Escudier_edit.qxp 27/7/07 05:03 Page 47
Treatment of Advanced Non-clear-cell Renal Cell Carcinoma
inducible factor-1 (HIF-1), with the subsequent activation of growth promising activity in advanced RCC.
26
A phase III trial compared temsirolimus,
factors such as vascular endothelial growth factor (VEGF), transforming interferon-alpha or a combination of both in patients with advanced RCC.
growth factor (TGF)-alpha and platelet-derived growth factor (PDGF)-beta. Although the majority of patients in the trial had clear-cell histology (82%), a
By targeting signalling pathways integral to the activation of these growth preliminary sub-analysis of the non-clear-cell histology cohort showed a
factors, novel targeted agents may have a significant impact on the significant advantage in hazard ratio for OS in the temsirolimus group.
26
An
management of RCC. Several agents, including the anti-VEGF antibody updated sub-analysis of the study showed that temsirolimus treatment in
bevacizumab, the multitargeted tyrosine kinase inhibitors (TKI) sorafenib patients with non-clear-cell histology resulted in improved median OS and
and sunitinib and the mammalian target of rapamycin (mTOR) inhibitor PFS compared with similar patients treated with interferon-alpha, with a
temsirolimus, have shown promising efficacy in metastatic RCC.
6,23–26
hazard ratio of 0.55 and 0.36, respectively. A subtype analysis revealed that
However, the majority of evidence is related to the predominant clear-cell within the non-clear-cell cohort 75% had papillary RCC.
29
RCC population and little information exists about the efficacy of the new
targeted agents in RCC with non-clear-cell histologies. Indeed, in many of Epidermal Growth Factor Receptor Inhibitors
the clinical trials evaluating the novel treatment modalities, the non-clear-cell Epidermal growth factor receptor (EGFR) has been investigated as a
RCC population was excluded. Thus, the question arises as to the role of potential therapeutic target in patients with clear-cell RCC, but clinical
these new agents in non-clear-cell RCC. Encouragingly, a number of clinical trials with single-agent EGFR inhibitors have produced disappointing
trials have been expanded to include patients with non-clear-cell histology results.
30,31
The Southwest Oncology Group reported preliminary results
and data are now beginning to emerge for this patient population. of a phase II trial with the EGFR-inhibitor erlotinib in patients with
papillary RCC.
32
Of 39 evaluable patients with advanced papillary RCC,
Multitargeted Agents 10% had objective responses with erlotinib therapy. Active treatment
Sorafenib and sunitinib are multitargeted TKIs that have produced promising was associated with six-month PFS of 30% and median survival was 26.9
results in large-scale clinical trials in metastatic RCC.
6,24,25
The Advanced months. The authors concluded that the efficacy of erlotinib was
Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial recruited insufficient to warrant further study of this drug in papillary RCC.
patients with advanced RCC not eligible for other sorafenib clinical trials.
27
However, this conclusion may be debatable, and there may be a place for
Preliminary data from this open-label, non-randomised trial showed that for these drugs in combination with other targeted agents.
patients with non-clear-cell RCC sorafenib treatment resulted in median
progression-free survival (PFS) of 34.5 weeks. Partial responses of 3.4 and Hepatocyte Growth Factor Receptor Tyrosine
5.6% were noted for patients with papillary and chromophobe RCC, Kinase Inhibitors
respectively. Stable disease was noted in 77.1% of patients with papillary XL880 is a novel oral TKI targeting the c-Met (hepatocyte growth factor)
RCC and in 88.8% of patients with chromophobe RCC. The activity of receptor and VEGF receptor. The familial form of papillary RCC is
sunitinib and sorafenib has been evaluated in a retrospective analysis in associated with germline-activating mutations of c-Met, while
patients with metastatic papillary and chromophobe RCC who had received amplification and overexpression of c-Met is seen in the sporadic form.
33
either agent as their initial TKI treatment.
28
Objective response rate (ORR), Preliminary results of a phase II study evaluating XL880 in previously
PFS and overall survival (OS) for the entire cohort were reported as 10%, 8.9 untreated patients with a histological diagnosis of metastatic papillary
months and 12.2 months, respectively. A sub-analysis revealed that ORR RCC noted that of the 51 patients assigned to one of two different
was achieved in 25% of chromophobe patients compared with only 4.8% schedules of XL880 – five days on/nine days off or a fixed daily dose – five
in patients with papillary RCC (p=0.07). Furthermore, PFS in the patients had objective responses. Five of eight patients who received the
chromophobe population was significantly longer (9.3 versus 6.6 months for fixed-dose schedule had stable disease for more than three months.
papillary patients, p=0.07), although there was no difference in OS across
histologies. This suggests that multitargeted TKI may have activity in Conclusion
metastatic chromophobe RCC similar to that in clear-cell histology patients. While much exciting data is being collated on the efficacy of targeted
However, the minimal activity noted in the papillary cohort warrants agents in metastatic clear-cell RCC, there is limited knowledge of the
continued investigations of these novel agents in this histology. activity of these agents in patients with non-clear-cell histology. Therefore,
it is encouraging to see the recent emergence of information within this
Mammalian Target of Rapamycin Inhibitors population, which is characterised by a resistance to systemic therapy and
The phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT)-mTOR signal- poor survival and for which there is no established treatment. Much work
transduction pathway is thought to play a role in tumour angiogenesis in needs to be done in terms of establishing the role of new targeted agents
clear-cell RCC and an mTOR inhibitor – temsirolimus – has demonstrated in metastatic non-clear-cell RCC but the initial findings look promising. ■
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