ATLANTA (FRONTLINE MEDICAL NEWS) – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD , MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

“Our mature data after a median follow-up of 6.5 years confirms a significant prolongation by the addition of sorafenib to standard chemotherapy in terms of event-free survival. We saw a significant [relapse-free survival] prolongation with sorafenib, with a hazard ratio of 0.64, which means that five to six patients need to be treated with sorafenib in order to prevent one relapse,” he said at the annual meeting of the American Society of Hematology.

Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.

In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.

Chemotherapy consisted of 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-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).

Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.

The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).

The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.

At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.

A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.

Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).

Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.

Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.

Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.

OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).

During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD , of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.

“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.

Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.

The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.

SOURCE: Röllig C et al. ASH 2017 Abstract 721 .


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