Sutent Is Official Standard For First-line Treatment Of Advanced Kidney Cancer: Research Now Probes Use In Earlier-stage Disease

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Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 01 Apr 2009 - 3:00 PDT

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Both the European Association of Urology (EAU) and the UK's National Institute for Health and Clinical Excellence (NICE) issued guidelines this month (March 2009) recommending that the multi-targeting tyrosine kinase inhibitor (TKI) therapy, sunitinib malate (Sutent) should now be used as the first-line therapy of choice for patients with metastatic renal cell cancer (mRCC) considered to have a good or intermediate prognosis of survival. It is the only targeted therapy of its type that NICE recommends for first-line use.

The recommendations are based largely on evidence showing that first-line use of Sutent doubles both overall and progression-free survival rates in advanced kidney cancer patients compared to the cytokine therapy interferon-alpha (IFNa) which was previously the standard therapy for the condition. Results of a phase III study presented last year and confirmed by a final analysis of the study data presented at the EAU's annual meeting in Stockholm, 6 per cent and more quality of life benefit in studies comparing it to IFNa.

EAU guidelines say the soluble VEGF-blocker bevacizumab (Avastin) plus IFN alpha can be considered as an alternative to Sutent for first-line therapy in patients of good or intermediate risk, however, oncology and urology researchers now invariably acknowledge Sutent as the reference standard therapy for mRCC. This means any new therapies in development for mRCC will have to be tested against it to show they are as good as or better than Sutent.

In the same week that these recommendations were announced, experts in oncology and urology speaking at EAU in Stockholm stressed that clinicians are still learning how to use Sutent to its best effect for patients at different disease stages, both as a single agent with regard to dose and duration of therapy, and as neoadjuvant or adjuvant therapy before or after nephrectomy. They are also looking at it in sequence with other therapies such as sorafenib, another targeted TKI therapy and M-Tor inhibitors such as everolimus and temsorilimus and in kidney cancer patients without metastases. Once it is known how to fully optimise therapy, Sutent and second-line drugs used in the right sequence or combination might potentially achieve much better survival outcomes, they suggest.

Sutent has both anti-angiogenesis and anti-tumour effects. It acts as an anti-angiogenesis agent, disrupting tumour blood supply by targeting vascular endothelial growth factors (VEGF) and platelet-derived growth factors (PDGF), but it also targets c-Kit and Flt-3 whose role is less well understood. Delivering the EAU's joint oncology and urology state-of-the-art lecture on biological agents in RCC, Susanne Osanto, Professor of Clinical Oncology, at Leiden University, The Netherlands, suggested that Sutent's other attributes may include an ability to boost the body's own cancer-fighting resources by influencing certain T lymphocytes: "What's very interesting is the fact that we know Sutent is probably also a drug that modulates immunity; there are data that indicate it modulates anti-tumour immunity by reversing tumour-induced immune suppression via regulatory T cells often found in the kidney" she explained. "This could be one of the markers we are going to use in future to select patients."

Getting the right dose for long enough is key to improved outcome

"The era of targeted therapy has now superseded the era of cytokine therapy. There really has been a major paradigm shift in mRCC therapy with recognition that Sutent and other targeted drugs improve survival," Professor Osanto noted. "But we need further studies to define the optimal dose, duration and sequencing of targeted therapies" she emphasised. Urologists would play a key role in defining the place of surgery in metastatic RCC and of adjuvant therapy.

Speaking at a Pfizer-sponsored satellite symposium during EAU, oncologist Professor Martin Gore of the Royal Marsden Hospital and Imperial College, London, also claimed the era where immunotherapy was the standard of care for mRCC is now well and truly over. "Only a small proportion of patients with a good prognosis benefited from cytokine therapy (who would have done well anyway) and toxicity was quite severe. For 90 per cent, in many respects, treatment was worse than the disease," he observed. Virtually all mRCC patients on the other hand benefited from one or other of the targeted therapies, he said: "Suddenly a door has been opened for these patients and that is a real change in the standard of care in our lifetime."

Over the next 5 to 10 years, specialists in kidney cancer will define which drugs are best for patients according to their disease-type and severity and which should be used as second-line or combination therapy if disease progresses after single-agent first-line therapy, he predicted. Specialists will also learn how to prolong survival simply by using Sutent at the right dose or for the right length of time without causing patients to experience intolerable side effects. Sutent's recommended dose is one 50mg tablet daily taken orally in a six-week cycle consisting of four weeks on treatment followed by a two-week break. The average patient remains on treatment for 10 to 12 months.

"Several studies show the higher the amount of drug the patient is exposed to the more likely their tumours will respond," he explained. This did not mean pushing up the dose but seeing they received an effective dose for sufficient time. Where patients are given a reduced dose in anticipation, or as a result, of side effects they may not derive a benefit, he warned. The same applied to stopping treatment too soon or interrupting it for extended periods. Basic research shows the benefit of Sutent in disrupting a tumour's blood supply is likely to be reversed very quickly, within days, he added.

