Midostaurin in AML: First Targeted Agent Improves Survival

Zosia Chustecka

December 06, 2015

ORLANDO, Florida — There hasn't been a new drug approved for the treatment of acute myeloid leukemia (AML) since 1990, but one may be coming soon, after results show that the first targeted agent for the disease, midostaurin (under development by Novartis), has shown an improvement in survival in a subset of patients.

For the last 30 years, the cornerstone of treatment of acute myeloid leukemia (AML) has been an anthracycline such as daunorubicin together with cytarabine (DepoCyt, Sigma Tau), given in a "3+7" schedule, and nothing added to this regimen has improved outcomes much. Even midostaurin, when it was first tested in AML, failed.

It was only the realization that this is a targeted agent and the restriction of this drug to patients with the FMS-like tyrosine kinase 3 (FLT3) mutation that produced the results showing an overall-survival benefit. That took 10 years and an unusual academia-industry collaboration, which resulted in the CALGB 10603 (RATIFY) study. The study was conducted by the Alliance for Clinical Trials in Oncology, with the drug and funding for the North American portion provided by Novartis.

"This trial is the first step in applying the theories of personalized medicine to patients with AML, specifically those patients with AML who have an FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard chemotherapy," commented lead author Richard Stone MD from the Dana Farber Cancer Center, Boston, Massachusetts.

Dr Richard Stone

Dr Stone presented the results at a plenary session here at the American Society of Hematology (ASH) 57th Annual Meeting.

The FLT3 mutation is seen in about 30% to 35% of patients with AML and mostly is associated with a worse prognosis, Dr Stone explained to Medscape Medical News. This mutation drives aggressive growth, so that such patients have a poor prognosis and a high chance of relapse. About 6% of patients with the mutation have a variant that is not associated with the worse prognosis, he explained, but the drug is active against both variants, he added.

Improved Overall Survival

The trial was conducted in seven countries and involved 717 patients aged 18 to 60 years with newly diagnosed AML and the FLT3 mutation — and in order to find these patients, the team screened 3279 AML patients.

They were randomized to receive either midostaurin or placebo together with standard chemotherapy (daunorubicin and cytarabine) for induction therapy. This was followed by high-dose cytarabine in the consolidation phase, and patients who achieved complete remission after consolidation chemotherapy continued treatment with midostaurin or placebo as a single agent for up to 1 year. Transplantation was allowed (and 57% of patients had a stem-cell transplant), and the median follow-up was 57 months.

The results show a significant improvement in both overall and event-free survival, Dr Stone reported.

Median overall survival was 74.7 months in the midostaurin vs 25.6 months in the placebo group (P = .0076). The 5-year survival rate was 50.9% in the midostaurin group vs 43.9% in the placebo group.

The event-free survival was 8 months in the midostaurin group vs 3.6 months in the placebo group (P = .0032). The 5-year event-free survival rate was 27.5% with midostaurin vs 19.3% with placebo.

The main toxicity seen with midostaurin was rash/desquamation, said Dr Stone.

The results suggest a new standard of care for AML patients with the FLT3 mutations, Dr Stone concluded.

The results were welcomed by experts in the field, and the abstract was highlighted in the Best of ASH lecture at the end of the meeting.

This trial is likely to be practice changing in the future once the drug is available, commented David Steensma, MD, senior physician at the adult leukemia program in the hematological malignancies division at the Dana Farber Cancer Institute and education cochair for the meeting. This is the first time in 30 years that an addition to the standard chemotherapy regimen has been shown to make a difference in the overall survival, he commented at a premeeting press cast.

Robert Hromas, MD, chair of the department of medicine at the University of Florida, Gainesville, also welcomed the results. "This is a very bad form of AML; the mutation is a driver in these patients, it makes the engine go faster," he explained, and so this subset of AML patients with the FLT3 mutation represents "an unmet medical need." He also noted that the improved outcome with midostaurin was seen whether or not the patient went on to have a stem-cell transplant, and he was hopeful that this may mean that some of the older patients may avoid having to have a transplant in the future.

Novartis has said that it will use these data to file an approval application for midostaurin in the first half of 2016, and it is collaborating with Invivoscribe Technologies, Inc., who will lead regulatory submissions for a companion diagnostic to identify AML patients with the FLT3 mutation.

Trial is "Proof of Concept"

This trial is proof of concept that targeting FLT3 improves survival, commented Eytan Stein, MD, from the Memorial Sloan Kettering Cancer Center in New York. Speaking at an educational session about AML, he noted that the difference in the objective survival rate was 7% (the difference between 5-year survival rate of 50.9% vs 43.9% in the placebo arm) and that the survival curves did not start to separate until about 6 months. He also noted that complete remission (CR) was similar in the two groups (59% in the midostaurin group vs 53% in the placebo group for CR by day 60, although there was a significant difference for when the looser term of CR during induction/consolidation was used, for which the rates were 66% in the midostaurin groups vs 59% in the placebo group).

"Let's hope that second-generation more potent FLT3 inhibitors will be even better," Dr Stein commented

He noted that phase 3 trials with next-generation FLT3 inhibitors are under way — with quizartinib (AC220, under development by Daiichi Sankyo) and with ASP2215 (under development by Astellas).

Dr Stone reports consultancy with Celgene, Sunesis, Amgen, Agios, Roche/Genentech, Merck, Pfizer, AROG, Celator, Juno, Abbvie, and Karyopharm and research funding from Novartis (manufacturer of midostaurin). Disclosures for the coauthors are listed in the abstract.

American Society of Hematology 57th Annual Meeting; Orlando, Florida. Abstract 6, presented December 6, 2015.


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