Novartis PKC412 drug improves overall survival by 23% in phase III study

In the study, adult patients under 60 years of age with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) who received the investigational compound PKC412 (midostaurin) plus standard induction and consolidation chemotherapy experienced a 23% improvement in overall survival (OS) (hazard ratio [HR] = 0.77, P = 0.0074) compared to those treated with standard induction and consolidation chemotherapy alone.

The median OS for patients in the PKC412 (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 PKC412 (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 PKC412 (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 AML to date, with 3,279 patients screened and 717 study participants from around the world.

"The overall survival results for midostaurin, plus standard chemotherapy, in treating FLT3-mutated AML is a long-awaited advancement for hematologists and the AML community," said Richard M. Stone, MD, Professor of Medicine at the Dana-Farber Cancer Institute and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial.

"FLT3 is a common genetic mutation in AML and is currently associated with poorer prognoses, underscoring the critical need for new treatment options."

The treatment strategy in AML has remained unchanged for more than 25 years. Of the approximately 350,000 people with leukemias worldwide, about 25% have AML.

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.

PKC412 (midostaurin) is the first drug to illustrate an overall survival benefit targeting FLT3 in AML – a hematological malignancy with no approved targeted treatments.

In addition to meeting the primary endpoint of OS, 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 PKC412 (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 (AEs). A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups.

Novartis Oncology Development and Medical Affairs global head Alessandro Riva said: "The RATIFY study, in partnership with the Alliance for Clinical Trials in Oncology, reflects our relentless pursuit to develop targeted therapies that can improve and extend people’s lives.

"Based on the results of this trial, we plan to move forward with global regulatory submissions for PKC412 (midostaurin) in the first half of 2016."

In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with Invivoscribe Technologies, Inc. who will lead regulatory submissions for a companion diagnostic.

About the RATIFY trial

RATIFY (Randomized AML Trial In FLT3 in patients <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 study compared PKC412 (midostaurin) to placebo administered orally with up to two cycles of standard induction (daunorubicin/cytarabine) chemotherapy, and up to four cycles of consolidation (high-dose cytarabine) chemotherapy, followed by PKC412 (midostaurin) or placebo treatment as a single agent for up to one year in patients who continue in complete remission after consolidation chemotherapy. The primary endpoint was OS and the key secondary endpoint was EFS.

The data were collected by the Alliance for Clinical Trials in Oncology ("Alliance") on behalf of 13 contributing international cooperative groups. The Alliance was the sponsor of the study in North America and Novartis was the sponsor in Europe and Australia. 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 AML 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 (>0.7) and ITD low allelic mutation fraction (0.05-0.7).

All three subtypes treated with PKC412 (midostaurin) demonstrated improved OS versus placebo[4]. Allogeneic hematopoietic stem cell transplantation (SCT) was allowed. PKC412 (midostaurin) benefited patients regardless of whether they went on to receive a SCT.