Kidney Cancer
intravenously [IV] once weekly), IFN-α (3MIU three times weekly) or a combination of both.53
Temsirolimus alone prolonged overall survival
(median 10.9 versus 7.3 months, HR 0.73; p=0.008) and PFS (median 3.8 versus 1.9 months, HR 0.42; p
Everolimus
Everolimus is another mTOR inhibitor that is available for the treatment of patients with mRCC. Unlike the intravenously administered temsirolimus, everolimus is orally active. Everolimus demonstrated encouraging antitumour activity in a phase II study of patients with previously treated mRCC.54
A subsequent phase III trial
randomised 410 patients with mRCC whose disease had progressed on sunitinib, sorafenib or both (prior therapy with cytokines or bevacizumab was also allowed) to receive either everolimus (10mg once daily) or placebo.55
The trial was stopped early after a second
interim analysis had shown a significant difference in the primary end-point of PFS between the two groups (median four versus 1.9 months, HR 0.30; p
Several retrospective analyses support the benefit of sequential sorafenib and sunitinib in this setting, suggesting that the sequencing of both of these TKIs is not hampered by cross-resistance, despite partly blocking the same signalling pathways.59–62
However, results
from prospective studies suggest that sorafenib has limited efficacy in patients who experience treatment failure with first-line sunitinib. A prospective study of 42 patients with mRCC refractory to either first- line bevacizumab or sunitinib was able to demonstrate a median PFS of 3.7 months with sorafenib as a second-line treatment, but no objective responses were observed.63
Furthermore, significant
This PFS benefit was maintained across all MSKCC risk- classification groups. The ORR with everolimus treatment was modest (1.8% in the updated analysis), suggesting that the effect of everolimus on PFS is the result of disease stabilisation. There was no significant difference in median overall survival between the arms (14.8 versus 14.4 months for everolimus and placebo, respectively, HR 0.87; p=0.162), although the survival results were likely to have been confounded by the majority of patients (80%) in the placebo arm who switched therapy following disease progression.56
According to a
post hoc exploratory analysis correcting for this cross-over effect, the corrected placebo overall survival was 10 months, a difference of 4.8 months compared with the observed everolimus overall survival.56 Adverse events reported with everolimus treatment were mostly grade 1 or 2. The most common events were stomatitis, rash, fatigue or asthenia and diarrhoea. Based on these data, the latest European Association of Urology (EAU) and NCCN (category 1 recommendation) guidelines recommend everolimus for the second-line treatment of mRCC after prior treatment with VEGF TKI therapies.
Sequencing Targeting Agents
Sequential therapy with targeted agents could potentially further improve outcomes in patients with mRCC. A sequential strategy could allow a treatment regimen to be established whereby patients are maintained on a continuum of treatments without tumour progression. Furthermore, targeting different pathways through sequential therapy could offer benefits in terms of overcoming resistance to individual agents.
44
toxicities were seen in this study (58% of patients experienced a grade 3 adverse event). Data from another prospective study of 52 sunitinib- refractory mRCC patients suggested that sorafenib has modest efficacy (partial response rate of 9.6%) in patients who experience treatment failure with first-line sunitinib.64
Taken together, these
prospective studies highlight potential problems of cross-resistance and overlapping toxicities between these agents, emphasising the need for further prospective clinical trials investigating the sequencing of sunitinib and sorafenib. An exploratory phase II study investigating the antitumour activity of sunitinib in 61 patients with bevacizumab- refractory mRCC demonstrated a PFS of 30.4 weeks and an ORR of 23%, suggesting a lack of cross-resistance between sunitinib and bevacizumab.65
Further ongoing studies should provide important insights into the sequencing of targeted therapies in mRCC. A phase III study is comparing the efficacy and safety of temsirolimus versus sorafenib as a second-line therapy in mRCC patients who have failed first-line sunitinib (Temsirolimus Versus Sorafenib as Second-Line Therapy in Patients With Advanced RCC Who Have Failed First-Line Sunitinib;
clinicaltrials.gov identifier NCT00474786), and a phase II trial (Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma [RECORD-3];
clinicaltrials.gov identifier NCT00903175) is comparing the efficacy and safety of the sequence of first-line everolimus followed by second-line sunitinib versus the reverse sequence in patients with mRCC. Preliminary evidence suggests a potential clinical benefit with VEGFR TKI treatment in selected mRCC patients refractory to VEGF-targeted therapies and mTOR inhibitors (i.e. a sequence of VEGFR TKI followed by mTOR inhibitor followed by VEGFR TKI), suggesting a potential for ‘re-sensitisation’ to VEGFR TKI
EUROPEAN ONCOLOGY
The first randomised phase III study that investigated sequential targeted therapy in mRCC compared the mTOR inhibitor everolimus versus placebo in patients who had progressed on sunitinib, sorafenib or both.55,56
The significant prolongation of PFS observed
with everolimus compared with placebo in the overall study population (HR 0.33) was maintained in subgroups of patients who had previously received sunitinib (HR 0.34) or sorafenib (HR 0.25). A retrospective analysis of temsirolimus in patients previously treated with VEGF-targeted therapy suggested that this sequence was feasible and active, albeit with an increased frequency of adverse events compared with that seen with temsirolimus in previously untreated poor-risk patients.57
These data suggest that the
development of cross-resistance between inhibitors of VEGF or mTOR pathways may be minimal. Furthermore, the distinct adverse event profiles of mTOR inhibitors and VEGFR TKI therapies suggest an absence of overlapping toxicities, which may prove advantageous when considering sequential strategies involving these two mechanistic classes of targeted agents.58
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