Vosaroxin/Cytarabine in AML

Transcript:Elias Jabbour, MD: Now we’re going to move to another drug. Last year, we had vosaroxin presented. In the VALOR trial, the primary endpoint wasn’t met. So, Harry, you want to update us on vosaroxin/cytarabine?

Harry P. Erba, MD, PhD: So, Farhad Ravandi is going to update us with a subset analysis of the VALOR trial, which was a study done in all adults comparing vosaroxin at 90 mL/m2 on days 1 and 4 with Ara-C, 1 g/m2, for 5 days, or just the Ara-C for 5 days. And, as we know, it was a negative study. It just barely missed being statistically significant for overall survival in this group of patients with relapsed refractory disease. But, remember, in the design of the study, patients were stratified based on age, and two-thirds of the patients were actually older than the age of 60, which would make that comparison of vosaroxin/Ara-C versus Ara-C alone the largest study in older relapsed refractory patients. And in that setting, it was a positive study. There was a survival benefit, and what Farhad has updated is that the survival curves have not come together 2 and 3 years after, with 2 or 3 years of follow-up.

Elias Jabbour, MD: But, do you think it’s enough to get an approval for an elderly patient at least for the time being?

Harry P. Erba, MD, PhD: I wish it were enough because I think it’s a shame to waste such a large number of patients and resources on a study that actually was positive. You can argue that the improvement of survival at 2 and 3 years of about 6% with high-dose Ara-C to 13% isn’t much to write home about. However, if you tell a patient that they’re twice as likely to be alive 3 years from now, they might actually go for that. I don’t think it’s going to be enough to get an approval. It would be a precedent setting approval of proving a drug based on a subset.

Richard M. Stone, MD: I think the other issue is the control arm of that trial. As we all know, that was discussed before the trial was mounted. It was an acceptable control arm. But, if you’re going to give somebody, even an older adult, intensive salvage chemotherapy, you might give them midostaurin/cytarabine, and that was not the control arm.

Harry P. Erba, MD, PhD: Yes. I think your point is well taken for a younger patient. I’m not quite so sure for older patients.

Mark J. Levis, MD, PhD: And yet, you look at the trial and you certainly get the sense that vosaroxin is active. And really what we’re seeing is the tyranny of P value, that 5.2 is definitely different than 4.8.

Martin S. Tallman, MD: Can I ask my colleagues a broader question? It’s never been a more exciting time in our field and the field AML. We have so many new targets, so many new novel agents with novel mechanisms of action. And the benefits have been somewhat incremental. Even the RATIFY trial, which is a major, major effort and a positive trial, as Rick said, is an improvement and an advance, but a modest one. What do we feel about the future? What will it take to make a leap in terms of an advance or do you think the future for the 1 to 2 decades is continuous small increments?

Elias Jabbour, MD: What has been, in solid tumors, a minor increment that will lead you to an approval of a drug? For pancreatic cancer, with a 12-day improvement the P value can be significant.

Martin S. Tallman, MD: But, if the drug is approved, if the drug is such a modest advance…

Mark J. Levis, MD, PhD: But, remember all the published curves that we see in our field in AML. Every 5 or 10 years, the overall survival inches up a little bit further.

Richard M. Stone, MD: Because of the supportive care, perhaps.

Mark J. Levis, MD, PhD: Quite possibly, but in fact, we’re continuing to make progress. I think it will be small and incremental.

Martin S. Tallman, MD: But, why not? Why won’t it? What is preventing it?

Richard M. Stone, MD: You’ve got 2 problems. The heterogeneous disease with disease subsets and it’s a polyclonal disease. So, to think that we can cure FLT3 AML, even IBH-positive AML, with one of these inhibitors is probably naïve. Because, it’s possible with adding chemotherapy to it, maybe in some patients in transplant, but most AMLs, especially older adults as Mark has eloquently pointed out on many occasions, have these root mutations like TET2 and ASXL1, which we haven’t really been able to deal with other than transplant so far. Whether prolonged hypomethylating agents will change that, I don’t know. But, I think we have to be happy with incremental increases. Myeloma has more drugs, adding them together, and we’ll be talking about some drugs that maybe will be more globally active.

Harry P. Erba, MD, PhD: With Marty, I think I sense his frustration because Marty has actually published, for the Intergroup, the first Intergroup trial in APL that showed such a monumental jump from chemotherapy to ATRA-based therapy in that North American clinical trial.

Martin S. Tallman, MD: But, it’s a relatively narrow aberrant pathway, which supports what Richard’s saying.

Transcript Edited for Clarity