Cancer Conference Update: A Multimedia Review of Key Presentations from the 2016 American Society of Hematology Annual MeetingAbstracts 590, 591: Antibody-drug conjugate vadastuximab talirine alone or in combination with hypomethylating agents in patients with CD33-positive AML
8:00 minutes.
TRANSCRIPTION:
DR STEENSMA: So this is the SGN-33 combination. It’s an antibody-drug conjugate. You can think of it very similarly to gemtuzumab ozogamicin, which we had approved for 10 years for MDS. But, importantly, both the linker molecule and the cytotoxin are different. And so the toxicity patterns seem to be a little bit different. For instance, there doesn’t seem to be as much hepatic veno-occlusive disease or sinusoidal obstruction syndrome with this agent as we see with calicheamicin-containing antibodies. And so that’s what this agent is. So this study was reporting an expansion cohort of this drug as monotherapy for patients with AML. And this drug is being used also in a number of different combinations, both with intensive chemotherapy and with hypomethylating agents. And those trials are ongoing. And so the hope is that by adding this agent to azacitidine or decitabine or intensive chemotherapy will improve responses. DR LOVE: Can you talk a little bit about what the monotherapy response rate is and also what kinds of toxicity or tolerability issues there are? DR STEENSMA: Yes. So the response rate is in the 70% range as monotherapy. And this is true even in patients with higher-risk disease, higher-risk cytogenetics. The adverse events that one sees are primarily myelosuppression, neutropenia, thrombocytopenia. But we also do see some of the other types of adverse events like decreased appetite, GI upset that seem to be quite common with any anti-AML therapy. The hepatotoxicity has been reported, but it seems to be quite uncommon. One of the things that we didn’t entirely understand about gemtuzumab ozogamicin was when we saw this veno-occlusive disease, how much was from the cytotoxin, the calicheamicin, how much was from the anti-CD33 therapy and how much was just because of inflammation from leukemia cells that were in the liver, in the sinusoids next to the Kupffer cells, where this antibody could bind and causing a local inflammatory reaction. And I think that’s still unresolved, but it does seem that it’s probably mostly the cytotoxin, the calicheamicin, that was the cause, because it is seen with CD33A antibody, but just not very commonly. DR LOVE: What about Abstract 591, looking at this agent with hypomethylating agents? DR STEENSMA: Yes. So this strategy, I think, also makes a lot of sense, looking at it with hypomethylating agents together. And, as I mentioned, there are randomized trials now going forward with this combination. This was a report of a Phase I study, because in combination, the worry was that it might not be as well tolerated as it was as a monotherapy. And so they gave a lower dose, 10 micrograms per kilogram, versus 40 as monotherapy, and then added that to a standard azacitidine or decitabine every 4-weeks backbone. And the response rate, I have to say, was quite impressive for this particularly refractory group — or high-risk group, I should say. The complete response rate was 43% for a full CR, 31% for incomplete CR, and then there were a few patients who had stable disease as well. The adverse events were similar to what was seen with the monotherapy; cytopenias and GI upset. DR LOVE: So anyhow, in terms of this agent, first of all, have you had any patients who received it as monotherapy who had clinical benefit? DR STEENSMA: We have, yes. We’ve been participating in these trials in our practice. It’s definitely an active drug. DR LOVE: And where do you see it heading? Do you see it coming into practice? DR STEENSMA: I think a lot of how we see this drug used depends on 2 things. One is the results of the randomized trials that are ongoing. Is there benefit from it in combination? Otherwise, it’s likely to be used as a salvage therapy after the patient’s been failed by an HMA. The other wild card here is, what’s going to happen with gemtuzumab ozogamicin? Is it going to be reapproved by the FDA, because since it was removed from the market in 2010, there was a positive survival study in AML, adding it to chemotherapy. And it’s also a very active drug, as we’re going to talk about, in promyelocytic leukemia, which often expresses CD33 quite brightly. So I think that there is the possibility that gemtuzumab ozogamicin will be reapproved. Hard to say what the indication will be, but that may influence usage patterns with both this drug, the vadastuximab and gemtuzumab. DR LOVE: What is the most likely population that the vadastuximab would be used in? DR STEENSMA: I think we’d probably see it in combination with hypomethylating agents in a patient population who’s not a great candidate for intensive chemotherapy. I think that’s likely to be the first shot across the bow. I think also that the APL data are very intriguing. And although we have quite a high response rate with the current arsenic and ATRA-based therapy, we can always do better, especially for high-risk patients. So that is another group where I think it’s potentially going to be quite useful. One of the things that I think we have to think about moving forward is, there are a lot of different chemotherapy or hypomethylating agent-plus trials. So azacitidine/decitabine plus IDH inhibitors, azacitidine/decitabine plus venetoclax, azacitidine/decitabine plus immune checkpoint inhibitors, azacitidine/decitabine plus this agent, vadastuximab. So is it going to end up being something where we’re using these in sequence? Is it something where we’re going to be adding 4 or 5 drugs together, potentially to get cures in some of these patients who just — therapy right now is palliative? Only time will tell. But that is definitely the trend right now in AML and higher-risk MDS therapy. |