RATIFYing a novel agent in the treatment of AML: Midostaurin shows efficacy in front-line therapy

by Stephanie Hawthorne; co-authored by Len Kusdra

Cytarabine-based intensive chemotherapy remains standard of care for patients with acute myeloid leukemia (AML); however, about 70% of patients will relapse within five years of initial therapy, thus highlighting the need for development of more efficacious regimens.1 While therapy has traditionally consisted of a “one-size-fits-all” concept, it is better appreciated that AML is a rather heterogeneous disease comprising various subtypes with complex genetic and chromosomal changes. Some of these genetic aberrations have been identified in AML, but it is unclear whether these changes represent viable therapeutic targets. Perhaps the only one that has been the focus of clinical development has been FLT3, a tyrosine kinase that plays a role in hematopoiesis; mutations in this gene are believed to play a role in the development of AML. Two major classes of mutations have been identified: point mutations in the tyrosine kinase domain (FLT3-TKD) or the presence of internal tandem repeats (FLT3-ITD). Of the two classes, FLT3-ITD is the more common aberration, occurring in about 30% of AML patients, and has been associated with poor prognosis and shorter overall survival.2 Despite the promise of FLT3-ITD as a target, its history has been turbulent, as evidenced by the failure of lestaurtinib (Cephalon), a FLT3-targeted agent that failed in its pivotal trial and called into question the rationale of inhibiting FLT3-ITD and threatening further clinical development on this target.

Novartis hopes to change that with its development of midostaurin, an oral multitargeted kinase inhibitor with activity against FLT3. In early-stage trials, midostaurin showed promising activity both as monotherapy and in combination with induction therapy in patients with FLT3 mutated AML compared with FLT3 wildtype AML. Encouraged by these data, Novartis initiated the RATIFY trial in collaboration with Cancer and Leukemia Group B (CALGB-10603; NCT00651261), a Phase III double-blind study evaluating midostaurin versus placebo, both in combination with standard first-line systemic therapy, in AML patients younger than 60. Only patients with FLT3 mutations were enrolled and stratified according to whether they had had a high FLT3 allelic fraction (≥0.7) or a low FLT3 allelic fraction (<0.7); a third cohort consisted of patients with mutations in the kinase domain (FLT-3 TKD). As part of induction therapy, patients received the 7+3 regimen (daunorubicin 60 mg/m2 IV d1-3 and cytarabine 200mg/m2 d1-7 IV) plus midostaurin (50mg oral daily) or placebo. Patients who achieved a complete remission after one or two cycles of induction went on to receive consolidation (four cycles of cytarabine (3g/m2 on days 1, 3, 5) plus midostaurin (50mg oral, daily) or placebo), followed by 12 months of maintenance with midostaurin or placebo at the same dose used during induction and consolidation.  There was no prespecified mandate on the use or not of stem cell transplantation, but the details presented at the 57th American Society of Hematology (ASH) Annual Meeting suggest that midostaurin (or placebo) was not continued for patients who received a stem cell transplantation (less than 50% of patients who received consolidation went on to receive maintenance). The primary endpoint of the trial was overall survival (OS), and secondary endpoints included event-free survival (EFS). While analysis of the results was set to occur at 509 deaths, the slow rate of events led the investigators to amend the protocol to allow for primary analysis at 357 events. With the shadow of lestaurtinib’s failure in its own clinical trial and the challenge in recruitment in RATIFY, many asked: Would midostaurin live up to its potential?

At the ASH annual meeting held in Orlando, that question was answered, with midostaurin demonstrating significant activity in FLT3+ AML patients.3 In total, 717 patients were enrolled, with 360 enrolled in the midostaurin arm and 357 receiving placebo. Evaluation of toxicity revealed no significant safety signals in the midostaurin arm. The most common Grade 3+ adverse events in the placebo versus midostaurin arms were febrile neutropenia (82% versus 81%), infection (38% versus 40%), diarrhea (16% versus 15%), and rash/desquamation (13% versus 8%). The rate of Grade 5 events was also similar between both arms (5.3% in the placebo arm and 5% in the midostaurin arm).

