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Renal Cell Carcinoma
occurred in 2.9 versus 0.4% and bleeding events occurred in 15.3 in median OS and a 1.8-month (95%) improvement in median PFS was
versus 8.2%, respectively.
20
observed in the temsirolimus arm. The four most common adverse
events were asthenia, anaemia, skin rash and dyspnoea. Of importance,
Mammalian Target of Rapamycin Inhibitors this was the first study to show a statistically significant improvement in
Growth factors through the PI3K-AKT-mTOR signal transduction survival in patients with advanced metastatic poor-risk RCC.
pathway are known to stimulate tumour angiogenesis. Furthermore,
the mTOR-AKT pathway is a nutrient-sensing pathway and in a Other Targeted Therapies Under Investigation
feedback loop is upregulated by HIF.
22
VHL mutations predict for In addition to the three agents discussed above, several other agents
sensitivity to mTOR inhibitors in the laboratory.
23
Rapamycin, an targeting signal transduction are under investigation for RCC. These
immunosuppressive agent, inhibits mTOR. Consequently, rapamycin include the mTOR inhibitors everolimus (RAD001) and Ariad (AP23573).
analogues have been developed as anticancer agents. The RECORD trial is a large phase III randomised 2:1 trial of everolimus
(RAD001) in clear-cell RCC patients who have failed sunitinib or sorafenib
Temsirolimus VEGF-R TK inhibitor therapy. Prior bevacizumab (a monoclonal antibody
Temsirolimus, an analogue of rapamycin, is an mTOR inhibitor and is against VEGFR-ligand inhibitor) is permitted. Other therapies include:
the latest targeted agent to be approved for use in advanced RCC. The
approval of temsirolimus was based on a phase III multicentre trial, • pazopanib, another novel multi-targeted inhibitor of VEGFR-1, -2, -3,
performed at 209 sites in 26 countries in previously untreated patients PDGFR-α and β, and c-Kit, which has completed a phase II randomised
with poor-prognosis metastatic RCC.
24
The trial investigated discontinuation trial,
26
and phase III results are eagerly awaited;
temsirolimus as a single agent versus combined therapy with IFN-α • axitinib (AG-013736), an orally available, potent inhibitor of
versus IFN-α alone. Pre-treatment features associated with shorter VEGFR-1, -2 and -3 and PDGFR;
survival after cytokine therapy, known as the Motzer criteria, were a • the angiogenesis inhibitor valatinib (PTK 787/ZK 222584, PTK/ZK),
low Karnofsky performance status (<80%), high lactate dehydrogenase which blocks all known VEGFR TKs including the lymphangiogenic
level (>1.5 x normal), low haemoglobin level, high serum calcium and VEGFR-3; and
the absence of nephrectomy.
25
In that particular study, poor-risk • lapatinib, an orally active, reversible inhibitor of epidermal growth
patients with advanced RCC and no previous systemic therapy were factor receptor (EGFR) and HER-2/c-neu (ErbB-2).
defined as having three or more of six high-risk factors – the five
Motzer criteria and more than one metastatic disease site – 67% had Conclusions
had a previous nephrectomy. Targeted therapies represent a promising therapeutic option for
advanced RCC, which is traditionally associated with a poor prognosis.
In the phase III temsirolimus study, patients were randomised in The VEGF signal transduction pathway is clearly an important target for
three arms: therapy in the treatment of advanced RCC, and there is increasing
awareness that validating therapeutic targets is necessary for the
• single-agent IFN-α up to 18mµ SC three times a week; discovery of new drugs, and to verify their success.
• single-agent temsirolimus 25mg intravenous (IV) once per week; or
•a combination of temsirolimus 15mg IV once per week plus IFN-α While the potential of these targeted therapies is exciting, their use also
6mµ SC three times a week. raises several questions regarding the optimal use of these novel agents.
Moreover, varying response rates and toxicity profiles among TKIs
The primary study end-point was OS. Of 626 patients enrolled, 442 died suggest that there are differences among these agents. Currently, no
and the follow-up was 13 months after the last patient was enrolled. In direct comparisons of these agents have been made and thus all have
the second planned interim analysis, patients treated with temsirolimus emerged as promising and viable options for patients with metastatic
had statistically longer survival than those treated with IFN-α. The RCC. Ongoing clinical trials of these agents in the adjuvant and
median survival with temsirolimus was 10.9 (8.6–12.7) months versus neoadjuvant settings and in combination will help to optimise timing,
7.3 (6.1–8.9) months (HR 0.73, 95% CI 0.57–0.92; p=0.007) on IFN-α. sequencing and combination of therapies in RCC. In addition,
Survival on the combined arm was 8.4 (6.6–10.2) months, not international efforts to identify prognostic factors are ongoing.
27
Further
statistically different (HR 0.95, 95% CI 0.76–1.2; p=0.691) from IFN-α research must additionally be dedicated towards those patients with non-
alone. Temsirolimus, as a single agent (25 mg IV weekly), significantly clear-cell histologies. Future management options may be characterised
improved OS and PFS in patients with metastatic RCC with poor-risk by new rational treatment strategies based on inhibition of specific
features compared with IFN-α alone. A 3.6-month (49%) improvement biological pathways. ■
1. Jemal A, et al., CA Cancer J Clin, 2006;56:106–30. 11. Arora A, Scholar EM, J Pharmacol Exp Ther, 2005;315:971–9. 21. Lamuraglia M, et al., J Clin Oncol, 2005 ASCO Annual
2. Vogelzang NJ, Stadler WM, Lancet, 1998;352:1691–6. 12. Rini BI, et al., BJU Int, 2005;96:286–90. Meeting Proceedings, 2005;23 (16S pt I of II):Abstract
3. Pantuck AJ, et al., J Urol, 2001;166:1611–23. 13. Motzer RJ, et al., J Clin Oncol, 2006;24:16–24. 3069.
4. Stenzl A, de Kernion JB, Semin Oncol, 1989;16(Suppl.):3–15. 14. Motzer RJ, et al., JAMA, 2006;295:2516–24. 22. Bayes M, et al., Methods Find Exp Clin Pharmacol,
5. Motzer RJ, Russo P, J Urol, 2000;163:408–16. 15. Motzer RJ, et al., N Engl J Med, 2007;356:115–24. 2006;28:31–63.
6. Rosenberg SA, et al., N Engl J Med, 1987;316:889–97. 16. de Mulder PH, et al., J Clin Oncol, 2006;24(18S):Abstract 23. Thomas GV, et al., Nat Med, 2006;12:122–7.
7. Vogelzang NJ, Sternberg CN, BJU Int, 2007;99:1289–95. 4529. 24. Hudes G, et al., J Clin Oncol, 2006;24 (18S):Abstract LBA4.
8. Lam JS, et al., Urology, 2005;66(Suppl. 5):1–5. 17. Rini BI, Expert Opin Pharmacother, 2006;7:453–61. 25. Motzer RJ, et al., J Clin Oncol, 1999;17:2530–40.
9. Mukhopadhyay D, et al., Mol Cell Biol, 1997;17:5629–39. 18. Ratain MJ, et al., J Clin Oncol, 2006;24:2505–12. 26. Hutson TE, et al., J Clin Oncol, 2007;25 (18S):Abstract 5031.
10. Mancuso A, Sternberg CN, Curr Opin Urol, 2006;16(5): 19. Escudier B, et al., N Engl J Med, 2007;356:125–34. 27. Bukowski RM, et al., Clin Cancer Res, 2004;10:6310S–4S.
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42 EUROPEAN GENITO-URINARY DISEASE 2007
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