Therapeutic developments in renal cell carcinoma

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Tom Geldart
Consultant Medical Oncologist
Royal Bournemouth Hospital NHS Trust, UK

Malignant renal tumours account for about 3% of all cancers worldwide. Across the European Union, age-adjusted incidence rates range from 4.3 to 23 per 100,000 and mortality rates range from 1.7 to 8.5 per 100,000. Over the last 30 years, both incidence rates and five-year survival figures have increased significantly. Much of this apparent increase relates to early detection through the increasing use of ultrasound and computerised tomographic imaging.

Classification
Eighty to ninety per cent of malignant renal tumours arise from renal parenchyma, with the remainder arising from uro-epithelial origin. Clear cell renal cell carcinoma (ccRCC) represents the most common histological subtype and accounts for roughly 80% of RCC incidence. Other less common variants of renal carcinoma include papillary (chromophil), chromophobe, collecting duct and medullary carcinoma.

At the molecular level, loss of function of the von-Hippel Lindau (VHL) tumour suppressor gene is now recognised as a key event in the development of sporadic ccRCC. VHL gene inactivation results in elevated levels of the transcription regulator hypoxia inducible factor (HIF), which in turn leads to upregulation of a repertoire of key genes important in both normal and malignant cell growth, proliferation and angiogenesis. Of these, arguably the most important to be identified to date is vascular endothelial growth factor (VEGF), a potent pro-angiogenic molecule which has been found to be very highly expressed in RCC. Furthermore, HIF and ultimately VEGF expression are influenced by another key pathway, the mammalian target of rapamycin (mTOR), which also has regulatory effects on cell cycle, cell growth and survival. Drug developments over the past decade have led to highly active drugs targeting the VEGF and mTOR pathways and resulted in dramatic improvements in the outcomes of patients presenting with advanced kidney cancer.

Clinical presentation
Approximately 50% of patients with RCC will present with localised disease, with the remainder presenting with locally advanced or metastatic disease. Surgical resection remains the cornerstone of management for patients presenting with early stage disease. Complete resection of tumour with kidney (radical nephrectomy) remains a standard approach, although the importance of nephron-sparing surgery (partial nephrectomy) or thermal ablative techniques (radiofrequency or cryotherapy) are increasingly recognised.

Advanced disease: historical treatments and prognostic groups
For patients presenting with metastatic disease, conventional anti-cancer systemic treatments such as cytotoxic chemotherapy have proven largely ineffective. Prior to the advent of targeted therapies, the mainstay of treatment for patients presenting with metastatic disease was immunotherapy with interferon alpha or, for highly selected patients, high-dose interleukin 2. A Cochrane review published in 2008 evaluated pooled data from randomised controlled immunotherapy trials in 6880 patients.(1) Overall response rates were low at 12.4% with a median survival of 13 months (range six–28 months).

Several retrospective multivariate analyses have confirmed that patient outcome is strongly associated with the presence or absence of key prognostic factors. The most widely used prognostic grouping is that from the Memorial Sloan-Kettering Cancer Centre (MSKCC) group, which categorised patients into good, intermediate and poor prognostic groups based on the presence or absence of key prognostic factors.(2) These included low haemoglobin, high calcium, high lactate dehydrogenase, poor performance status and time from diagnosis to treatment of less than one year. Patients classified as favourable risk (zero risk factors) treated with interferon had a median survival of 30 months in comparison to the intermediate risk group (one or two risk factors), who had a survival of 14 months, and poor risk group (three or more risk factors), whose median survival was particularly low at five months.

Advanced disease: current therapeutic options
Over the last 10 years there has been an explosion in the number of new drugs available that target the underlying biological basis of RCC. Novel therapies have revolutionised the outlook for patients with new, highly active treatment options now representing the standard of care.

Although there are a large number of drugs currently being evaluated in early phase clinical trials, there are six agents with published phase III, randomised controlled clinical trial evidence supporting their use in advanced RCC. These agents can be categorised into three broad groups comprising multi-targeted receptor tyrosine kinase inhibitors (rTKIs) (sunitinib, sorafenib, pazopanib), monoclonal antibodies (bevacizumab) and mTOR inhibitors (temsirolimus, everolimus).

