Sorafenib Showed Efficacy as Chemotherapy Add-On in AML

Results from the phase II SORAML trial indicated that adding sorafenib to standard chemotherapy for younger patients with acute myeloid leukemia (AML) was effective, but also resulted in increased toxicity.

The drug increased event-free survival and reduced need for salvage therapy and allogeneic stem cell transplantation, but also produced worse grade 3 or higher fever, diarrhea, bleeding, cardiac events, and rash compared with placebo.

“After a decade of assessing the potential of kinase inhibitors in acute myeloid leukemia, their use in combination with standard treatment is becoming an important option for newly diagnosed younger patients,” wrote Christoph Röllig, MD, of Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität in Dresden, Germany, and colleagues in Lancet Oncology.

Patients age 18 to 60 years were enrolled in the phase II study between 2009 and 2011. All patients had to have newly diagnosed, treatment-naive AML and a performance status of 0–2. Patients were randomly assigned to 2 cycles of induction daunorubicin plus cytarabine followed by 3 cycles of high-dose cytarabine consolidation therapy plus either sorafenib 400 mg twice daily (n = 134) or placebo (n = 133).

With a median follow-up of 3 years, the researchers found that adding sorafenib to standard chemotherapy significantly improved event-free survival, from a median of 9 months with placebo to a median of 21 months with sorafenib. Patients assigned sorafenib had a 3-year event-free survival rate of 40% compared with 22% for patients assigned placebo (P = .013).

“The improvement in event-free survival and relapse-free survival is significant and clinically relevant since salvage treatment with or without allogeneic stem cell transplantation could be prevented or substantially delayed by sorafenib treatment,” the researchers wrote.

At 3 years, 63% of patients assigned sorafenib and 56% of patients assigned placebo were still alive, and the median overall survival was not reached in either group. Patients assigned sorafenib had fewer relapses after complete remission compared with placebo (54 vs 34) and, therefore, fewer allogeneic stem cell transplantations were required among patients assigned sorafenib (31 vs 18).

Finally, withdrawal from the trial due to adverse events was more common among patients assigned sorafenib (24% vs 12%).

In an editorial published with the study, Naval Daver, MD, and Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that these results contrast findings by Serve et al who found that “the addition of sorafenib to standard chemotherapy in patients older than 60 years with acute myeloid leukemia resulted in increased toxicity and early mortality,” without improved antileukemic efficacy compared with placebo, suggesting that older patients were unable to tolerate the toxicities associated with the addition of sorafenib to standard chemotherapy.

Daver and Konopleva agreed with Röllig and colleagues, writing that the lack of improvement in overall survival despite an improvement in event-free survival requires “further investigation to develop future strategies that will improve overall survival.”