications

68Ga-EMP-100 PET/CT—a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma—first in-human biodistribution and imaging results

68Ga-EMP-100 PET/CT—a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma—first in-human biodistribution and imaging results

Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies

Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma

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