The European Medicines Agency (EMA) has approved the use of sunitinib (Sutent), bevacizumab (Avastin) in combination with interferon alpha and pazopanib (Votrient) for the first-line treatment of patients with advanced RCC. In patients considered unsuitable for first-line cytokine therapy, sorafenib (Nexavar) has EMA approval. Both sorafenib and pazopanib have also been approved for use subsequent to initial cytokine therapy. In patients with poor prognosis disease, temsirolimus (Torisel) has approval for first-line use. Following the failure of VEGF-targeted therapy, everolimus (Afinitor) is the only agent currently approved in this setting.

Availability across the UK depends not only on EMA approval but also on national regulatory approval. Within the UK, the National Institute for Health and Clinical Excellence (NICE) has only approved sunitinib as a first-line therapy. No second-line agent is currently approved for routine use, although the use of everolimus is currently under review by appeal. NICE recommended pazopanib as first-line treatment for advanced RCC in 2011.(3)

VEGF inhibition
Interfering with the angiogenic drive in RCC through the use of VEGF receptor inhibitors or the targeting of VEGF ligand dominates the first-line therapeutic options in advanced RCC.
Sunitinib is an oral rTKI, which targets VEGFR-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α/β, c-kit, Fms-like tyrosine kinase-3 (Flt-3), colony stimulating factor Type 1 (CSF-1R) and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib is the rTKI in most widespread use with the highest objective response rate. The pivotal trial, published in 2007 by Motzer and colleagues and updated in 2009, compared sunitinib 50mg daily in a four-week on, two-week off schedule to interferon alpha 9MU given subcutaneously three times per week as a first-line treatment for patients with advanced ccRCC and predominantly good or intermediate risk disease by MSKCC criteria.(4,5) The trial demonstrated a highly significant doubling of progression-free survival (11 months vs five months, P<0.001). Response rates were dramatically improved in the sunitinib arm (47% vs 12%), with the majority of the remaining patients (40%) achieving disease stabilisation. Median overall survival for patients treated with sunitinib was 26.4 months compared with 21.8 months (hazard ratio [HR] 0.821; confidence interval [CI] 0.67–1.00; P=0.51) with cytokine therapy. Survival in the interferon arm was influenced by the 65% of patients who went on to receive other VEGF-directed therapy following progression.(5) An exploratory analysis in patients who did not receive any post-study systemic therapy revealed a doubling of overall survival in the sunitinib arm (28.1 months versus 14.1 months; HR 0.647; P=0.003). Non-laboratory toxicities commonly experienced included hypertension, fatigue, diarrhoea, mucositis, mild nausea and reversible skin discolouration. Laboratory toxicities included mild myelosuppression and hypothyroidism. Toxicities can often be moderated by supportive therapies, but for some patients dose reduction is required.

Sorafenib is an oral rTKI which inhibits raf kinase, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-kit. The TARGET study compared sorafenib to placebo in a phase III trial in patients with advanced RCC resistant to standard first-line therapy.(6,7) Use of sorafenib was associated with a statistically significant improvement in disease-free survival (5.5 months vs 2.8 months). Although no statistically significant difference in overall survival was demonstrated (17.8 months vs 15.2 months), there was significant cross-over of patients receiving placebo to sorafenib treatment at progression. Censoring survival data for cross-over resulted in the survival difference becoming significant (17.8 months vs 14.3 months; HR 0.78). Common side-effects included diarrhoea, fatigue, skin rash and hand–foot reactions. Practically, the use of sorafenib in this indication is low as the vast majority of patients will receive a VEGF or mTOR directed therapy as a first-line treatment for advanced disease.

Pazopanib is the third oral multi-targeted rTKI with a phase III trial demonstrating efficacy in advanced RCC.8 Pazopanib has activity against VEGFR1,2,4, PDGF-α/β and c-kit. The pivotal trial compared oral pazopanib 800mg with placebo in either first-line metastatic patients or cytokine pre-treated patients and demonstrated a statistically significant overall progression-free survival of 9.2 months versus 4.2 months in favour of pazopanib and a response rate of 30% versus 3%. The separation of progression-free survival was greater in the treatment-naive group (11.1 months vs 2.8 months).

