San Francisco, CA—Sorafenib added to standard therapy significantly improves event-free survival (EFS) and relapse-free survival compared with standard chemotherapy alone in younger patients with newly diagnosed acute myeloid leukemia (AML).
In a phase 2 clinical trial of 267 patients with AML aged ≤60 years, sorafenib extended median EFS by 20.5 months versus 9.2 months with placebo, but it did not improve overall survival (OS), reported Christoph Röllig, MD, MSc, Universitätsklinikum Dresden, Germany, at ASH 2014.
“These data constitute the first randomized evidence that kinase inhibitors work in AML,” Dr Röllig said. “Based on these results, we cannot call sorafenib a standard treatment for AML yet. It would be nice to have a second confirmatory trial, and we would like to see what happens to overall survival after a longer period of follow-up.” Nevertheless, the improvement in EFS is clinically meaningful, he said.
Sorafenib is a multikinase inhibitor with activity against several oncogenic kinases that may play a role in AML. The drug is approved for the treatment of several types of solid tumors, including thyroid, liver, and kidney cancer.
In this study, patients aged 18 to 60 years with newly diagnosed AML received daunorubicin 60 mg/m2 on days 3 to 5 plus cytarabine 100 mg/m2 continuous intravenous infusion on days 1 to 7 for 2 cycles, followed by cytarabine 3 g/m2 twice daily on days 1, 3, and 5 for 3 cycles. Nonresponders received second induction with cytarabine plus mitoxantrone. Allogeneic stem-cell transplant was scheduled for intermediate- or high-risk patients.
Patients were randomized to sorafenib 800 mg daily or to placebo in addition to standard chemotherapy on days 10 to 19 of induction, from day 8 of each consolidation until 3 days before the start of the next consolidation, and as maintenance for 12 months after consolidation.
Complete response was 59% in the placebo arm versus 60% in the sorafenib arm (P = .764). With a median follow-up of 3 years, the median EFS was 20.5 months with sorafenib and 9.2 months with placebo; the 3-year EFS rate was 40% versus 22%, respectively (P = .013).
The median relapse-free survival was 23 months in the placebo arm but has not yet been reached in the sorafenib arm, corresponding to a 3-year relapse-free survival of 38% with placebo versus 56% for sorafenib (P = .017). The median OS had not yet been reached for either arm, but the 3-year OS rates are 56% and 63% for placebo and sorafenib, respectively.
Toxicity was much more likely with sorafenib compared with placebo. Hazard ratios with sorafenib were 3.61 for bleeding, 3.84 for rash, 3.36 for liver toxicity, and 3.53 for fever. Hand-foot syndrome occurred only in the sorafenib arm. The most common reported grade ≥3 adverse events were fever (40%), infections (22%), and bleeding events (2%).—WK