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Based on the following published article: N Engl J Med 2007;356(2):125-34

According to the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), treatment with sorafenib, a multitargeted tyrosine kinase inhibitor of tumour-cell proliferation and angiogenesis, prolongs progression-free survival (PFS) in patients with advanced clear cell renal cell carcinoma (RCC) in whom previous therapy had proven inadequate.

As the TARGET investigators indicated, the prognosis for patients with metastatic RCC has not appreciably improved during the past 25 years. Indeed, at five years, fewer than 10% of patients with metastatic RCC are still alive. Both high-dose interleukin-2 therapy and interferon-alfa are used to treat advanced disease but as the study group reported, “These agents have limited efficacy and are associated with considerable toxic effects.”

Sorafenib primarily inhibits pro-angiogenic kinases, thereby disrupting tumour vasculature. Another vascular endothelial growth factor (VEGF) antagonist, bevacizumab, has also been shown to improve PFS in RCC patients.

Dr. Bernard Escudier, Head, Immunotherapy and Innovative Therapy Unit, Institut Gustave-Roussy, Paris, France, and multicentre colleagues randomized 903 patients with advanced RCC to receive either sorafenib 400 mg b.i.d. or placebo. An equal number of patients were enrolled in each of the treatment arms. All patients had histologically confirmed metastatic clear cell RCC which had progressed following prior therapy within the previous eight months.

According to Memorial Sloan-Kettering Cancer Center criteria, 51% of the cohort had low-risk disease while the remainder had intermediate-risk disease. Active treatment or placebo was given continuously in six-week cycles for the first 24 weeks, then in eight-week cycles thereafter until disease progression, withdrawal due to adverse events or death. The median duration of treatment was 23 weeks in the sorafenib group and 12 weeks in their placebo counterparts.

“The primary end point was overall survival [OS],” investigators indicated, with an analysis of PFS data planned for January 2005. Secondary end points included PFS (measured from the date of randomization until disease progression) as well as best overall response rate (judged on the basis of RECIST criteria) within the last 10 days of each treatment cycle. The median follow-up was 6.6 months for both groups.

TARGET Results

“At the January 2005 cutoff, the median PFS was 5.5 months in the sorafenib group and 2.8 months in the placebo group,” investigators noted—or a 56% reduction in risk of disease progression in favour of active therapy (P<0.001). Patients originally assigned to placebo were permitted to cross over to sorafenib starting in May 2005, at which time the first planned analysis of OS was performed. According to results from this analysis, active treatment reduced the risk of death by 28% (hazard ratio: 0.72), a finding which was clinically but not statistically significant, investigators pointed out. However, as they later observed, at the same median follow-up of 6.6 months, “the median actuarial OS was 14.7 months in the placebo group but had not yet been reached in the sorafenib group,” a finding which prompted Dr. Escudier to conclude that sorafenib “probably improves OS as well as PFS.”

Another analysis of OS was carried out six months later after approximately half of patients initially randomized to placebo had been switched to sorafenib starting in May 2005. Among this cohort, the median OS was 19.3 months for the actively treated group vs. 15.9 months for placebo controls, again suggesting active therapy may well improve OS in advanced clear cell RCC.

At the January 2005 analysis, best responses were assessed independently among 335 patients randomized to sorafenib and 337 patients treated with placebo. Some seven patients (2%) achieved a partial response (PR) to sorafenib, while disease stabilized in 78% of the group and 9% had disease progression. In the placebo group, no patients achieved a PR, disease stabilized in 55% of the group and 30% experienced progressive disease. Investigator-assessed best responses at the May 2005 cutoff included one complete response (CR) out of 451 patients in the sorafenib group and a 10% PR rate. Among those patients who achieved a CR or PR to sorafenib, the median time to response was 80 days while the median duration of response was 182 days.

The proportion of patients who discontinued the study agent due to adverse events was low and similar in the two groups (10% for active therapy, 8% for placebo). “Discontinuation was mostly due to constitutional, gastrointestinal, dermatologic or pulmonary-upper respiratory tract symptoms,” researchers reported.

Questions and Answers

This question-and-answer session was conducted with TARGET principal investigator Dr. Bernard Escudier, Head, Immunotherapy and Innovative Therapy Unit, Institut Gustave-Roussy, Paris, France.

Q: There is obviously a need for improved therapies for advanced RCC. How important are findings from the TARGET study?

A: This study is the first phase III trial showing that sorafenib has a good effect in advanced RCC, so results are encouraging for all of us who treat this disease, as it is very important that we have good drugs to treat this cancer.

Q: Could you compare the responses you achieved with sorafenib in this study to the kind of responses that you would typically achieve with interleukin-2 or interferon-alfa?

A: Overall, sorafenib achieves a better result than the cytokines. That said, the cytokines are still good drugs for a small group of patients where you have a chance to induce a complete remission. With this new agent, you cannot induce a complete remission but you can aim for a long-lasting remission so in this way, the two types of drugs are different.

Q: In your view, what are some of the more appealing features of sorafenib?

A: It is well tolerated in general; in 90% of patients, the drug had a very good safety profile. The fact that it can be taken orally is also convenient for patients, so when you have an oral drug that is well tolerated, it is always good for patients.

Q: How does sorafenib work to slow disease progression in this malignancy?

A: The growth of RCC itself is dependent on an over-expression of VEGF, so the cancer is VEGF-dependent, and the higher the concentration of VGEF, the worse the prognosis. Sorafenib works primarily by inhibiting the VEGF receptor, and its activity is probably quite comparable to the activity seen with bevacizumab, another VEGF antagonist, which in a phase II trial, also improved PFS. Median PFS was also significantly longer in previously untreated metastatic RCC patients receiving sunitinib compared with those who received interferon-alfa.

Q: Can you foresee administering the agent at a much earlier point in RCC disease and potentially achieve better response rates in earlier than advanced disease?

A: Yes, it does make sense to try to give the drug as adjuvant therapy but we still have to demonstrate that it works in this setting first.

Q: Does the availability of sorafenib and other novel compounds usher in a new era in the treatment of advanced RCC?

A: Yes, we can now achieve longer remissions and longer survival times for these patients. In fact, median survival has increased considerably in metastatic RCC. We now have several new drugs which we can probably give sequentially, so the general consensus is that we are at the very least doubling median survival with these new drugs compared to survival times when we did not have them.