The majority of patients were either good or intermediate risk category by MSKCC criteria and had clear cell histology. Similar toxicities to other rTKIs were seen, and the most common grade III/IV clinical abnormalities were hypertension and diarrhoea. The most commonly detected grade III or IV laboratory abnormalities were elevated liver transaminases, which occurred early on in the course of treatment.

Bevacizumab, a humanised anti-VEGF monoclonal antibody, is the only EMA-approved antibody for the treatment of advanced RCC. It was initially evaluated in combination with interferon in two large phase III trials (CALGB and AVOREN) and approved for use on the basis of these results.(9,10) As a first-line treatment, combination treatment has broadly similar efficacy to multi-targeted rTKIs, with response rates of circa 30% and progression-free survival rates of eight to 10 months in patients categorised by MSKCC as having good or intermediate risk prognosis. In both studies, interferon was given subcutaneously at a dose of 9MU three times per week, with bevacizumab 10mg/kg given intravenously every two weeks. As a parenterally administered treatment, this regimen may be less convenient for patients, although compliance may be easier to monitor. Bevacizumab has a differing side-effect profile from the rTKIs, with less hand–foot syndrome and diarrhoea, similar rates of hypertension, but more proteinuria and vascular events. The use of interferon means that fatigue and asthenia are common dose-limiting toxicities, although subsequently published data suggest that interferon may be given at lower dose without compromising effect.(11)

mTOR inhibitors
Temsirolimus and everolimus are mTOR inhibitors with activity against advanced RCC. In contrast to other first-line studies where the patient population is dominated by good and intermediate prognosis patients, the phase III trial evaluated temsirolimus 25mg given weekly in comparison to temsirolimus in combination with interferon alpha and interferon alpha alone as a first-line treatment for patients with at least three of six poor prognostic features.12 In this poor prognosis group response rates were low at 8.6% (vs 4.8 % for interferon alone), although a significant proportion of patients derived clinical benefit through disease stabilisation. Roughly one third of patients achieved clinical benefit (objective response or stable disease for greater than 24 weeks) from temsirolimus vs 15.5% with interferon alone. Median overall survival for temsirolimus alone was 10.9 months compared with 7.3 months. Combination treatment with temsirolimus and interferon was associated with increased toxicity without additional benefit.

Everolimus, an orally available mTOR inhibitor, is currently the only agent which has phase III evidence to support its use in patients who have failed VEGF targeted therapy.(13,14) The study compared everolimus 10mg to placebo and demonstrated a benefit in favour of everolimus in progression-free survival (4.9 months vs 1.9 months; HR 0.33; P<0.001). Overall survival was not statistically significantly different at 14.8 months vs 14.4 months, although, of note, 80% of patients in the placebo arm crossed over to receive everolimus at progression. Response rates were low (1%), and everolimus appeared to act primarily as a disease-stabilising drug with approximately twice as many patients (63% vs 32%) achieving disease stabilisation compared to placebo.
The toxicity profile from mTOR inhibitors differs to that seen with rTKI or bevacizumab therapy. Side-effects include skin rash, stomatitis, oedema and fatigue. Drug-induced pneumonitis is a recognised toxicity and can be severe in some patients. Commonly detected biochemical abnormalities include hyperglycaemia, hypercholesterolaemia and hyperlipidaemia.

Conclusions
The management of advanced RCC has changed dramatically over the last 10 years. We now have a plethora of targeted drugs developed from an understanding of key molecular pathways regulating the development and progression of RCC. To date, combining novel therapies has led to increased toxicity without appreciable improvement in outcome.
The challenge for the future is how best to select therapies on an individual patient basis, and how to optimally sequence available therapeutic options whilst effectively minimising treatment-related toxicity.

References

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3. National Institute for Health and Clinical Excellence. Pazopanib for the first-line treatment of renal cell carcinoma. 2011. www,nice.org.uk/guidance/TA215.
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