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Sorafenib extends EFS, increases toxicity in patients with AML
The addition of sorafenib to standard chemotherapy displayed antileukemic activity in nongeriatric patients with acute myeloid leukemia, but the agent also appeared to increase toxicity, according to phase 2 study results.
Preclinical and nonrandomized trials have suggested sorafenib (Nexavar, Bayer Healthcare) may serve as an effective treatment option for patients with AML.
Christoph Röllig, MD, MSc, professor in the department of internal medicine, hematology and oncology at Universitätklinikum Carl Gustav Carus in Dresden, Germany, and colleagues conducted a double blind, randomized controlled trial to compare sorafenib with placebo in patients aged 60 years or younger with newly diagnosed AML.
The researchers randomly assigned patients to two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) and 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 sorafenib (400 mg twice daily) or placebo on days 10 through 19 of induction cycles 1 and 2. Patients then received sorafenib or placebo on day 8 of each consolidation, followed by 12 months of maintenance.
All intermediate-risk patients with a sibling donor and all high-risk patients with a matched donor were scheduled for allogeneic hematopoietic stem cell transplantation in first remission.
EFS served as the primary endpoint. Key secondary endpoints included RFS, OS, complete remission and toxicity.
Median follow-up was 36 months (interquartile range, 35.5-38.1).
The final analysis included data from 267 patients (median age, 50 years; range, 43-56), of whom 134 received sorafenib and 133 received placebo.
Patients assigned sorafenib achieved longer median EFS (21 months vs. 9 months) and a higher rate of 3-year EFS (40% vs. 22%; HR = 0.64; 95% CI, 0.45-0.91).
Median OS had not been reached in either group. After 3 years of follow-up, 63% of patients assigned sorafenib and 56% of patients assigned placebo remained alive.
The most common grade 3 or higher adverse events in both study groups included fever (54% for sorafenib vs. 53% for placebo), infections (34% vs. 41%), pneumonia (14% vs. 16%) and pain (11% vs. 10%).
Several grade 3 or higher adverse events occurred at significantly higher rates in the sorafenib arm, including fever (RR = 1.54; 95% CI, 1.04-2.28), diarrhea (RR = 7.89; 95% CI, 2.94-25.2), bleeding (RR = 3.75; 95% CI, 1.5-10), cardiac events (RR = 3.46; 95% CI, 1.15-11.8) and rash (RR = 4.06; 95% CI, 1.25-15.7).
Grade 3 or higher hand-foot-skin reactions only occurred in the sorafenib group.
Seven treatment-related deaths occurred (sorafenib, n =4; placebo, n =3). Causes of treatment-related death included pneumonia (sorafenib, n = 2; placebo, n = 2), toxic liver failure (placebo, n = 1) and other infections (sorafenib, n = 2).
“The data provide the first randomized evidence for the efficacy of a multikinase inhibitor in unselected AML, but also show the additional toxicity of sorafenib in combination with standard chemotherapy,” Röllig and colleagues wrote. “OS after long-term follow-up and a confirmatory trial are needed for a final assessment on the value of sorafenib in the treatment of AML.”
In an accompanying editorial, Naval Daver, MD, and Marina Konopleva, MD, PhD, both of the department of leukemia at The University of Texas MD Anderson Cancer Center, examined the homogeneity of response in certain areas.
“The proportion of patients achieving complete remission and 60-day mortality were similar in the two groups,” Daver and Konopleva wrote. “A possible explanation for this finding is that the overall population of allogeneic HSCTs (including as salvage therapy) was higher in the placebo group than in the sorafenib group (79 [59%] of 133 vs. 68 [51%] of 134). Similar survival with a lower proportion of allogeneic HSCTs in the sorafenib group argues for the potential benefit of incorporating this drug in standard first-line therapy in patients 60 years or younger with AML."
Daver and Konopleva further hypothesized that salvage therapy options may influence OS.
“Patients relapsing in the placebo group had a significantly improved OS with subsequent salvage strategies compared with patients relapsing on sorafenib treatment,” they wrote. “This improved survival with salvage treatments suggests that treatment with sorafenib selects resistant leukemic cells that can more readily adapt to therapeutic pressures and are more refractory to subsequent therapies. Potential strategies to prevent the selection and expansion of such subclones are currently under investigation.” – by Cameron Kelsall
Disclosure: Bayer Healthcare provided funding for this study. Röllig reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Daver reports grants and personal fees outside the submitted work from Bristol-Myers Squibb, Incyte, Karyopharm, Novartis and Sunesis. Konopleva reports grants outside the submitted work from AbbVie, Lilly Oncology and Novartis.