"There is some intriguing evidence suggesting that patients are more likely to experience a response with a longer treatment period," he noted. When patients were followed up over six months, the response rate, in terms of tumour shrinkage, was 31 per cent but by 11 months, 39 per cent had responded. "This was a subset analysis," he cautioned, "but it certainly is an indication there may be a late response and that treating longer could be of benefit."

Expanded access data confirms phase III findings in 'real-world' practice

Data following over 4000 patients treated with Sutent in clinical practice show that many receive Sutent for up to15 months suggesting a majority of patients is able to tolerate therapy well. Patients in clinical trials can often be a highly selected population handpicked to exclude those more likely to experience adverse reactions to treatment. But data collected about larger numbers of patients treated in everyday clinical practice settings show the findings of the pivotal phase III study of Sutent are replicated in the "real world" with no unexpected findings or concerns about the emergence of serious adverse events, said Professor Gore.

The most bothersome side effects typically experienced are usually gastro-intestinal symptoms (diarrhoea), fatigue, hypertension, taste disturbance, reversible haematological abnormalities and skin toxicity particularly on the ball of the foot or on the hands of manual workers (hand-foot syndrome), he noted. Most patients do not experience these at a severe (grade 3 or 4) level.

Side effects could be minimised by assessing patients properly before instigating treatment and pre-treating those more likely to be affected. Any patients with high blood pressure, for example, needed to have this controlled first before starting treatment and those whose hands and feet were already in poor condition needed treatment from a chiropodist or dermatologist beforehand, he advised. "Above all you need to educate patients. Its not enough to give them a booklet" he stressed. Patients should be able to touch base with their prescribing physician or a specialist nurse should they develop side effects and be given advice immediately on how to manage them. "There is no point in reducing the dose to a sub-therapeutic level. So listening to patients and educating them about side-effect management is vital to maintain efficacy."

Remaining questions about getting the best results form Sutent therapy are to be addressed by several large clinical trials, likely to start soon. Details were announced by Professor Osanto in the official EAU meeting and in the satellite symposium by Dr Axel Bex, a urological surgeon of the Division of Surgical Oncology at the Netherlands Cancer Institute, Amsterdam, The Netherlands. A key unanswered question concerns whether or not patients with mRCC who receive targeted therapy require a nephrectomy at all or if so which patients qualify and when they should undergo the procedure.

The French-led CARMENA trial scheduled to start in June or July 2009 will compare 500 patients randomised to receive either nephrectomy followed by Sutent 50mg once daily, or Sutent 50mg OD alone, with a primary endpoint of overall survival. Another phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) addressing the same question will compare nephrectomy followed by Sutent against three cycles of Sutent followed by nephrectomy. The primary endpoint is progression-free survival. Both trials are expected to yield important information on gene and protein expression from tissue biopsies.

In non-metastatic disease, trials are in progress to answer the question of whether or not adjuvant treatment with targeted therapies following surgery prolongs survival in high-risk patients with localised disease. The Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) study is an international randomised study comparing Sutent with placebo in patients deemed at high risk of recurrence following surgery for localised disease. The Adjuvant Sorafininb Sunitinib Unfavourable Renal Cell Carcinoma (ASSURE) trial in the USA will compare 12 months adjuvant sorafinib against 12 months sunitinib and against 12 months placebo. The largest trial, to be conducted in the UK by the Medical Research Council and EORTC, is the Sorafenib with Placebo in Patients with Resected Primary Renal Cell Carcinoma (SORCE). This will compare the risk of disease progression in patients at high risk of relapse following resection who are exposed to either one year's sorafinib plus two years placebo or to three years of placebo. The primary endpoint of all three trials is disease-free survival.

Further studies are looking for biomarkers to predict patients who are most likely to respond to Sutent and to identify those who are likely to be non-responders and who may need first-line treatment with a mammalian target of rapamycin (mTOR) inhibitor. Dr Laurence Bastien of Hopital Henri Mondor in Creteil, France, presented data at EAU from retrospective research involving immunohistochemistry staining for VEGF expression on renal tumours of 64 patients from several centres. Those tumours over-expressing VEGF on the front rather than in the centre of the tumour were nine times more likely to have responded to Sutent predicting an 80 per cent response rate. A prospective study is now being planned, said Dr Bastien.

Other studies are needed to determine the best choice of second-line treatment for patients failing first-line Sutent, say experts. Ultimately, the answers to these questions will refine the treatment algorithm so that targeted drugs are used in sequence to their best advantage. But clinicians must wait for the answers especially with regard to adjuvant therapy with Sutent in non-metastatic disease, Professor Gore stressed. "It would be really wrong to try Sutent as adjuvant therapy outside of a clinical trial. It could be to the patients' detriment. These are not curative agents and at this stage we should save these drugs until we know they will work well for patients when they really need them."

Written by Olwen Glynn Owen
Glynnowen(at)macline.co.uk


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