Sorafenib versus placebo in combination with intensive chemotherapy in previously untreated FLT3-ITD AML: Results of a phase II study

The role of sorafenib, a tyrosine kinase inhibitor, as first-line treatment in FLT3-ITD-mutated acute myeloid leukemia (AML) remains unclear. FLT3-ITD is present in approximately 22% of AML cases and is associated with a poor prognosis. However, previous studies have shown sorafenib in combination with induction and consolidation therapy, followed by 12 months of maintenance treatment, to improve response rates to > 90% and lead to 2-year survival rates of > 60%.¹

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, the results of a phase II study (ALLG AMLM16) that compared sorafenib to placebo in patients diagnosed with FLT3-ITD AML were presented by Andrew Wei, AML Hub Executive Steering Committee member, on behalf of the Australasian Leukemia and Lymphoma group.¹

Study Design  

Adults (18–65 years old) with untreated FLT3-ITD AML, Eastern Cooperative Oncology Group (ECOG) score 0–2, and no major co-morbidity or central nervous system disease were randomized to receive induction and two cycles of consolidation based on age, followed by 12 months of sorafenib or placebo maintenance. The primary hypothesis was to show that sorafenib and intensive and consolidation chemotherapy could improve outcomes in untreated FLT3-ITD AML.

The primary endpoint was 2-year event-free survival (EFS) with a median follow up of 16.5 months in untreated adults with FLT3-ITD AMIL after receiving sorafenib or placebo for 12 months. Secondary endpoints were to assess response rate: complete response (CR), CR with incomplete hematologic recovery (CRi), relapse-free survival (RFS), and overall survival (OS). Exploratory secondary endpoints included biomarkers of response, such as plasma inhibitory activity, plasma FLT3 ligand, FLT3-ITD measurable residual disease (MRD), and drug-resistant mutations.

Treatment schedule

Patients (N = 102) were stratified based on age to receive:

• Induction therapy
  • 18–55 years old: IDAC-3 (idarubicin [IDA] 12 mg/m² D1–3 and cytarabine 1.5 g/m² BD D1,3,5,7)
  • 56–65 years old: 7+3 (IDA 12 mg/m² D1–3 and cytarabine 100 mg/m² D1–7)
• Followed by two cycles of consolidation
  • 18–55 years old: IcE (IDA 9 mg/m² D1–2, cytarabine 100 mg/m² D1–5, and etoposide 75 mg/m² D1–5)
  • 56–65 years old: IDAC-2 (IDA 12 mg/m² D1-2 and cytarabine 1 g/m2 BD D1,3,5)

On Day 4–10 of induction and consolidation, 98 patients were randomized 2:1 (n = 65) and (n = 33) sorafenib or placebo 400 mg twice daily, orally. This was followed by a maintenance phase of 12 months of the same therapy.

Patient characteristics

The baseline patient characteristics are reported in Table 1.

Table 1. Baseline patient characteristics¹

In the maintenance phase, 21 out of 65 patients received sorafenib and 9 out of 33 patients received placebo, with three and one patient receiving ongoing therapy, respectively. In the sorafenib arm, 62 patients discontinued treatment, with 35 patients transplanted and two experiencing heart failure. In the placebo arm, 32 discontinued treatment, with 18 patients undergoing transplant and one experiencing heart failure.

Results

Efficacy endpoints are shown in Table 2, with 62% and 58% patients undergoing transplantation during their first CR in the sorafenib and placebo arms, respectively.

Table 2. Efficacy and primary endpoints¹

Secondary Endpoints

With a median follow up of 25 months, the median OS was 47.7 months versus 25.3 months for sorafenib versus placebo (HR, 0.70; 95% CI, 0.38–1.38; p = 0.259). The 2-year OS was 66.8% with sorafenib and 56.4% for patients in the placebo arm.

After induction, CR with FLT3-ITD MRD negativity was more common in the sorafenib arm. Two-year OS after relapse was higher in the sorafenib arm (37%) versus placebo (12%). Table 3 summarizes the results of MRD measurements (by next-generation sequencing) and RFS at 2 years, and their association with overall response.

Table 3. Secondary endpoints¹

There were indications that 2-year OS after relapse was higher in the sorafenib arm (n = 24; 37%) versus placebo arm (n = 13; 12%). An analysis of FLT3-ITD in tissue samples at the time of relapse indicated a higher rate of FLT3-negative relapse in the sorafenib arm (53% versus 18%) using a > 5% threshold.

Safety

There was a higher incidence of ≥ Grade 3 diarrhea (12% vs 3%), palmar-plantar syndrome (8% vs 0%), and hypertension (8% vs 0%) in the sorafenib group. Treatment-related mortality was 1.5% and 3% at 30 days in sorafenib- and placebo-treated patients, respectively.

Conclusion

Sorafenib did not improve EFS in FLT3-ITD AML. Both treatment arms had a RR of > 90% with a high rate of hematopoietic cell transplant. There was trend for improved outcomes in patients with high FLT3-ITD allelic ratio and a higher rate of undetectable FLT3-ITD MRD in CR in those treated with sorafenib. There was also a trend for improved RFS in CR with sorafenib with a greater proportion of FLT3-ITD-negative relapse. This study was not powered to show a statistically significant OS advantage for sorafenib.  Results of ongoing studies are needed with more potent FLT3-ITD inhibitors to confirm a significant treatment advantage as first-line therapy.