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EHA 2024 | Phase I study of pevonedistat, azacitidine, and venetoclax in patients with R/R AML
Guru Subramanian Guru Murthy, MD, Medical College of Wisconsin, Milwaukee, WI, presents the findings of a Phase I study (NCT04172844) investigating pevonedistat, a NEDD8-activating enzyme inhibitor, added to an azacitidine/venetoclax backbone in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). The combination of agents was well tolerated and demonstrated encouraging preliminary activity. A high complete response (CR) rate was observed in patients who had not previously received azacitidine and venetoclax treatment. This interview took place at the 29th Congress of the European Hematology Association (EHA) in Madrid, Spain.
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Transcript
We conducted a Phase I clinical trial using pevonedistat with azacitidine and venetoclax in patients with relapsed and refractory AML. So generally relapsed/refractory AML, these are patients who have unfortunately poor prognosis and they need more novel therapies. Pevonedistat is actually an inhibitor of an enzyme called NEDD8-activating enzyme, and what it really does is it upregulates Noxa and inhibits MCL1...
We conducted a Phase I clinical trial using pevonedistat with azacitidine and venetoclax in patients with relapsed and refractory AML. So generally relapsed/refractory AML, these are patients who have unfortunately poor prognosis and they need more novel therapies. Pevonedistat is actually an inhibitor of an enzyme called NEDD8-activating enzyme, and what it really does is it upregulates Noxa and inhibits MCL1. And MCL1 is an important pathway that is upregulated in patients who have BCL2 inhibitor resistance, such as venetoclax-resistant patients. So what we try to do on this study is to basically see, by adding pevonedistat, are we able to actually improve the outcomes of patients with relapsed/refractory AML who otherwise get treated with an azacitidine/venetoclax-based therapy.
So this was a Phase I study. It’s a dose escalation study where we use the standard doses of azactidine and venetoclax in these patients. These are relapsed/refractory AML patients. We use three different doses of pevonedistat in a dose escalation separate cohorts. And what we found was generally the drug was well tolerated. It was safe to combine with an azacitidine and venetoclax backbone in this patient population. We observed an overall response rate of about 46.7% in the whole population. But what was very interesting was in patients who had relapsed or refractory AML but they never received azacitidine or venetoclax before, five out of seven of those patients actually achieved a CR. So numerically, a very high number. Although it’s a small population of patients in the study, it was very provocative to see those high numbers, and it at least establishes the proof of concept that trying to target the NEDD8 pathway and potentially trying to see if we can overcome BCL2 resistance, could be a potential way to actually improve the outcomes of patients with AML, and hopefully, we’ll have more studies in the future to explore that pathway as well.
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