Midostaurin Is an Exciting Step Toward a Cure, But Won't Benefit All AML Patients, Expert Says

Richard M. Stone, MD

Richard M. Stone, MD

As not many advancements have been made to improve the standard of care for patients with acute myeloid leukemia (AML) over the past few years, Richard M. Stone, MD, says that any new drug able to improve the cure rate for these patients will be heralded with excitement, including the recently FDA-approved agent midostaurin (Rydapt).

Midostaurin was granted FDA approval last week, based on results of the phase III RATIFY trial, which showed a reduction in the risk of death by about 23% by adding midostaurin to standard chemotherapy for treatment-naïve patients with aFLT3mutation.

In an interview withTargeted Oncology, Stone, director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, discussed the impact that midostaurin could have for patients with AML, as well as ongoing research with the agent.

TARGETED ONCOLOGY:What impact do you see midostaurin making in the AML community?

Stone:AML is a devastating disease that affects about 15,000 people in the United States annually. Unfortunately, about 40% to 50% of the people who get this disease die of it. It’s particularly difficult in older adults who get this disease, and the median age is about 68 to 70, so it is a disease of older adults. But, young people do get it as well. Even in young people, a lot of patients die of it.

We haven’t really done much to change or improve the care of people between the ages of 18 and 60 who have AML, and we’ve done even less, frankly, for those with AML who are over the age of 60 over the last few years. We are desperately looking for drugs to improve the outcome. There haven’t been any drug approvals for AML in several decades, so any new drug in AML that is going to improve the cure rate is going to be heralded with some degree of excitement.

With midostaurin, when added to chemotherapy, one has a better outcome in the long run, and in the short run, for that matter, than if one added placebo to chemotherapy. That’s why we are excited about this. I wish I could say that we cured everybody who was eligible to get midostaurin by adding it to chemotherapy. That is not the case, but it is an advance compared to chemotherapy alone for people withFLT3-mutant AML.

TARGETED ONCOLOGY:What benefit was seen with midostaurin in the phase III RATIFY clinical trial, which was the basis for the FDA’s approval of the agent?

Stone:This trial had a simple design with the control group getting standard induction chemotherapy, which was daunorubicin and cytarabine, and if those individuals achieved remission, they got standard high-dose post-remission therapy.

The experimental arm got the same chemotherapy, but instead of placebo being added to it, which was the case in the control arm, they got midostaurin at a dose of 50 mg twice daily orally given on days 8 through 22, which is 14 days after the chemotherapy completed. They got the midostaurin during induction during each of the post-remission courses, and there was also randomization to placebo or midostaurin for 12 months after the chemotherapy was concluded. It wasn’t a re-randomization—the people who got midostaurin got it all along.

With any trial, the important thing to think about is what is the endpoint, so what was the most important finding we were looking for, because that primary endpoint determines the number of patients that had to be enrolled on the trial. The primary endpoint we chose was overall survival—would more people on midostaurin plus chemotherapy survive than people who had chemotherapy plus placebo.

The trial was based on seeing a risk reduction of at least 22% in the risk of dying for those randomized to midostaurin plus chemotherapy versus placebo plus chemotherapy. The trial met its primary endpoint, meaning that indeed the risk of dying was lower by about 24% if you were randomized to midostaurin than if you were randomized to placebo. It took 714 patients to see that difference.

The overall risk of dying was about 24% lower on the midostaurin arm. That doesn’t have to do with the median survival. The median survival depends on where you have the 50% cutoff on the Kaplan-Meier curve. It is true that the median survival for patients on midostaurin was years longer than it was for people who got placebo, but one shouldn’t overdraw conclusions based on that seemingly exciting number. It’s really the hazard ratio that is important, because the number of people on the trial was large enough. ThePvalue was quite significant, even though the hazard ratio was 24%.

Another important piece of data that is helpful in understanding the magnitude of the benefit is how many patients were alive at 4 years who were randomized to midostaurin, compared to those who were alive at 4 years who were randomized to placebo plus chemotherapy. Approximately 44% of people on the placebo arm were alive at 4 years, and about 51% on the midostaurin arm were alive at 4 years, so that’s a 7% difference. Is that huge? No. But it is highly significant and has clinical benefit. I think anybody in their right mind would want to be on the arm that had a 7% longer chance of being alive, and therefore, probably cured, at 4 years. That’s why median survival is misleading. Overall survival, hazard ratio, and the number of patients alive at 4 years probably has more clinical meaning and is more relevant to the absolute magnitude of the benefit relative to the median survival comparisons.

