Abstract
A recent clinical trial shows that sorafenib is effective against desmoid tumors. The study found that 33% of tumors shrank in patients who received the drug. The estimated 1-year progression-free survival for the sorafenib-treated patients was 89%, and the 2-year rate was 81%.
Sorafenib (Nexavar; Bayer) shrinks desmoid tumors in one third of patients, according to a recent clinical trial thatcould lead to the first drug approval for the disease (N Engl J Med 2018;379:2417–28).
Desmoid tumors develop in connective tissue. Although they don't metastasize, they expand and force their way into other connective tissues, making them difficult to remove. More than 40% of tumors recur after surgery.
Although the tumors usually show mutations in the WNT pathway genes APC or CTNNB1, the molecular mechanisms driving their growth remain unclear. Because a standard treatment doesn't exist, physicians prescribe a variety of drugs, including doxorubicin and the receptor tyrosine kinase inhibitor (TKI) imatinib (Gleevec; Novartis). The rationale for using imatinib is that it blocks the receptor tyrosine kinases (RTK) KIT and PDGFR, which are often overexpressed in desmoid tumors, and has shown some effectiveness in clinical trials.
After one of his patients couldn't get into an imatinib clinical trial, Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, and his colleagues began to investigate sorafenib, which blocks some of the same RTKs. When they performed a retrospective study in 2011, they found that sorafenib induced tumor shrinkage in 25% of 24 patients (Clin Can Res 2011;17:4082–90).
That study inspired a phase III trial in which the researchers randomly assigned 87 patients with desmoid tumors to receive sorafenib or a placebo. The researchers measured tumor responses for a median of 27.2 months. At that time, median progression-free survival (PFS) had not yet been reached. However, the team estimated that the 1-year PFS for the sorafenib group was 89%, versus 46% for the placebo group. The estimated 2-year PFS was 81% and 36%, respectively. “Sorafenib is very active and could be considered as a front-line or second-line option,” says Gounder.
As in other studies of desmoid tumors, patients who received a placebo experienced a high rate of spontaneous tumor regression: Tumors shrank in 20% of them versus 33% of the patients treated with sorafenib. Why these regressions occur remains unclear, says Gounder.
To limit side effects, the patients were given half the usual dose of sorafenib. The most common grade 1 or 2 adverse effects in the treatment group were rash, which affected 73% of patients, and fatigue, which affected 67% of them. In the placebo group, those side effects occurred in 42% and 61% of patients, respectively. The high rate of rash in the placebo patients is a mystery but may result from misattribution of symptoms by the investigators, says Gounder.
“It's a terrific study,” says Chandrajit Raut, MD, of Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, MA, who wasn't connected to the research. The results show that “this is an effective drug to consider in patients who need some kind of intervention for desmoid tumors that are refractory or symptomatic.”
However, Keith Skubitz, MD, of the University of Minnesota in Minneapolis, notes that the trial didn't compare sorafenib to other potential treatments, such as imatinib. “It demonstrates that the drug is beneficial, but it doesn't clarify where among the possible treatments it fits in.”
Gounder, Raut, and Skubitz agree that the high rate of spontaneous regressions in the placebo group indicates that a watch-and-wait strategy is the best first step for many patients. Sorafenib “should not be considered up front in patients who haven't been given a period of observation,” says Raut. –Mitch Leslie
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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