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Treatment with the TKI sorafenib in combination with standard chemotherapy increased event-free survival by 11.3 months compared with standard chemotherapy plus placebo in patients with newly diagnosed acute myeloid leukemia.
Christoph Röllig, MD
Treatment with the TKI sorafenib in combination with standard chemotherapy increased event-free survival (EFS) by 11.3 months compared with standard chemotherapy plus placebo in patients with newly diagnosed acute myeloid leukemia (AML), according to results from the SORAML phase II study presented during the 2014 ASH Annual Meeting by Christoph Röllig, MD.
“These data provide a high level of evidence for the efficacy of sorafenib in younger AML patients. Most importantly, these data constitute the first randomized evidence that kinase inhibitors work in AML,” said Röllig, of University Hospital Dresden in Germany.
In the trial, a total of 267 patients aged 18 to 60 years with newly diagnosed AML received a standard chemotherapy protocol for induction, consolidation, and maintenance, and were randomized 1:1 for the addition of either sorafenib or placebo. The primary endpoint was EFS, with an event defined as relapse, death, or failure to achieve complete remission (CR) after induction. Secondary endpoints were relapse-free survival (RFS), overall survival (OS), CR rate, and incidence of adverse events (AEs).
After 3 years of follow-up, the sorafenib-treated patients in the trial had a median EFS of 20.5 months compared with 9.2 months for patients receiving placebo (P = .013). The EFS rate was 40% in the sorafenib arm compared with 22% in the placebo arm for the 3-year period. Median RFS after standard treatment plus placebo was 23 months, but RFS for the sorafenib arm was not reached, corresponding to a 3-year RFS rate of 38% for placebo and 56% for sorafenib (P = .017).
The median OS and CR was not reached in either arm; the calculated 3-year rates for OS (56% for patients in the placebo arm compared with 63% in the sorafenib arm, P = .382) and CR (equivalent at 59% with placebo vs 60% with sorafenib, P = .764) did not meet standards of statistical significance.
“To sum up the results, we could show that sorafenib plus chemotherapy is a feasible treatment for younger AML patients. Sorafenib produced a significant and relevant prolongation of event-free survival and relapse-free survival, but had no overall survival benefit at this time,” said Röllig, who added that he looked forward to a larger confirmatory trial to establish sorafenib as an effective and safe treatment for AML.
The AEs with the highest relative risk in the sorafenib arm versus the placebo arm were hand-foot syndrome (exclusive to sorafenib), bleeding, rash, liver toxicity, and fever. The incidence of all other AEs showed no significant differencesbetween the sorafenib and control arms. Fever (40%), infections (22%), and bleeding events (2%) comprised AEs of grade 3 or higher.
In vitro data, mutations seen in AML, and results from nonrandomized clinical trials have all suggested that TKIs could be effective in treating AML. Sorafenib, an inhibitor of multiple TKs and approved for treatment of liver and renal cancers, was selected by the researchers heading up SORAML partially on the basis of its inhibition of FLT3, a tyrosine kinase receptorgene often mutated in AML to form internal tandem repeats (FLT3-ITD) and presumed to be potentially causative for the disease.
“We thought that FLT3-ITD-positive patients would be the target population, as we thought that the main effect of sorafenib in AML was to inhibit FLT3-ITD,” Röllig said. “However, only 17% of patients in this study were FLT3-ITD-positive, and we see an effect even if we take these patients out; therefore, the observed effect must be due to inhibition by sorafenib of more kinases than just FLT3-ITD.”
Röllig C, Müllerâ€Tidow C, Hüttmann A, et al. Sorafenib versus placebo in addition to standard therapy in adult patients ≤60 years with newly diagnosed acute myeloid leukemia: results from the randomizedâ€controlled SORAML trial. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.