Targeted Oncology: Was there a difference seen in the toxicity profile as well?

Stone:The adverse event rate in both arms was quite similar. The only side effect or life-threatening thing that was worse on midostaurin was skin rash, and that wasn’t very common. Despite the fact that single-agent trials and some of the early trials of midostaurin suggested a fair degree of gastrointestinal toxicity, in terms of nausea and vomiting, we didn’t actually see that in this placebo-controlled trial. Toxicities were very similar between the 2 arms, suggesting it’s a safe drug to give at this dosing schedule.

TARGETED ONCOLOGY:Which patients will benefit from midostaurin?

Stone:People who would have been eligible for the trial are the appropriate candidates for midostaurin—people between the ages of 18 and 60 who had aFLT3mutation in the leukemic cells at the time of diagnosis. Those are the ones that would get chemotherapy plus midostaurin—that represents about 30% or 35% of all AML patients.

A couple other important pieces of data are that over half of the patients on the trial got transplanted at some point. About a quarter of the patients got transplanted during the first remission, and about a quarter of the patients got transplanted later after they had relapsed or had not gone into remission. I think the positive total outcome that we saw was due, at least in part, to the fairly high transplant rate. As it turns out, compared to the beginning when the trial was started, we learned that it was a good idea to transplant people that had this type of mutation. That is why the transplant rate was higher than we estimated at the beginning. I think that’s an important part of the management.

For a patient with AML and aFLT3mutation who was between 18 and 60, I would give them midostaurin. If they were a transplant candidate, I would give them 1 cycle of consolidation, or whenever the transplant was ready I would then transplant them. I think that’s going to lead to a pretty good outcome. If you look at the curve of patients who had midostaurin and were transplanted in first remission, the 5-year survival rate was about 60%, so if you were in that category, you did pretty well.

TARGETED ONCOLOGY:Is there ongoing research exploring whether it would be better to give midostaurin post-transplant?

Stone:The RATIFY trial did not include use of midostaurin either after relapse or transplantation. Subsequently, there had been a lot of trials using medicines like midostaurin, or midostaurin itself, in people that are either at risk for relapse after transplant because they had aFLT3mutation going in, or people actually had relapse after the transplant, and it seemed like using the tyrosine kinase inhibitors to inhibit FLT3 in the post-transplant setting was a good idea. Many investigators are either studying the use of FLT3 inhibitors after transplant or incorporating it into trials.

An important subsequent research issue will be whether to use midostaurin or other FLT3 inhibitors after transplant. There’s actually a big bone marrow transplant Clinical Trials Network trial ongoing now of people that haveFLT3mutations, get a transplant, and then they’re randomized to a different FLT3 inhibitor called gilteritinib versus observation. FLT3 inhibitors, including midostaurin, will be evaluated in the post-transplant setting. A drug like midostaurin is a multikinase inhibitor. It doesn’t just inhibit FLT3. There was some data from my trial that suggests that maybe it didn’t work by inhibiting FLT3, maybe it worked by inhibiting other enzymes that might be relevant for the leukemia state. As such, there will likely be a trial evaluating chemotherapy plus midostaurin versus chemotherapy plus placebo inFLT3wild-type patients, so the other 70% of patients could possibly benefit from this, but we have no idea if that’s true or not. We have to do a clinical trial to figure it out.

TARGETED ONCOLOGY:Do you think this agent could open the door for other targeted agents in AML?

Stone:Absolutely. I think midostaurin will help to pave the way for additional targeted therapies. Even now, in the days [following the approval], there is a lot of research with targeted therapies, which is either ongoing or soon to start, specifically of FLT3 inhibitors that are being tested in different situations. There’s also IDH1 and IDH2 inhibitors that are being tested in patients withIDH1andIDH2mutations.

The good news is that AML might be dealt with in a better way than we’ve done in the past by using targeted therapies. The difficulty is that AML is not the most common disease in the world, which is good because nobody wants to have AML. The challenge is that you’re subdividing a relatively rare disease into even more rare subtypes, each of which might require a different targeted therapy.