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31st Congress of the European Society for Medical Oncology

Istanbul, Turkey / September 29-October 3, 2006

Recent insights into the crucial role of genetic changes in intracellular signalling pathways in the progression of cancer has led to a new generation of tumour-specific agents that target molecular mechanisms controlling tumour cell proliferation and angiogenesis which enable the malignancy to spread. Mutations can result in tumour cell proliferation among patients at risk whereas certain growth factors play key roles in angiogenesis, which is essential for the growth and spread of tumours. Targeting more than one oncogene is presently perceived as the way ahead in targeted therapy.

According to Dr. Martin Gore, Medical Director, Royal Marsden Hospital, London, UK, “Evidence of activity in advanced renal cell carcinoma [RCC] has recently been obtained for a number of new targeted therapies, including the multi-targeted tyrosine kinase inhibitors sorafenib and sunitinib.” Dr. Gore reported that sunitinib achieved response rates of nearly 40% in two second-line phase II trials and improved response rates with a highly significant more than twofold increase of progression-free survival (PFS) compared with IFN-a in a phase III first-line trial of 750 previously untreated patients with clear cell histology. Sorafenib also significantly doubled PFS in first- and second-line trials, including the pivotal phase III TARGETs (Treatment Approaches in Renal Cancer Global Evaluation Trial) of more than 900 patients mostly with metastatic or unresectable disease and clear cell histology who had failed prior systemic therapy in the preceding eight months.

In the clinical setting, Dr. Bernard Escudier, Head, Immunotherapy and Innovative Therapy Unit, Institut Gustave-Roussy, Paris, France, reported that the TARGETs study, which he headed, showed that 84% of sorafenib-treated patients attained clinical benefit compared with the 55% assigned to placebo and improved survival by 39%. The multitargeted agent consistently improved PFS in different populations. Patients older than 65 years of age, for example, obtained the same benefit as did younger patients and the safety profile in those two populations was virtually identical.

Dr. Tim Eisen, Professor of Medical Oncology, Cambridge Research Institute, University of Cambridge, UK, remarked that elderly patients are often under-represented in oncology trials because they are inherently considered to be at higher risk of toxicity and less likely to achieve optimal outcomes. His subgroup analysis of 269 TARGETs study patients 65 years of age and older and 634 younger than 65 showed clinical benefit to be similar—about 85% in both groups. He said sorafenib doubled PFS compared to placebo, regardless of age category, and tumour responses were similar by age within the two groups, adding that health-related quality-of-life measures were improved and health status deterioration was delayed for both age groups compared to placebo and there were no differences in side effects by age.

Dr. Escudier told delegates, “If you want to select patients based on their metastatic site of disease, you can rest assured that outcome in terms of PFS is equivalent, whatever the site. Patients who are lung metastatic at baseline get the same benefit in terms of tumour shrinkage as those who have no metastasis. This compound shrinks tumours, sometimes impressively, in 76% of patients. Targeted agents decrease tumour vascularization. Being hypervascular tumours which depend on angiogenesis for growth and metastasis, RCCs become almost vessel-free when given the tyrosine kinase inhibitor.”

He noted, too, that clinical metastasis to the brain was much more frequent among placebo-treated patients than those randomized to sorafenib. One possible explanation is that the active treatment is able to pass through the blood-brain barrier. Dr. Escudier’s colleague, researcher Dr. Christophe Massard, reported that of 139 patients evaluated, 10 developed brain metastasis, which was significantly fewer than with placebo (3% vs. 12%; P=0.049). The one-year incidence of brain metastasis for sorafenib vs. best supportive care was 3% and 10%, respectively, and 4% vs. 20% at two years. Therefore, he concluded, anti-angiogenic therapy with the oral multikinase inhibitor could be an effective treatment to prevent metastasis to the brain.

Drs. Escudier and Gore both agreed that conventional clinical end points to measure response to targeted therapy, such as WHO (World Health Organization) or RECIST (Response Evaluation Criteria in Solid Tumors) criteria, might underestimate the efficacy of treatment with targeted agents because the new multitargeted agents act more by inducing tumour necrosis than by causing tumour shrinkage. Viewed on a scan, therefore, tumour responses present a picture of tumour destruction with central necrosis progressing from inside the tumour toward the periphery, rather than tumour shrinkage progressing from the periphery to the interior, as is the case with cytokine treatment, Dr. Gore explained.

In a related presentation, Dr. John Wagstaff, Professor and Honorary Consultant in Medical Oncology, South West Wales Cancer Institute, Singleton Hospital, Swansea, UK, stated that in terms of survival benefit, achieving stable disease with a multikinase inhibitor appears to be just as important as having an objective response. Response rates with sorafenib, for example, are lower than with sunitinib, but the clinical benefit rate, defined as response plus stable disease and reflecting PFS, are in the order of 80% for both compounds, with both demonstrating significant benefits in PFS.

Dr. Escudier noted that sorafenib is much less toxic than high-dose IL-2 and likely better tolerated than IFN-a. Common side effects of sorafenib treatment include hypertension, diarrhea, rash and, above all, hand-foot skin reactions which may be painful but can usually be managed by supportive measures, preventive therapies and/or dose modifications.

New Paradigms

Dr. Sylvie Négrier, Medical Oncology Department, Centre Léon-Bérard, Lyon, France, believes that based on the PERCY Duo and Quattro trials, only about 15% of the whole population of metastatic RCC patients are likely to derive any response rate benefit from treatment with IL-2 or IFN-a. In addition, she commented, these patients must have a very good performance status to begin with and disease limited to not more than one metastatic organ site, which are very rigorous and strict criteria. “But for the large majority of patients [85%], cytokines are no longer recommended,” she noted. “New agents, like anti-angiogenic compounds, must now be the initial treatment of choice.” Moreover, she added, the outcome of patients in the TARGETs trial demonstrated that those given sorafenib with or without prior therapy with IFN-a, IL-2 or both achieve the same duration of PFS. “In terms of response rates, 9% of patients who did not get prior cytokines had partial responses compared with 10% of those who had been given cytokines earlier, while the figures for stable disease were 75% and 74%, respectively, giving an overall clinical benefit of 84% in both groups, whether receiving cytokines or not,” she reported.

Dr. Négrier concluded that sorafenib demonstrated a consistent, significant clinical benefit with an improved disease control rate and a twofold improvement in PFS, with similar toxicities in cytokine-naive and cytokine-treated patients with advanced RCC.