AML: The RATIFY Clinical Trial

Transcript:Richard M. Stone, MD: There have really been no new drugs in non-APL AML for a long while, if you discount gemtuzumab ozogamicin, which was briefly approved and then withdrawn. We certainly wanted to take advantage of the inhibition properties of FLT3 of midostaurin to see if it might benefit patients with AML. There were single-agent trials with midostaurin, which showed some biological activity, but insufficient clinical activity to make it useful as a single agent. We then combined midostaurin with chemotherapy to be sure it was safe, and we proved that we could do it with a given dose of the drug, namely 50 mg twice daily, given on days 8 through 14 after a chemotherapy cycle. We knew from the trial that it was safe to deliver midostaurin along with chemotherapy, that the combination might be better than chemotherapy. But it was a nonrandomized trial, and we really weren’t sure at all.

Then, we embarked upon a complicated and wide-ranging, geographically, phase III trial called CALGB-10603, or RATIFY. That was sponsored by the US government and Novartis. It took patients who were between ages 18 and 60 and gave them standard chemotherapy with either a placebo or with midostaurin at the dose and schedule I mentioned earlier in my remarks. So, it was simple in its design, though complicated in its execution trial. Why was it complicated? Well, first of all, FLT3 mutations occur in about 30% of AML, and the trial was the only one to treat the patients we thought would be likely to benefit (ie, those with FLT3 mutations). So, we had to screen about 3300 patients to find the 717 that had a FLT3 mutation and were willing to go on this randomized trial of chemotherapy with a placebo versus chemotherapy with midostaurin.

The primary endpoint of the trial was overall survival. So, did the patients who got chemotherapy plus placebo live shorter, the same, or longer than those who got chemotherapy plus midostaurin? And we were happy to learn, when we had a chance to analyze the results, that those who were on the midostaurin arm lived longer than those who were on the placebo arm, meaning that we could affect the natural history of this generally adverse type of AML by adding this oral agent to standard chemotherapy.

Hervé Dombret, MD: At the moment, the RATIFY results were presented by Dr. Stone during the last ASH meeting during the plenary session. And we were impressed by the results of that trial because it’s a positive trial. There is no doubt about that, in terms of survival of the patients. We are still waiting on the complete publication of the results because it would be important to go into details. At the present time, we just heard Richard Stone for 10 minutes, and we need to have more precise data on the publication. But it will change the game in Europe, probably in the United States, as well. And when midostaurin becomes available in my country, we will certainly use midostaurin in all the patients with FLT3 mutations.

Richard M. Stone, MD: This positive result hopefully will result in the availability of the drug for people who have AML, up to age 60 anyway, with FLT3-mutant disease. The drug company that sponsored the trial along with the Cancer Therapy Evaluation Program in the US, Novartis, is in the process of presenting all the data from the trial to the FDA so it can determine that actually, yes, it did improve survival and therefore it should be available for use with those who have documented FLT3 mutations with newly diagnosed AML who are between the ages of 18 and 60. Whether or not the approval will extend to people who are older remains to be seen. It certainly makes sense that if you’re going to get chemotherapy anyway, and you happen to be 65 and you have a FLT3 mutation, one would think that the benefit would still be there. But that remains to be determined by the FDA, since we don’t have primary data in that regard.

The good news is that those who were randomized to midostaurin, except for a slightly increased incidence of rash, had no increased adverse events compared to those who were randomized to placebo, which was quite reassuring, maybe even surprising—because midostaurin was known to have some GI toxicity. But in this context of this randomized trial, where patients didn’t know and the doctors didn’t know which of the arms they were on, you had an unbiased determination of toxicities. There wasn’t really any increased toxicity except for a slightly increased risk of grade 3/4 rash in those who were randomized to midostaurin.

Transcript Edited for Clarity