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Cabozantinib in the treatment of advanced renal cell carcinoma


Renal cell carcinoma ( RCC ) accounts for approximately 330,000 cases diagnosed each year and 140,000 deaths worldwide.
Most cases are localized; however, one-third of patients present with an advanced disease at diagnosis and approximately 30% of subjects eventually develop metastatic disease after nephrectomy.

The VHL protein plays a major role in renal cell carcinoma, being downregulated due to gene inactivation or epigenetic silencing. As a consequence, the hypoxia-inducible factors ( HIFs ) are stabilized and VEGF, MET, and AXL genes are upregulated.
This effect on VEGF can explain the angiogenic drive of clear-cell RCC ( ccRCC ), and expression of MET or AXL can be associated with an invasive tumor phenotype and poor prognosis.

Preclinical evidence also showed that MET and AXL upregulation in ccRCC can also occur in response to VEGFR tyrosine kinase inhibitor ( TKI ) therapies, underlying a potential role for MET and AXL in the development of secondary resistance.
Moreover, overexpression of angiopoietin, FGF, MET, and HGF has been associated with the mechanisms of resistance to VEGF inhibitors.

Therapeutic strategies for metastatic disease are mostly based on VEGF inhibitors such as Sunitinib, Pazopanib, Bevacizumab, Sorafenib, and Axitinib and mTOR inhibitors, including Temsirolimus and Everolimus.
Nevertheless, despite an impressive improvement of outcome with targeted agents, complete remissions are rarely achieved and either primary or secondary resistance eventually develops.

In addition, cross talk between the MET and VEGFR pathways is involved in tumor neoangiogenesis and progression but is implicated in the resistance to anti-VEGFR agents.
Cabozantinib is able to target both the VEGF and c-Met pathways in order to overcome resistance to TKIs while maintaining VEGF inhibition.

Cabozantinib as an orally bioavailable multikinase inhibitor that has shown a significant improvement in progression-free survival ( PFS ) and overall survival ( OS ) of patients with metastatic renal cell carcinoma ( mRCC ) after failure of TKIs compared to Everolimus.
Based on the information from the recently reported trial, its position among other agents will be as a second-line therapy option for mRCC subjects progressing after at least one VEGF-TKI treatment.

The overall progression-free survival and that reported in patients receiving Cabozantinib after Sunitinib showed the best outcome for a single agent used for mRCC treatment.
Besides, the progression-free survival reported in the same study with Everolimus was similar to that reported in the phase III RECORD 1 study.
This supports the METEOR study that suggests that the characteristics of this study population may not be more favorable in comparison to previous studies.

Significant side effects ( diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia, and hypertension ) have been observed with Cabozantinib therapy, resulting in approximately 60% of patients undergoing a dose reduction in the phase III trial versus Everolimus.
As a result, the management of the toxicity of patients receiving Cabozantinib may be a potential key driver for treatment choice.

Focusing on special populations such as patients with bone metastases from renal cell carcinoma would be a strategy to achieve improved efficacy in patients where currently approved drugs have shown less efficacy.
Moreover, association studies are evaluating the effect of the combination of Cabozantinib with checkpoint inhibitors in patients with metastatic renal cell carcinoma.

The ability of Cabozantinib to cross the blood–brain barrier as shown in glioblastoma warrants investigation in mRCC.
Targeting the MET and VEGFR pathways simultaneously represents a promising approach for renal cell carcinoma treatment since this will target multiple pathways.
Cabozantinib has demonstrated an improvement in progression-free survival, overall response rate ( ORR ), and overall survival of pretreated mRCC patients.
The peculiar safety profile of cabozantinib requires a prompt management of adverse effects in order to minimize dose reduction and optimize outcome.
Clinical trials to evaluate specific subpopulations such as patients with bone and brain metastases from metastatic renal cell cancer need further evaluation. ( Xagena )

Grassi P et al, Drug Des Devel Ther 2016;10:2167-2172

XagenaMedicine_2016



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