Vibecotamab Shows Safety/Activity in Low-Blast, High-Risk Myeloid Diseases

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Vibecotamab (formally XmAb14045) demonstrated promising results in a phase 2 study evaluating low-blast myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) after hypomethylating agent (HMA) failure and minimal residual disease (MRD)-positive acute myeloid leukemia (AML).¹

In an open-label, 2-arm, phase 2 study, the agent was assessed and patients were treated with vibecotamab, a CD3-CD123 bispecific antibody. via intravenous infusion in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of the agent given at a dose of 1.7µg/kg. Treatment was administered up to 4 cycles, each of which were 28 days long.

The primary end point of the MDS/CMML cohort was response rate within 4 cycles, and the primary end point assessed in the AML MRD cohort was the MRD negativity rate within 4 cycles.

Overall, vibecotamab was well-tolerated in the study. Specifically, the treatment led to a response rate of 64% in MDS/CMML after HMA failure and 25% in patients with MRD-positive AML. Even in patients who had received prior treatments like venetoclax (Venclexta) or hematopoietic stem cell transplant, the agent was effective, and unlike other cancer treatments, it did not cause clinically significant myelosuppression.

These findings suggest vibecotamab could be a valuable addition to treatment regimens for MDS, CMML, and AML.

In an interview with Targeted Oncology^TM, Daniel Nguyen, MD, PhD, hematology fellow at MD Anderson Cancer Center, further discussed the findings from this phase 2 trial and the potential of vibecotamab.

Targeted Oncology: Can you provide a clinical review of the phase 2 study which looked at vibecotamab for MDS or CMML after hypomethylating failure and in MRD-positive AML?

Nguyen: Vibecotamab is a CD3-CD123 bispecific antibody, and we are essentially using it in 2 separate cohorts. One is MDS or CMML after hypomethylating agent failure, and the other is MRD-positive AML, both of which we feel like represent patient populations with unmet needs.

How were the cohorts assessed decided upon?

They were essentially based on the results of the phase 1 study. In the phase 1 study, the drug was tested on [patients with] relapsed/refractory AML. What we found was that the patients who did respond typically had lower blast count. So, our thoughts were that this drug might be effective in other diseases with kind of a low blast state. That is kind of how we arrived at expanding the study to involve MRD-positive AML, as well as MDS and CMML.

How does the response rate seen in the MDS/CMML cohort compare with that of other treatment options?

We feel most excited about this cohort, particularly the MDS section of the MDS/CMML enrolled cohort. We know that after hypomethylating agent failure, these patients, unfortunately, tend to do quite poorly. So far, we are seeing responses of 67% to 70%, but for the question of how long we may see those responses still remains to be seen. So far, our median duration of response is over 7 months, but we expect that to increase as we study the drug for longer.

Since there is no real standard of care for these patients, we hope that this drug can provide a better option than essentially no option right now. We hope that this drug can provide better quality of life for these patients and give them something that is well-tolerated and [has] minimal [adverse] effects, and that can keep them from progressing to AML or something like that.

What were the safety findings of the agent?

Overall, it seems to be well-tolerated. The major [adverse] effects that we are encountering are infusion reactions, which kind of has some overlap with cytokine release syndrome as well. In fact, in the phase 1 study, we saw quite a lot of that. Based on what we learned from the phase 1 study, we have done this kind of low primer dose again, to start off with, and we kind of slowly ramp up for dosages over the course of the first week, to sort of minimize or mitigate the amount of infusion reactions or cytokine release syndrome episodes. We have seen that this is quite effective in reducing these events from happening.

What is the biggest takeaway from these results in your opinion?

Even in the AML MRD cohort with only 27% response rates, both cohorts really do represent patient populations who are high-risk, have lots of poor cytogenetics, and heavily pretreated as well. Most of these patients have received not just 1 line of therapy, but a second line of therapy, even prior transplants. What is exciting for us is that this drug seems to be working even in these sorts of high-risk and heavily pretreated patients.

For the AML cohort, what was the median time to MRD negativity in patients who responded?

It is actually not reached yet. We only have 4 responders of the 15 or 27%, so the median duration has not been met yet. Based on that, I can kind of break it down since we have 4 responders. Two responders are still in ongoing MRD-negative remission. It is over 15 months at this point, so we are excited about that. Another responder, more recently, is still receiving protocol therapy. The fourth responder, unfortunately, did relapse about 4 or 5 months after achieving MRD negativity.

What were the main factors associated with response?

Hard to say as all 4 of these patients were very high-risk, heavily pretreated, but nothing that we can identify in these patients vs the ones who did not respond, at least not right now.

Do you think it can be used as a maintenance therapy to prevent relapse in patients with AML with MRD negativity?

Yes, in fact, we have already amended the study to sort of give the drug essentially indefinitely. We borrowed this kind of way when we are timing or are dosing the drug from blinatumomab [Blincyto], which we use a lot in AML, which is a time-limited treatment. They get a couple of cycles of blinatumomab and move on to something else. We are kind of amending our study since we are seeing responses. And we do not know if we continue to give them drugs if their responses will be more durable or longer lasting, so the next phase of our amendment of the study is to continue to give the drug to the responders not just at the 4 cycles, but for longer.

What are the next steps for this research?

We are expanding our study. Now that we have had some encouraging results, we are trying to enroll more patients. The biggest key is to give the drug continuously to responders rather than just stopping after 4 cycles and moving on to something else. That is the biggest thing that we are moving forward to.

How do you think this agent may fit in these different treatment landscapes?

We can kind of look at it from both different cohorts. In the AML MRD cohort, it could very well be that if we can get patients who are MRD-positive to become MRD-negative, and then subsequently moving on to transplant, we hope that this can provide essentially better outcomes, right? We know that patients who are MRD-positive, they go into transplant, their risk for relapse is going to be higher, and they just do not do as well. So, we are hoping that our drug can potentially serve as a bridge to get patients to become MRD-negative. If they can proceed to transplant, that would be fantastic. We would expect to see better outcomes.

For the MDS/CMML cohort, [it is] a little bit tricky. These patients tend to be much older and may not necessarily be candidates for transplant, but if they were or if they are, it would be the same. We hope that the drug can kind of double the amount of blast before moving on to transplant, if they are eligible. If not, then like I mentioned before, we can potentially give the drug continuously as a maintenance therapy.

REFERENCE:

Nguyen D, Ravandi F, Wang SA, et al. A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MDS or CMML after hypomethylating failure and in MRD-positive AML. Blood. 2023;142(suppl 1):322. doi:10.1182/blood-2023-190693