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Renal cancer, also called hypernephroma or renal cell carcinoma (RCC), accounts for 3% of all malignancies in humans and is a histologically diverse disease with an often unpredictable course. The American Cancer Society predicts there will be approximately 36,000 new cases of renal cancer in the US during 2005, resulting in around 26,000 deaths.

The prognosis of renal cancer is worsened with the onset of metastasis, and therapies currently available are of limited success. In addition, over-expression of the multi-drug resistance (MDR) protein in renal cancer means there is a low response rate to chemotherapy. The unpredictable nature of RCC and its difficulty to treat has driven pharmaceutical companies to fund research into finding alternative treatment options.

Therapy options

According to IMS LifeCycle R&Dfocus there are more than 80 products being investigated for the potential treatment of renal cancer. Table 1 details a selection of products that are in later-stage development for RCC in the US and Europe.

Table 1: Renal cancer therapies in the pipeline

The mechanism of action of compounds being developed for use in renal cancer includes anti-angiogenic drugs, growth factor receptor inhibitors, kinase inhibitors and tumour antigen inhibitors. A number were featured at the 41st annual meeting of the American Society of Clinical Oncology, held in Orlando in May 2005.

Angiogenesis, the process by which tumour vasculature develops, is essential for the growth and metastasis of cancer cells. Renal cancer is a highly vascularized tumour type and vascular endothelial growth factor (VEGF) receptor is over-expressed in the majority of patients. Binding of VEGF ligand to its receptor leads to tyrosine kinase phosphorylation and downstream activation of several signaling pathways that stimulate angiogenesis. Therefore, molecular inhibition of this pathway is a targeted therapeutic approach for RCC.

VEGF inhibitors

Genentech and majority-owner Roche are developing Avastin (bevacizumab), a humanized monoclonal antibody against VEGF, for RCC; it was launched as a therapy for colorectal cancer in February 2004. At the 41st ASCO meeting, an update of results was reported from Phase II trials of Avastin in combination with Tarceva (erlotinib) for renal cancer; Tarceva is being co-developed by OSI, Genentech and Roche. Results showed that 15 of 59 evaluable patients (25%) had objective responses (14 partial responses and one complete response) and 36 patients (61%) had stable disease. Median survival in the trial has not been reached; 78% and 60% of patients were alive at 12 and 18 months, respectively. Grade III adverse events observed included diarrhea, rash, nausea/vomiting, hypertension, bleeding, proteinuria and pruritus; two patients discontinued treatment because of Grade III skin toxicity. In addition, one Grade IV toxicity (gastrointestinal bleeding) occurred.

In February 2005, Roche initiated a Phase III trial in the US with bevacizumab plus interferon in metastatic RCC.

Sutent (sunitinib malate), an orally bioavailable inhibitor of VEGF receptor, platelet-derived growth factor receptor, and KIT and FLT3 tyrosine kinases, is being developed by Pfizer for a variety of tumour types. In a US Phase II RCC trial, conducted during 2004, Sutent induced a partial response, stable disease and progressive disease in 15 (24%), 29 (46%) and 19 (30%) patients, respectively. Phase III trials are under way in renal cancer in the US and Europe.

Kinase inhibitors

Stimulation of growth factor receptors leads to activation of a number of downstream signaling pathways. The Ras/Raf/MEK/ERK and mammalian target of rapamycin (mTOR) intracellular pathways, which couple growth receptor signaling to transcription factor activation, are of particular importance in renal cancer. mTOR regulates the cell cycle to stimulate cell cycle progression, angiogenesis, and cell proliferation, survival and mobility. Inhibition of these intracellular pathways is another approach to the treatment of RCC.

Bayer and Onyx are developing sorafenib (BAY 439006), an orally bioavailable inhibitor of raf kinase and the VEGF-2 and PDGFR tyrosine kinases. A world-wide, randomized Phase III trial to evaluate the safety and efficacy of sorafenib in advanced RCC, which completed enrolment in March 2005, is ongoing. The trial, the largest ever for RCC, will involve more than 900 patients with unresectable and/or metastatic disease who have failed a previous systemic therapy. The primary endpoint of the trial is improvement in survival; the study will also examine time-to-disease progression, overall response rate, safety, pharmacokinetics and quality of life.

At the 41st ASCO meeting, preliminary data from this trial were reported. Sorefenib delayed the progress of advanced kidney cancer, extending disease progression to 24 weeks compared with 12 weeks for placebo. Pending regulatory approval, Bayer and Onyx expect to begin selling the drug in the first half of 2006. Despite the release of this positive data at ASCO, however, Onyx's shares fell after some analysts said they considered Pfizer's earlier-stage data for Sutent more impressive. On the other hand, Sutent patients must take a two-week break after each four-week period of treatment to recover from the fatigue and other side-effects it can cause.

Wyeth’s temsirolimus (CCI 779), a sirolimus (Rapamune) analogue and inhibitor of mTOR, was granted FDA Fast Track designation as a first-line treatment for poor prognosis RCC in August 2004. In February 2004, Wyeth initiated a randomized, Phase III trial comparing temsirolimus with alpha-interferon, a standard current treatment, in 600 patients with metastatic renal cancer; the trial is ongoing. Wyeth expects to file for FDA approval of temsirolimus in RCC during the first quarter of 2007.

Tumour-associated antigen inhibitors

Tumour cells express a variety of markers on the cell surface that allow for the targeting of therapies to cancerous tissue. G250 is a cell surface antigen that is expressed on the surface of more than 90% of clear cell adenocarcinomas; G250 expression in normal tissue is restricted to the larger bile ducts and mucosa of the upper gastrointestinal tract, where levels are negligible.

Wilex is developing Rencarex (WX G250), a chimaeric monoclonal antibody against G250 (or MN), for the treatment of both metastasized and non-metastasized renal cancer through a partnership with Esteve. A US and European Phase III trial, initiated in June 2004 and designated ARISER, is evaluating Rencarex versus placebo as an adjuvant therapy for non-metastasized RCC patients at high risk of recurrence after resection of the primary tumour.

What does the future hold?

Renal cancer is a disease with a complicated etiology that currently has a high mortality rate. Advances in the understanding of the molecular mechanisms underlying the disease, however, have enabled the initiation of clinical investigation into potential targeted treatment options. Data presented at the 41st ASCO meeting highlighted the benefit of therapeutics currently in development both as monotherapies and combination treatments. According to ClinicalTrials.gov, the clinical trial database of the US National Institutes of Health, there are presently 189 studies recruiting RCC patients. These trials, together with continuing preclinical research into the mechanism behind renal cancer, will enable progression towards reducing the mortality rate of this aggressive disease.