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Renal Cell Carcinoma
Table 3: Ongoing or Planned Phase I/II Trials for the Therapy of
rationale can generally be made for continued targeting of angiogenesis
Advanced Renal Cell Carcinoma
with a sequence of different agents (see Table 2).
Setting Agent Class of Agent
Everolimus
First-line AV-96=51 TKI
A phase III trial of a novel oral mammalian target of rapamycin (mTOR)
First-line Cediranib TKI
First-line Bay-73-4506 TKI
kinase inhibitor, everolimus (RAD-001), versus placebo was completed with
First-line Bevacizumab-HD IL-2 Bev–cytokine
a 2:1 randomisation.
24
These data were presented at the American Society
First-line Sunitinib-IL-21 TKI–cytokine of Clinical Oncology 2008 annual meeting. Four hundred and ten patients
First-line Dendritic cells vaccine Vaccine
were enrolled; patients who had received sunitinib only, sorafenib only or
First-line Sorafenib-AMG 386 TKI–angiopoietin inhibitor
both constituted approximately 45, 30 and 25%, respectively. Additionally,
Second-line VEGF-trap VEGF solubilised receptor
50% of patients had received prior IFN, and approximately 50% had
Second-line Perifosine Akt inhibitor
received interleukin (IL)-2, chemotherapy or bevacizumab, but none had
Second-line ABT-869 TKI
Second-line IMC-1121B VEGFR-2 monoclonal
received prior temsirolimus. Almost all patients had undergone prior
antibody
nephrectomy. Treatment with everolimus was associated with a significant
Second-line LBH589 HDAC inhibitor improvement in PFS compared with placebo, the primary end-point of the
Second-line Bevacizumab-vorinostat Bev–HDAC inhibitor trial (4.0 versus 1.9 months, HR 0.30, 95% CI 0.22–0.40; p<0.001). The six-
Second-line Ixabepilone Epothilone-B chemotherapy
month PFS was 26% versus 2%, although the Response Evaluation Criteria
Second/third-line Sorafenib-everolimus TKI–mTOR inhibitor
in Solid Tumors (RECIST) response rate with everolimus was low at only 1%.
First-line papillary RCC XL-880 Met inhibitor
Additionally, all risk groups appeared to benefit. Everolimus exhibited a
First-line papillary RCC ARQ-197 Met inhibitor
favourable toxicity profile, with a low incidence of myelosuppression and a
VEGF = vascular endothelial growth factor; TKI = tyrosine kinase inhibitor; IL-2 = interleukin-2;
Bev = bevacizumab; VEGFR-2 = VEGF receptor-2; HDAC = histone deacetylase inhibitor;
low incidence of grade 3–4 non-haematological toxicities (12%
mTOR = mammalian target of rapamycin.
hyperglycaemia, 4% hypophosphataemia, 3% hypercholesteroleamia,
(9%), diarrhoea (1%), peripheral oedema (2%), hyperlipidaemia (3%) stomatitis, pneumonitis, infections and fatigue). Based on these data,
and hyperglycaemia (11%). Based on these data derived from a large everolimus should be considered a standard for patients with progressive
phase III trial, temsirolimus should be considered the preferred agent for clear-cell RCC following prior TKIs, and formal approval by regulatory
poor-risk RCC, and perhaps the preferred agent for non-clear-cell RCC, agencies is awaited.
although this needs further evaluation.
High-dose Interleukin-2
Sorafenib High-dose (HD) IL-2 has been employed for metastatic RCC based on a
The Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) small fraction (~7%) of patients who demonstrate durable complete
enrolled 903 patients with only good- and intermediate-risk clear-cell RCC remission (CR) and apparent cures.
25
Clinical trials have demonstrated
and compared sorafenib, a multitargeted TKI, with placebo following prior improved objective RRs and response duration when HD IL-2 was
cytokine therapy (see Table 1).
17
The median PFS was 5.5 months with compared with other administration schedules of IL-2 and IFN.
26,27
sorafenib and 2.8 months with placebo (HR 0.44; p<0.01). Responses were However, no randomised trial has demonstrated an overall survival
seen in 10% of patients receiving sorafenib and in 2% of those receiving advantage. Additionally, the commonly observed life-threatening toxicities
placebo (p<0.001). The survival improvement of 13.5% for sorafenib was of HD IL-2 severely limit its application. The best outcomes have been
not significant (median 17.8 versus 15.2 months, HR 0.88; p=0.146). associated with good- and intermediate-risk clear-cell RCC, certain
However, secondary analysis censoring cross-over data showed a significant histological features (clear-cell and alveolar features; absence of papillary
OS benefit for sorafenib (HR 0.78; p=0.0287), since patients received benefit and granular features), carbonic anhydrase IX (G250 antigen) expression
from sorafenib upon cross-over.
18
Severe grade 3–4 diarrhoea, rash, fatigue, and certain gene expression profiles.
28–31
hypertension and hand–foot skin reactions occurred in a small proportion
(1–6%) of patients with sorafenib. The Cytokine Working Group recently launched the HD IL-2 Select trial to
prospectively determine whether predictive factors (baseline immune
A smaller randomised phase II trial in the front-line setting did not function, immunohistochemical markers and gene expression patterns) can
demonstrate improved outcomes with sorafenib compared with IFN-α.
19
identify patients more likely to respond to HD IL-2 than a historical,
Sorafenib is an active agent, but is increasingly reserved for salvage therapy unselected patient population.
following other agents given the lack of robust front-line data (see Table 2).
Role of Cytoreductive Nephrectomy
In a recently reported phase II trial, 27 evaluable patients with clear-cell RCC Randomised trials have demonstrated a significant survival advantage in
refractory to either bevacizumab (n=11) or sunitinib (n=16) were treated metastatic RCC with cytoreductive nephrectomy followed by IFN-α.
32,33
with sorafenib.
20
No objective responses have been observed, although nine Retrospective reviews also suggest that this approach may improve
patients (33%) had >5% decrease in tumour burden, with a median PFS of outcomes in patients receiving HD IL-2.
34
The vast majority of patients
3.7 months. Interestingly, there was no association between tumour accrued on trials with novel TKIs had undergone prior nephrectomy.
shrinkage and response to prior therapy. Toxicities were significant, with However, the role of prior nephrectomy in improving outcomes in the era
grade 3 toxicities experienced by 67% of patients. of novel highly active agents remains to be defined.
Other retrospective reports support the presence of only partial cross- The paradigm of pre-surgical systemic therapy followed by cytoreductive
resistance between available novel anti-angiogenic agents.
21–23
Hence, a nephrectomy may be employed to develop individualised therapy, elucidate
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