German Phase II Trial Shows Benefit and Increased Toxicity With Addition of Sorafenib to Standard Therapy in Newly Diagnosed AML


Key Points

  • The addition of sorafenib to standard therapy significantly improved event-free survival in patients younger than age 60 with newly diagnosed acute myeloid leukemia.
  • The addition of sorafenib to standard therapy was associated with increased toxicity.

In a German phase II trial reported in The Lancet Oncology, Röllig et al found that the addition of sorafenib (Nexavar) to standard therapy improved event-free survival but increased toxicity vs placebo in patients aged ≤ 60 years with newly diagnosed acute myeloid leukemia (AML).

Study Details

In the double-blind trial, 267 patients from 25 sites in Germany were randomized between March 2009 and November 2011 to receive two cycles of induction therapy with daunorubicin (60 mg/m² on days 3–5) plus cytarabine (100 mg/m² on days 1–7) followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m² twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily; n = 134) or placebo (n = 133) on days 10 to 19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem cell transplantation was planned for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. The primary endpoint was event-free survival.

Event-Free Survival

After a median follow-up of 36 months, in an analysis censoring patients at the time of transplantation, median event-free survival was 21 months (95% confidence interval [CI] = 9–32 months) in the sorafenib group vs 9 months (95% CI = 4–15 months) in the placebo group, corresponding to a 3-year event-free survival of 40% vs 22% (hazard ratio [HR] = 0.64, P = .013). In a noncensored sensitivity analysis, median event-free survival was 25 vs 9 months (HR = 0.66, P = .01).

Adverse Events

The most common grade 3 or 4 adverse events in both groups were fever (54% vs 53%), infections (34% vs 41%), pneumonia (14% vs 16%), and pain (11% vs 10%). Grade ≥ 3 adverse events that were significantly more common in the sorafenib group were fever (relative risk [RR] = 1.54, P = .03), diarrhea (RR = 7.89, P < .0001), bleeding (RR = 3.75, P = .006), cardiac events (RR = 3.46, P = .03), hand-foot skin reaction (7% vs 0%), and rash (RR = 4.06, P = .03). Adverse events led to discontinuation of study treatment in 31% of the sorafenib group and 14% of the placebo group.

The investigators concluded: “In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease.”

This study was funded by Bayer HealthCare.

Christoph Röllig, MD, of the Universitätsklinikum der Technischen Universität Dresden, Germany, is the corresponding author of The Lancet Oncology article.

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