Treatment Strategies in Metastatic Renal Cell Carcinoma
However, the survival end-point may have been confounded by cross-over treatments and is potentially underestimated.
A significant improvement in median PFS (the primary end-point) was observed in the sunitinib arm compared with IFN-α (11 versus five months, hazard ratio [HR] 0.42; p
Based on these data, sunitinib is approved multinationally for the first-line treatment of mRCC and is considered a reference standard of care in the first-line setting for patients at favourable or intermediate prognostic risk. Based on the antitumour activity observed with sunitinib in the second-line setting,30,31
the US National
Comprehensive Cancer Network (NCCN) Kidney Cancer Guidelines also recommend sunitinib treatment following cytokine therapy (category 1 recommendation) or after prior TKI therapy (category 2A recommendation).34
months, respectively).41,42 However, increased toxicities with the
combination regimen compared with either drug alone was a concern in both of these studies.
Pazopanib
Pazopanib is an inhibitor of several kinases, including VEGFR1, -2 and -3, PDGFR-α/β and c-KIT. This agent demonstrated monotherapy activity in RCC during phase I/II evaluation,43,44
paving the way for a
phase III randomised, placebo-controlled trial in treatment-naïve and cytokine-refractory mRCC patients (n=435).45
PFS (the primary end-
Studies investigating the scheduling of sunitinib and the combination of this agent with other active compounds are ongoing, although results from a phase I evaluation of sunitinib plus IFN-α in first-line mRCC patients were disappointing.35
Sorafenib
Sorafenib is an oral TKI that targets the receptor tyrosine kinases VEGFR2, VEGFR3, FLT3, c-KIT and PDGFR and the non-receptor serine/threonine kinase RAF1, a major protein of the mitogen-activated protein kinase (MAPK) pathway.36
Therefore, sorafenib is able to target
both tumour angiogenesis and proliferation. Based on the results of a pivotal phase III randomised trial, sorafenib is recommended for the second-line treatment of mRCC following cytokine therapy.37
In this
study, 903 patients who had either received or were ineligible for cytokine therapy were randomised to receive sorafenib (at a dose of 400mg twice daily) or placebo; this dose of sorafenib was previously shown to be effective in a randomised phase II trial in mRCC.38
point) was significantly prolonged with pazopanib (oral dose of 800mg once daily) compared with placebo in the overall study population (median 9.2 versus 4.2 months, HR 0.46; p
Anti-vascular Endothelial Growth Factor Agents Bevacizumab
A planned
interim analysis of PFS in this phase III study showed a statistically significant advantage in the sorafenib arm (5.5 versus 2.8 months, HR 0.44; p
these results, placebo patients were permitted to cross-over to sorafenib. A significant survival advantage was seen with sorafenib in a per-protocol analysis adjusting for cross-over (17.8 versus 14.3 months, HR 0.78; p=0.0287).39
Significant advantages in median PFS and ORR were reported for the bevacizumab arm compared with IFN-α alone (PFS 10.2 versus 5.4 months, HR 0.63; p=0.0001; ORR 31 versus 13%; p
Bevacizumab is a humanised monoclonal antibody that binds and neutralises circulating VEGF, thus preventing it from binding to its receptor. A controlled, double-blind phase III study (AVOREN) randomised 649 first-line mRCC patients to receive IFN-α (9MIU three times weekly) and bevacizumab (10mg/kg every two weeks) or IFN-α and placebo.46
These results were confirmed in the Cancer and As a consequence of
Leukaemia Group B 90206 (CALGB 90206) open-label phase III study, which randomised 732 first-line mRCC patients to either bevacizumab plus IFN-α or IFN-α monotherapy without placebo control (median PFS 8.5 versus 5.2 months, HR 0.71; p
Adverse events were generally manageable:
diarrhoea, rash, fatigue and hand–foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischaemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo. In the first-line mRCC setting, a randomised phase II study of 189 patients demonstrated no difference in median PFS with sorafenib treatment compared with IFN-α (5.7 and 5.6 months, respectively), although sorafenib-treated patients demonstrated greater rates of tumour size reduction, better quality of life and improved tolerability.40
Finally, two phase II studies investigating the combination of sorafenib and IFN-α in mRCC demonstrated an ORR of 19 and 33%, respectively, and an encouraging median PFS (seven and 10
EUROPEAN ONCOLOGY
As seen with the AVOREN study, median overall survival
Grade 3–4 hypertension, anorexia, fatigue and proteinuria were more commonly observed in the bevacizumab plus IFN-α arm. Based on these data, bevacizumab plus IFN-α is recommended as a first-line therapy for patients with mRCC. However, both studies demonstrated that poor-prognosis patients were unlikely to benefit from this combination.
favoured the bevacizumab plus IFN-α arm but did not meet the pre-defined criteria for significance (18.3 versus 17.4 months, HR 0.86; p=0.069).49
Mammalian Target of Rapamycin Inhibitors Temsirolimus
Temsirolimus was the first inhibitor of mTOR kinase available for treating mRCC. Promising phase II results50,51
led to the initiation of a phase III trial
in which 626 mRCC patients with previously untreated poor prognosis (according to the Memorial Sloan-Kettering Cancer Center [MSKCC] prognostic score)52
were randomised to receive temsirolimus (25mg 43
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