Nephrology & Urology Xagena

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Xagena Newsletter

Advanced clear-cell renal cell carcinoma: Cabozantinib, an inhibitor of multiple tyrosine kinases, more effective than Everolimus, a mTOR inhibitor

Treatment with Cabozantinib ( Cometriq ) has reduced the rate of disease progression or death by 42% compared to Everolimus ( Afinitor ) in METEOR, a phase III trial comparing Cabozantinib to Everolimus in patients with advanced clear-cell renal cell carcinoma.
The results were reported at the European Cancer Congress ( ECC 2015 ).

Cabozantinib is an inhibitor of multiple tyrosine kinases, including MET, VEGFRs, AXL and RET that has demonstrated encouraging clinical activity in earlier trials and is currently authorised for treatment of adult patients with progressive, unresectable locally-advanced, or metastatic medullary thyroid cancer.
Expression of MET or AXL may be associated with enhanced tumour cell viability and more aggressive tumour phenotype that negatively impacts overall survival.

Cabozantinib was granted Breakthrough Therapy Designation by the US Food and Drug Administration ( FDA ) on 24 August 2015 for patients with renal cell carcinoma ( RCC ) who experienced disease progression following treatment with a tyrosine kinase inhibitor ( TKI ). This decision was based upon the results of the METEOR study.

In METEOR, patients with measurable disease by RECIST 1.1 and Karnofsky performance status greater than or equal to 70% were stratified by Memorial Sloan Kettering Cancer Center ( MSKCC ) prognostic criteria and by the number of prior treatments with VEGFR TKIs, then randomised 1:1 to receive daily administration of Cabozantinib at 60 mg or Everolimus at 10 mg.
Patients were required to have progressed within 6 months of their prior VEGFR tyrosine kinase inhibitors.

Of the 658 patients randomised between August 2013 and November 2014, 71% had undergone treatment with one and 29% of patients had received 2 or more prior VEGFR TKIs.
According to MSKCC criteria 46% of patients were favourable, 41% intermediate, and 13% of patients were classified as poor risk.

The study met the primary endpoint of progression-free survival ( PFS ) per independent radiology committee; the estimated median PFS among the first 375 randomised patients was 7.4 months with Cabozantinib compared to 3.8 months with Everolimus ( hazard ratio, HR=0.58; 95% CI 0.45 to 0.75; p less than 0.001 ).

Secondary endpoints, including the overall response rate ( ORR ) and overall survival ( OS ), also favoured Cabozantinib.
The ORR was significantly improved with Cabozantinib over Everolimus; ORR was 21% with Cabozantinib compared to 5% with Everolimus ( p less than 0.001 ).
At the interim OS analysis ( 49% information fraction ), the HR was 0.67; 95% CI 0.51, 0.89 ( p = 0.0050 ) favouring Cabozantinib.
The criteria for early rejection of the hypothesis was not met ( p less than or equal to 0.0019 ), but median overall survival could not yet be estimated.

Cabozantib was well-tolerated by patients in this setting. The most commonly reported serious adverse events ( SAEs ) with Cabozantinib were abdominal pain, pleural effusion, and diarrhoea, which occurred in 3%, 2.7%, and 2.1% of patients, respectively.
Serious adverse events with Everolimus included anaemia, dyspnoea, and pneumonia, which were each reported in 3.7% of patients.
Treatment discontinuation due to adverse events was reported for 9.1% of patients receiving Cabozantinib and 10% of patients receiving Everolimus.

In conclusion, improved progression-free survival and overall response rate were demonstrated with Cabozantinib over Everolimus in patients with advanced clear-cell renal cell carcinoma who had been pretreated with VEGFR TKIs.
Also, the interim overall survival analysis showed a trend towards prolonged survival for patients receiving Cabozantinib. ( Xagena )

Source: European Society for Medical Oncology ( ESMO ) Congress, 2015