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Midostaurin confers OS, EFS benefits in FLT3-mutated AML
ORLANDO, Fla. — The addition of midostaurin to standard chemotherapy, followed by 1 year of maintenance therapy, significantly improved EFS and OS for patients with newly diagnosed acute myeloid leukemia and FLT3 mutations, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.
“This particular subtype of AML has an unmet medical need,” Richard M. Stone, MD, clinical director of the adult leukemia program at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, told HemOnc Today. “Most patients with FLT3-mutated AML have a poor prognosis. This mutation itself causes a gain of function, so the enzyme is more active than usual when it is mutated. Therefore, it is relatively more straightforward to inhibit.”
Midostaurin (PKC412, Novartis) — a multi-targeted small molecule FLT3 inhibitor — has shown single-agent activity in AML with internal tandem duplication (ITD) and tyrosine kinase domain (TKD) FLT3 mutations, according to study background.
Thus, Stone and colleagues sought to study whether the addition of midostaurin to induction and consolidation therapy, followed by maintenance therapy, would improve OS compared with standard chemotherapy in younger adult patients with FLT3–mutated AML.
The researchers enrolled patients aged 18 to 60 years with previously untreated AML. They screened 3,279 patients for FLT3 mutation, stratifying patients by mutation subtype (TKD vs. ITD; high allelic mutation fraction [> 0.7] vs. low mutation fraction [0.05-0.7]).
The trial included data from 717 patients (FLT3 ITD-low, n = 341; FLT3 ITD-high, n = 214; FLT3 TKD, n = 162). The median age of the population was 48 years.
Patients received induction chemotherapy — which consisted of IV daunorubicin (60 mg/m2 on days 1-3) and cytarabine (200 mg/m2 on days 1-7) — plus midostaurin (50 mg; n = 360) or placebo (n = 357) on days 8 through 22.
The cohorts had comparable characteristics with the exception of sex (midostaurin, 48.2% men; placebo, 40.6% men; P = .04).
Patients could undergo a second blinded course if residual AML was seen on a 21-day marrow examination. Those who achieved a complete remission went on to receive four cycles of cytarabine (3 g/m2 on days 1, 3 and 5), plus midostaurin or placebo, followed by a year of maintenance therapy with midostaurin or placebo. The researchers permitted stem cell transplantation (SCT).
The researchers amended the study to add EFS as a key secondary endpoint, due to a slow rate of events.
All patients have gone off treatment, according to the researchers. The median follow-up for all surviving patients was 57 months.
The researchers did not observe a significant difference in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events between study arms.
Patients experienced a total of 37 grade 5 adverse events (midostaurin, 5.3%; placebo, 5%). There were no observed differences in treatment-related grade 5 adverse events (midostaurin, 3.1%; placebo, 2.5%).
Fifty-nine percent of patients assigned midostaurin and 54% of patients assigned placebo achieved complete remission.
Patients assigned midostaurin achieved significantly longer median OS (74.7 months vs. 26 months; P = .007) and EFS (8 months vs. 3 months; P = .0044). More patients assigned midostaurin achieved 5-year OS (50.9% vs. 43.9%; HR = 0.77; 95% CI, 0.63-0.95) and 5-year EFS (27.5% vs. 19.3%; HR = 0.8; 95% CI, 0.67-0.95).
Fifty-seven percent of patients (n = 402) underwent allogeneic SCT at any time, with a similar time to transplantation in each arm (midostaurin = 5 months; placebo = 4.6 months). Secondary analyses censoring at the time of SCT provided similar results in favor of midostaurin for OS (HR = 0.77; 95% CI, 0.56-1.05) and EFS (HR = 0.84; 95% CI, 0.7-1.002).
Further, the OS and EFS benefit of midostaurin extended across all FLT3 subgroups.
“Pending FDA approval, I think this may become the standard of care for this AML subtype,” Stone said. “I think we can be optimistic that it will be approved and used. From a research standpoint, there are many other areas where you might explode midostaurin: post-transplantation, in older patients with AML or in patients without a FLT3 mutation.” – by Cameron Kelsall
Reference:
Stone RM, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
For more information:
Richard M. Stone, MD, can be reached at Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115; email: richard_stone@dfci.harvard.edu.
Disclosure: Stone reports consultant roles with Abbvie, Agios, Amgen, AROG, Celator, Celgene, Genentech/Roche, Juno, Karyopharm, Merck, Novartis and Sunesis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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It was nice to see was that this was very well tolerated and did not seem to introduce any significant toxicity into the preexisting backbone of 7+3. It will be even more interesting, as we have better inhibitors in the pipeline, to see whether they can build on the advances of midostaurin.
Reference:
Röllig C, et al Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.Perspective
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This represents a major advance in AML therapy, a field where there is a major unmet medical need. We have not had therapies approved by the FDA for this disease in decades. The investigators are to be congratulated on the study.
However, there are a number of questions that need to be addressed. One important question is whether the benefits were seen both in patients with internal tandem duplication and tyrosine kinase domain mutations. Further, the mutations are not present in all cells of patients who harbor the mutation. The researchers plan to analyze whether there is a difference in benefit between patients who have a majority of cells carrying the mutation vs. patients where it is only present in a small population of cells.
Also, is there a benefit in patients who do not carry either class of FLT3 mutations? That was unaddressed in this trial, but that will be a subject for future study.
It has been a long time since we have seen a new therapy in newly diagnosed patients with AML confer a significant improvement in reducing their relapse risk and improving OS. It is likely that the results from this study will lead to a change in the standard of care for these patients.
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Midostaurin (PKC412, Novartis) really made a meaningful impact for those patients with the FLT3 mutation, and the therapy was clearly complementary to standard induction chemotherapy.
As a practicing hematologist and oncologist, I think this will be very impactful for my patients. Having a potential new option to augment the efficacy of their induction and consolidation really will be a great advance.
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In this study, Stone and colleagues added a first-generation tyrosine kinase inhibitor to the standard therapy for acute myeloid leukemia. This is not the first time this has been done — other TKIs have been used in this setting — but in this case, the TKI used was midostaurin (PKC412, Novartis). One previous study showed a benefit with a similar drug called sorafenib (Nexavar, Bayer Healthcare).
Patients in this study have FLT3 mutations, which put them at a high likelihood for responding. The study found improvements in EFS and OS, which is significant, because the previous sorafenib study only saw an improvement in EFS. That could be due to differences in the inhibitory targets of the drugs or in the dosing schedules between the two studies.
Further, similar to the previous study, the effects seemed to not necessarily depend on FLT3 mutation status. In the previous study, which included patients without FLT3 mutations, the researchers saw responses even where they could not identify the mutation.
This study didn’t include FLT3-negative patients, but the researchers did characterize patients into three groups: patients with the most active mutations, as well as those with activating mutations in high copy number and low copy number, who you might expect would be affected less by the inhibitor. The results showed that independent of category, improvement occurred. Similar to sorafenib, there appeared to be an effect beyond just FLT3 mutation status.
We still generally use the same backbone of therapy for AML — we haven’t had a new drug approved for AML in some time. With this study, it appears that adding a TKI to the treatment of young adults with AML outside of clinical studies will probably become a standard of care.