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Targeted Therapy in Advanced Renal Cell Carcinoma: Extending Patients’ Lives

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

22nd European Association of Urology Annual Congress

Berlin, Germany / March 21-24, 2007

Until recently, cytokine therapy was considered the mainstay systemic treatment of advanced renal cell carcinoma (RCC), although robust and durable responses could only be attained in certain patients. Detailed research into the molecular mechanisms of cancer has lead to the development of tyrosine kinase inhibitors (TKIs), which interfere with tumour angiogenesis. Unlike short cycles of chemotherapy regimens that aim for tumour regression, TKIs are administered continually over longer periods of time and aim to prolong survival rather than provide a complete cure. Accordingly, the evaluation of toxicity for TKI therapies is necessarily different and other factors such as quality of life become more important.

TARGET Findings

The TKI sorafenib has been used for therapy in advanced RCC following the positive findings of the pivotal TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial). According to Dr. Marc-Oliver Grimm, Technical University of Dresden, Germany, “This study was in fact the largest randomized placebo-controlled trial conducted in RCC.” It compared sorafenib 400 mg b.i.d. with placebo as second-line therapy in 903 patients with advanced clear-cell RCC. In the analysis of the overall population, the median progression-free survival (PFS), one of the primary end points, was 5.5 months in the active treatment group compared to 2.8 months in the placebo group (P<0.01) (Escudier et al. N Engl J Med 2007; 356(2):125-34).

Dr. Grimm remarked, “It is an important question whether prior cytokine therapy has an effect on the clinical benefit of sorafenib.” He presented a detailed subgroup analysis of the TARGET population stratified by whether patients had received such therapy (n=742) or not (n=161). “Irrespective of the type of prior treatment, there was a doubling of the PFS from 12 weeks in the placebo arm to 24 or 25 weeks with sorafenib,” he reported. This difference was maintained after further stratifying according to categories such as gender, performance status, risk category or lung metastasis. Furthermore, the percentage of patients with clinical benefit (defined as complete remission, partial remission or stable disease) was approximately 85%, regardless of prior cytokine therapy. In the safety analysis, differences in the incidences of individual reactions could be discerned, but generally, the safety profile was comparable for cytokine-treated and non-cytokine-treated patients.

According to Dr. Tim Eisen, Professor of Medical Oncology, Cambridge Research Institute, University of Cambridge, UK, “The elderly are often underrepresented in oncology trials.” Therefore, a subgroup analysis of the TARGET by <65 or ³65 years of age was of interest. Approximately one-third of the TARGET population was >65 years old. PFS was longer in the active-treatment arm of both groups and the percentage of patients with clinical benefit from treatment was also similar (approximately 85%). On the other side of the risk-benefit equation, the toxicity profile was similarly comparable for the two groups. Likewise, analysis of other end points such as health-related quality of life and patient-reported deterioration in health status showed no group differences. Dr. Eisen summed up by saying, “I think I have said the same thing in a number of different ways: age does not seem to have an impact on benefit.”

Placebo Crossover in TARGET: Further Supportive Evidence

As Dr. Eisen explained, “TARGET had co-primary end points—PFS and overall survival [OS]—but after an interim analysis of the PFS, it was decided to offer active treatment to those on placebo.” Just under half of all patients who entered the placebo arm, corresponding to the majority of those still on placebo at the time, crossed over to active treatment. At the time of crossover, the median OS for placebo patients was 14.7 months whereas the median had not yet been reached for those receiving sorafenib (hazard ratio: 0.72 [P=0.018]). According to the O’Brien-Fleming rule, this analysis did not reach the prespecified level for statistical significance. But Dr. Eisen pointed out that this study had co-primary end points, and the other end point had already been reached; therefore, “We will never get purer data than these.” According to the analysis six months after crossover, median OS in the sorafenib arm had now been reached (19.3 months). In the placebo arm, median OS had risen to 15.9 months, consistent with a late effect of active treatment. Moreover, a certain degree of tumour regression was observed in some of these patients from the placebo arm, suggesting that patients can benefit from late treatment with sorafenib.

Treatment in the Real World

When it had been determined that active treatment had met its primary end point, but before the compound became available, approximately 2500 patients received sorafenib in ARCCS (Advanced Renal Cell Carcinoma Sorafenib), an expanded access program. Exclusion criteria were kept to a minimum in this open-label study. “As such, this represents a closer to real-life assessment of how patients might take this drug,” explained Dr. David Quinn, Kenneth J. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles. Patients had to have advanced RCC, but there was no subtype restriction. Brain metastasis was allowed and patients with renal impairment of any severity could be enrolled, provided they were not receiving dialysis. The ARCCS study population differed from the TARGET population in that approximately half the patients received sorafenib as first-line therapy (with a slightly higher median age) and although the majority of patients were still Caucasian, non-Caucasian groups were more represented. The tumour histology showed 163 papillary tumours and 25 chromophobe tumours, the largest populations of patients with such tumours studied in a metastatic setting. “This will be interesting,” Dr. Quinn told listeners, “because at present there is no direct therapy for them.”

The actual mean overall dose was 677 mg/day. The most common adverse events included hand-foot skin reaction, rash and hypertension. Interestingly, the toxicity profiles for patients receiving sorafenib as first-line and second-line therapy were similar. In summary, these results provide further support for the clinical benefit of sorafenib in a less selected population.

TARGET Discussion

The findings of the TARGET study and their application in clinical practice were further discussed here during the scientific sessions. The findings and all subanalyses showed benefit of sorafenib treatment in terms of improved PFS, and the analysis of placebo crossover to active treatment suggested prolonged OS. However, a treatment that aims to prolong survival rather than cure the cancer might be subject to different safety criteria and in clinical practice, management of the side effects is important. For Dr. Jürgen Gschwend, Technical University of Munich, Germany, “Sorafenib-related side effects are usually manageable and reversible… Good communication between the patient and doctor is necessary to identify side effects as early as possible to allow early detection and management of symptoms and this, in turn, will help maintain the optimum dosing of sorafenib and ensure that the patients enjoy as good a quality of life as possible.”

Summary

The results from clinical trials with sorafenib are significant. PFS was twice as long in treated patients with advanced RCC compared to placebo patients, regardless of age or prior cytokine treatment, and OS also appeared longer. Prompt diagnosis and treatment of side effects can help ensure that these patients enjoy the best possible quality of life.

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