First-line sunitinib and sequential therapy ‘optimal’ for metastatic RCC
medwireNews: Researchers suggest that the optimal sequencing scheme for treating patients with clear cell metastatic renal cell carcinoma (mRCC) is sunitinib followed by axitinib and then everolimus.
Maxine Sun (University of Montreal Health Center, Québec, Canada) and team say in Therapeutic Advances in Urology that "most would agree that sunitinib represents the ideal first-line standard of care option."
There are currently four molecules - sunitinib, pazopanib, bevacizumab plus interferon, and temsirolimus - that are considered as first-line therapy for RCC. The researchers' recommendation of sunitinib as first-line therapy is based on the abundance of studies that have reported the efficacy of this tyrosine kinase inhibitor in the treatment of RCC, along with the availability of data substantiating the efficacy of second and subsequent lines of therapy after sunitinib failure.
By contrast, the data supporting sequential use of other targeted agents after bevacizumab plus interferon failure are limited and suggest only "modest efficacy," they say.
Similarly, for pazopanib, the weight of evidence supporting its use as a first-line therapy is modest relative to sunitinib, with just one phase III trial, and its use is "undermined by the lack of published data that specifically validate or quantify the efficacy of sequential therapies after pazopanib failure," Sun and co-workers write.
The evidence in support of temsirolimus limits its use to a very narrow subset of individuals with strict poor risk Memorial Sloan-Kettering Cancer Center criteria, so it may be best used for patients who have poor performance status, say the researchers.
They acknowledge that other novel agents - sorafenib and everolimus - are being tested in phase II and III trials as possible challengers to sunitinib for first-line therapy, but they say that small sample sizes and limited patient selection make it "unlikely that novel data from ongoing studies will displace sunitinib from its established first-line status."
The efficacy of two molecules - everolimus and axitinib - for sequential therapy have been confirmed in two phase III trials, but Sun and team believe that axitinib should be the second-line standard of care for mRCC, followed by sequential everolimus as standard third-line therapy.
"This sequence allows the maximum use of phase III data to select first-, second- and third-line therapy," they write.
Indeed, their justifications for this recommendation stem from the fact that most (around 95%) of the participants in the phase III everolimus trial, which found superior progression-free survival compared with placebo, had received multiple agents before randomization.
For axitinib, the trial data demonstrated its superior efficacy relative to sorafenib in patients previously given either sunitinib alone or cytokine alone. The sample size was also substantially larger than that of the everolimus trial.
"Specifically, the axitinib population represents a true second-line population. Conversely, the majority of patients… received everolimus as third-line treatment," the researchers note.
They say that subsequent treatment options rely on lower-weight evidence, but could consist of fourth-line sorafenib or sunitinib rechallenge.
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By Lucy Piper, Senior medwireNews Reporter