Positive results from the global phase III RATIFY ( CALGB 10603 ) clinical trial were announced. In the study, adult patients under 60 years of age with newly-diagnosed FLT3-mutated acute myeloid leukemia ( AML ) who received the investigational compound Midostaurin ( PKC412 ) plus standard induction and consolidation chemotherapy experienced a 23% improvement in overall survival ( hazard ratio, HR= 0.77, P = 0.0074 ) compared to those treated with standard induction and consolidation chemotherapy alone.
The median overall survival for patients in the Midostaurin treatment group was 74.7 months ( 95% confidence interval [ CI ]: 31.7, not attained ), versus 25.6 months ( 95% CI: 18.6, 42.9 ) for patients in the placebo group.
The trial evaluated the addition of either Midostaurin or placebo to Daunorubicin / Cytarabine in the induction phase, followed by high-dose Cytarabine in the consolidation phase; patients who achieved complete remission after consolidation chemotherapy continued treatment with Midostaurin or placebo as a single agent for up to one year.
The data, collected and analyzed in partnership with the Alliance for Clinical Trials in Oncology, are from the largest clinical trial in FLT3-mutated acute myeloid leukemia to date, with 3,279 patients screened and 717 study participants from around the world.
The treatment strategy in acute myeloid leukemia has remained unchanged for more than 25 years. Of the approximately 350,000 people with leukemias worldwide, about 25% have acute myeloid leukemia.
One-third of AML patients also harbor a FLT3 gene mutation, which is associated with worse outcomes and shorter survival than in those without the mutation.
Midostaurin is the first drug to illustrate an overall survival benefit targeting FLT3 in acute myeloid leukemia - a hematological malignancy with no approved targeted treatments.
In addition to meeting the primary endpoint of overall survival, event free survival ( EFS, defined as the earliest death, relapse or no complete response within 60 days of the start of induction therapy ) was significantly higher in the Midostaurin treatment group versus the placebo group [ HR = 0.79, P = 0.0025 and median of 8.0 months ( 95% CI: 5.14, 10.6 ) vs. 3.0 months ( 95% CI: 1.9, 5.9 ) ].
No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events.
A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups.
RATIFY ( Randomized AML Trial In FLT3 in patients less than 60 Years old; also known as CALGB 10603 ) was a phase III, international, randomized, placebo-controlled, double-blind group trial of newly-diagnosed AML patients aged 18 to less than 60 with a FLT3 mutation.
The primary endpoint was overall survival and the key secondary endpoint was event-free survival.
A total of 225 sites from 17 countries participated in this study, spanning North America, Europe and Australia.
A total of 3,279 patients with acute myeloid leukemia were screened, and 717 patients with an activating FLT3 mutation aged 18 to less than 60 were enrolled.
Patients were stratified according to the following mutation subtypes: tyrosine kinase domain ( TKD ), internal tandem duplications ( ITD ) high allelic mutation fraction ( more than 0.7 ) and ITD low allelic mutation fraction ( 0.05-0.7 ).
All three subtypes treated with Midostaurin demonstrated improved overall survival versus placebo.
Allogeneic hematopoietic stem cell transplantation ( SCT ) was allowed. Midostaurin benefited patients regardless of whether they went on to receive a SCT.
Mutations in specific genes are found in many cases of acute myeloid leukemia, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option.
FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells.
Midostaurin is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with acute myeloid leukemia with a FLT3 mutation.
Midostaurin inhibits multiple kinases, including FLT3, that help regulate many essential cell processes, thereby interrupting cancer cells' ability to grow and multiply. ( Xagena )
Source: Novartis, 2015