A Phase II Study Evaluating the Efficacy and Safety of Imetelstat in Patients with Advanced Myelodysplastic Neoplasms or AML Failing HMA-Based Therapy - Interim Analysis Results of the Impress Study

Uwe Platzbecker, Steven Lane and Lionel Adès contributed equally. A study by the European Myelodysplastic Neoplasms Cooperative Group (EMSCO) Background: Hypomethylating agents (HMAs), alone or in combination with venetoclax, are the standard of care for patients with higher-risk myelodysplastic neoplasm (HR-MDS) or acute myeloid leukemia (AML), not eligible for intensive chemotherapy or allogeneic stem cell transplantation. However, the majority of patients do not respond or subsequently relapse. Patients failing HMA therapy still have a dismal outcome with very limited treatment options available. Imetelstat (GRN163L) is a potent specific inhibitor of telomerase, the latter being upregulated in various cancers. Telomerase inhibition leads to loss of a cancer cell's ability to maintain telomere length (TL), resulting in cell-cycle arrest, apoptosis or senescence. In June 2024, imetelstat became the first telomerase inhibitor to be approved by the FDA and is indicated for the treatment of patients with transfusion-dependent lower-risk (LR) MDS who are ESA ineligible or relapsed/refractory. Its clinical activity in HR-MDS or AML is unknown. Methods: The multicenter phase 2 IMpress trial led by the European Myelodysplastic Neoplasms Cooperative Group (EMSCO) evaluates the safety and efficacy of imetelstat in patients with HR-MDS or AML, refractory, relapsing or intolerant after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively, or 3 cycles of venetoclax (VEN) plus AZA. In this first part of the trial, patients received imetelstat at a dose of 7.5 mg/kg i. v. once every 4 weeks for 4 cycles of 28 days until disease progression, unacceptable toxicity, withdrawal of consent or lack of response. Responding patients (defined as at least PR - partial remission or HI - hematologic improvement) were eligible to continue treatment until loss of response/disease progression. The primary endpoint (PE) was overall response rate assessed after 4 months of treatment (CR, CRi, PR, HI). All patients achieving CR, CRi, PR or HI after 4 months of imetelstat were considered as responders and allowed to continue treatment until loss of response/disease progression. Non-responding patients had to stop treatment after 4 months. Results: Between June and October 2023, 29 patients in 9 centers in Germany, France and Australia were screened and 23 patients (MDS=6, AML=17) received at least one dose of imetelstat with an average of 2.8 doses administered per patient. In this first part of the trial, none of the 23 treated subjects reached the primary endpoint visit (V9), which was scheduled after 4 cycles of treatment. 16 of the 23 patients reached the first (preliminary) disease assessment visit (V5) after two cycles of imetelstat. At this assessment, only 1 patient showed a response in form of both HI-E and HI-P. Seven patients had stable disease (SD) and 8 had progressive disease (PD). In addition, short-term transient improvement in hematological values was observed in individual cases. Notably, with the current LR-MDS schedule (i. e. once every 4 weeks), imetelstat showed some antiproliferative effects, including a decline in blasts and leukocytes. A total of 30 serious adverse events (SAEs) occurred in 18 patients of which 21 SAEs required hospitalizations. The majority of SAEs (17/30) was of infectious nature with infections of the lung, febrile neutropenia and sepsis being the most common complications (n=8, n=3 and n=2, respectively). Overall, 10 of the 30 SAEs resulted in death (n=5 due to disease progression/ transformation to AML, n=4 due to infectious complications and n=1 due to ileus) and one was assessed as being possibly related to imetelstat (pneumonia). 11 of the SAEs resolved without sequalae. Overall, no new safety signals occurred beyond those already known for imetelstat. Conclusions: Absence of responses according to the stringent primary efficacy endpoint was observed in this interim analysis. Although adverse events were documented, they were all disease related to patients with HR-MDS and AML. Based on the observations in this first cohort, the protocol was amended to a more frequent dosing schedule for a second cohort of patients being enrolled and treated with this modified schedule starting in August 2024.