Addition of midostaurin to initial therapy led to a statistically significant improvement in OS and EFS. Patients receiving midostaurin had an OS of 74.7 months (95% CI: 31.5 months-not reached) versus 25.6 months in the placebo group (95% CI: 18.5-42.9 months) (HR=0.77, p=0.007). The four-year survival rate in the midostaurin arm was 51.4% and 44.2% in the placebo group. The benefit in OS was seen across all three subgroups, although it was strongest in patients carrying the FLT3-TKD mutation (HR=0.65, p=0.05), compared with patients with FLT3-ITD high (HR=0.8, p=0.09) and FLT3-ITD low (HR=0.8, p=0.08). The complete response (CR) rates at day 60 were similar between patients receiving midostaurin (59%) and placebo (53%) (p=0.15). Censoring of OS data at the time of transplant (57% of patients received a transplant at some time during their treatment) maintained the OS benefit achieved in patients in the midostaurin arm compared with placebo (four-year OS 63.8% versus 55.7%; HR=0.75, p=0.04). EFS also was significantly improved in patients receiving midostaurin versus placebo (8.0 months versus 3.0 months; HR=0.79, p=0.0.0025), and once again the greater level of benefit was achieved in FLT3-TKD patients (HR 0.75, p=0.02) compared with FLT3-ITD high (HR 0.77, p=0.04) or FLT3-ITD low patients (HR 0.85, p=0.10). Among all patients achieving a CR during induction or consolidation, the EFS benefit achieved with midostaurin was still significant (11.3 months versus 6.1 months, HR 0.73, p=0.0002).

Novartis has guided that it plans to submit regulatory applications in 2016,4 and results from the RATIFY trial should support approval. If approved, what will physicians’ reception to midostaurin be? The dearth of novel agents in this disease will certainly favor its utilization. While Mylotarg® (gemtuzumab ozogamicin, Pfizer) also is being studied in newly diagnosed patients, its troubled history may hinder its utilization, which would help midostaurin be the first novel agent to be approved in for newly diagnosed patients.  However, midostaurin faces challenges of its own. RATIFY was initiated almost eight years ago, and since then the standard of care in AML has changed with respect to utilization of stem-cell transplantation increasing as part of initial therapy. This poses problems for the interpretation of the OS data from RATIFY and whether the survival data presented here will translate into long-term benefits for both transplanted and non-transplanted patients. However, that analysis would extend the trial even longer. Indeed, the investigators noted that in 2014 and 2015 the rates of events plateaued down to six events and three events, respectively, thus providing rationale for the trial amendment to shorten the time for primary analysis. Even so, physicians may hesitate to adopt midostaurin without clear longer-term results. Adding to this hesitation is the decision as to which patient population to administer midostaurin. Elderly patients are less likely to receive an intensive chemotherapeutic regimen such as 7+3, and indeed patients older than 60 years were excluded from eligibility in RATIFY.  The limitation of enrollment to ages 18-60 narrows the eligible population to only one-quarter of newly diagnosed AML patients, and layering on the 30% incidence rate of FLT3+ disease (assuming incidence does not vary by age) leaves less than 10% of AML patients eligible for treatment with midostaurin. Another challenge is midostaurin’s mechanism of action as a FLT3 inhibitor.

Other FLT3-targeted agents ‒ quizartinib (Daiichi-Sankyo Inc.; previously Ambit Biosciences), crenolanib (Arog Pharmaceuticals) and ASP-2215 (Astellas) ‒ are being evaluated in the relapsed setting, and encouraging data has been reported for sorafenib in this setting (when used in combination with azacitidine), which has led to its recommended use in relapsed FLT3+ patients  by the National Comprehensive Cancer Network (NCCN).  Midostaurin will be unchallenged initially in newly diagnosed FLT3+ patients, but should any of these competitors move into first-line testing they could pose a direct threat to midostaurin. For now, midostaurin represents a move forward in the right direction in a disease that has historically suffered from a lack of significant innovation.


  1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December 6, 2015.
  2. Frohling S, Schelnk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372-4380.
  3. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Plenary session, Abstract 6, American Society of Hematology Meeting, December, 2015
  4. Novartis, press release, December 6, 2015

article register

Recent Posts

Recent Comments



Post a Comment

You must be logged in to post a comment