Uproleselan didn’t enhance total survival in relapsed/refractory AML sufferers in a section 3 trial, although it could profit sufferers with major refractory AML.
A section 3 worldwide medical trial evaluating the efficacy of uproleselan (GMI-1271) together with chemotherapy versus chemotherapy alone in sufferers with relapsed/refractory acute myeloid leukemia (AML) didn’t display a statistically important enchancment in total survival (OS) within the intent-to-treat (ITT) inhabitants.
These findings offered on the 2024 ASH Annual Assembly.
At a median follow-up of 37.9 months, the median OS for the ITT inhabitants was 13 months amongst these within the uproleselan arm (194 sufferers) versus 12.3 months within the placebo plus chemotherapy arm (194 sufferers). This distinction was not statistically important. Nevertheless, OS survival chances at 48 months have been 34.1% for the uproleselan group and 25.5% for the placebo group.
Regardless of not assembly the first OS finish level, uproleselan confirmed encouraging leads to sure subgroups, notably for sufferers with major refractory AML, who skilled a survival benefit.
“Sadly, this massive worldwide section 3 examine didn’t meet its total major finish level of total survival. Nevertheless, I feel there are some clinically significant advantages noticed within the uproleselan arm throughout a number of predefined subgroups,” defined Dr. Daniel J. DeAngelo, chief of the Division of Leukemia at Dana-Farber Most cancers Institute, throughout a presentation of the information.
Glossary:
Total survival: the time from analysis or the beginning of remedy when a affected person with most cancers remains to be alive.
Intent-to-treat inhabitants: all sufferers who’re randomly assigned to a remedy group no matter whether or not they obtained the assigned remedy or accomplished the trial.
Oral mucositis: a facet impact that causes painful sores and irritation within the mouth and throat.
Full response: the disappearance of all indicators of most cancers from remedy.
Full response with incomplete depend restoration: all indicators of most cancers have disappeared from the physique, however the affected person’s blood cell counts haven’t totally recovered.
Median length of response: the midpoint of the time interval throughout which sufferers expertise a optimistic response to remedy.
Minimal residual illness: a really small variety of most cancers cells within the physique after remedy.
CYP inhibition: when a drugs interferes with the exercise of an enzyme referred to as CYP, that are essential for metabolizing varied substances within the physique together with medicine.
QTc prolongation: a sign on an electrocardiogram that may enhance the chance for harmful coronary heart rhythms.
Differentiation syndrome: a facet impact attributable to a fast launch of cytokines from leukemia cells affected by anticancer medicine.
Sufferers with major refractory AML, which consisted of 33% of enrolled sufferers, had a considerable profit from uproleselan. The median OS on this affected person inhabitants was 31.2 months with uproleselan (62 sufferers) versus 10.1 months with the placebo arm (66 sufferers).
The survival profit was constant whatever the chemotherapy spine used. For sufferers handled with fludarabine, cytarabine, idarubicin (FAI) chemotherapy mixed with uproleselan, the hazard ratio was 0.53, indicating a survival benefit. For these handled with mitoxantrone, etoposide, cytarabine (MEC) chemotherapy plus uproleselan, the hazard ratio was 0.68, suggesting a development towards profit.
Research Design and Affected person Traits
Uproleselan is an E-selectin antagonist that works by disrupting AML cell survival pathways and overcoming chemotherapy resistance. The agent can doubtlessly deepen chemotherapy response.
This trial enrolled 388 sufferers aged 18 to 75 years, with both major refractory AML or first or second relapse. Sufferers have been required to be eligible for intensive salvage remedy.
As soon as enrolled, sufferers have been randomly assigned to obtain uproleselan with chemotherapy or chemotherapy alone, with MEC or FAI because the chemotherapy spine, based mostly on investigator selection. Uproleselan was administered through the induction section and continued by means of as much as three cycles of consolidation, with the choice of continuing to transplant.
The first finish level was OS. Key secondary finish factors have been extreme oral mucositis throughout induction, full response (CR) and remission charges.
Further Findings
The median length of response (DOR) among the many uproleselan-treated major refractory sufferers was not reached, in contrast with a median DOR of 12.7 months within the placebo group.
Minimal residual illness (MRD) standing on the finish of induction was a key secondary finish level of the examine. In sufferers who achieved CR or CR or CR with incomplete depend restoration (CRi), uproleselan confirmed a better price of MRD negativity. Amongst sufferers reaching CR, 67.1% of these handled with uproleselan have been MRD-negative versus 61.5% within the placebo group.
Additional, over 50% of sufferers in each arms underwent allogeneic stem cell transplantation (allo-SCT) after remedy. Notably, sufferers who underwent transplantation skilled a marked survival profit when handled with uproleselan. Of those that achieved CR and proceeded to allo-SCT, the median OS was not reached (NR) for the uproleselan group in contrast with 24.8 months for the placebo group. The five-year survival chances for transplanted sufferers have been 57.5% within the uproleselan arm versus 27.7% within the placebo arm.
Taking a look at security, there was no enhance in severe unwanted side effects or any grade 3 (extreme) or increased treatment-emergent unwanted side effects noticed with uproleselan. No discontinuations as a consequence of unwanted side effects have been seen.
“There was no identified CYP inhibition, QTc prolongation or differentiation syndrome seen on this examine. The security profile was in line with what we anticipate from the chemotherapy spine, with no important variations,” defined DeAngelo, sharing that uproleselan didn’t add any additional toxicity to the chemotherapy spine.
“Whereas the examine didn’t meet the first endpoint of total survival, the findings present clinically significant advantages in major refractory AML and post-transplant survival, suggesting that uproleselan has the potential to enhance outcomes on this difficult inhabitants,” added DeAngelo.
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