Early Results Show Promise With Venetoclax-Idasanutlin Combo for Relapsed/Refractory AML


Gail Roboz, MD, Professor of Medicine, Weill Cornell Medicine, NewYork-Presbyterian Hospital, spoke to Oncology Learning Network about a recent trial presented at the 2018 ASH Annual Meeting involving the use of a venetoclax plus idasanutlin combination regimen in patients with relapsed or refractory AML.




My name is Dr. Gail Roboz. I'm a professor of medicine and director of the Clinical and Translational Leukemia program at Weill Cornell Medicine and the New York Presbyterian Hospital in New York City.

Today, I'm happy discuss an interesting abstract that was presented at ASH 2018. This was a collaborative effort with a number of different centers led by Dr. Daver at MD Anderson Cancer Center in Houston.

The title of the abstract was "Safety, Efficacy, Pharmacokinetic, and Biomarker Analyses of BCL2 Inhibitor Venetoclax Plus MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refactory AML ‑‑ A Phase Ib, Non‑Randomized, Open‑Label Study."

We have been very excited recently by approvals of several novel agents for the treatment of patients with acute myeloid leukemia. This has definitely generated a lot of enthusiasm and excitement in the field, but it still remains the case, despite these exciting improvements, that patients with relapsed or refractory AML are in trouble.

There is no definitive standard of care for these patients because the circumstances of their relapse and the biology of the specific AML dictates what will happen.

For example, patients who relapse after stem cell transplant versus patients who relapse after induction chemotherapy versus those who never attain a remission after AML induction are very, very different groups of patients biologically but, unfortunately, are united by the fact that outcomes are poor.

Even with molecularly selected subgroups, overall outcomes are generally measured in months for relapsed AML patients, not in years. It's very clear that novel therapies are needed for these patients.

One interesting trial that was presented at ASH 2018 involved a combination of venetoclax with the MDM2 inhibitor idasanutlin. Venetoclax is a BCL2 inhibitor that has been FDA approved for the treatment of CLL and recently approved in combination with azacitidine for newly diagnosed patients with AML.

It has also been used, both as a single agent and in combination, with patients with relapsed AML. There are data suggesting some responses. Of course, nothing near the percentages of response or duration of response that we would like to see.

With venetoclax, the current story is maybe some utility in relapsed disease but nothing fantastic by itself or in combination with, for example, hypomethylating agents. Some pre‑clinical data suggested that combining venetoclax with an MDM inhibitor would be synergistic. This actually led to a clinical trial.

Initially, the clinical trial also included combination with a drug called cobimetinib but that proved to have limited efficacy and toxicity issues. Instead, the trial went forward combining venetoclax with idasanutlin.

Basically, the idea is that MDM2 inhibition promotes degradation of MCL1, which is a known resistance factor to BCL2 inhibition. The idea therefore would be to capitalize on what we thought was preclinical synergy between venetoclax and idasanutlin.

The clinical trial is very early data, but basically there was phase I dose escalation followed, then, by venetoclax with idasanutlin at a recommended phase II dose, which is the planned study. The data that were presented at ASH this year were, again, quite preliminary but involving escalating doses so that we had a DLT period, and then an expansion, and a typical phase I design.

Basically, what we can tell so far is that there were pretty manageable, overall, side effects. There was no evidence of PK interaction between the two drugs with some encouraging blast count reduction across multiple dose cohorts.

Our conclusion was that because blast counts were going down, because the drug combination looked like it was reasonably safe, and because there were some responses observed in patients with different mutational and cytogenetic subgroups that this would be something that would be potentially considered for additional development.

The overall antileukemic response rate was 46 percent. The CR plus CRI plus CRP rate was 33 percent. These are at dose levels being considered for the recommended phase II dosing. It would be venetoclax 600 milligrams plus idasanutlin 150 or 200.

Again, these are very early data. I think that the mechanism of potential synergy is exciting. This would be not something that can be applied currently to clinical practice, but rather it is, I would say, a strong platform for further development. Idasanutlin as an interesting agent is also being further considered in combination with a standard cytotoxic chemotherapy for newly diagnosed patients with AML.

I would say, in conclusion, that the benefits of presenting these types of early studies is to show, first of all, whether there is corroboration of the initial preclinical data suggesting synergy in a manner that is tolerable for the patient. That appears to be the case here. I would say there is a strong mechanistic rationale, which was then corroborated by a relatively high response rate.

The development of this combination is ongoing. As I mentioned, idasanutlin will also be available in a clinical trial in combination with standard chemotherapy for younger patients eligible for intensive induction.


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