Tapotoclax Shows Manageable Safety, Limited Efficacy in High-Risk MDS After HMA Therapy
A phase 1 study of tapotoclax in high-risk myelodysplastic syndromes demonstrated the agent was tolerable but showed limited efficacy.
Red blood cells flowing realistically, 3D rendering: © Kodjovi - stock.adobe.com
When given to patients with high-risk myelodysplastic syndromes (MDS) after hypomethylating agents (HMAs), tapotoclax (AMG 176) demonstrated a manageable safety profile, but limited clinical efficacy, according to findings from a phase 1 study (NCT05209152) presented at the 2024 European Hematology Association (EHA) Congress.1
Although no objective responses were observed among the 7 evaluable patients, the findings showed a reduction in bone marrow blasts and transfusion needs among 2 of 3 patients who had a bone marrow blast of at least 5%. A total of 71% of the patients, all of whom were transfusion dependent at the start of the study, required at least 2 fewer packed red blood cell units between cycles 1 and 2. Notably, 1 patient became transfusion independent for roughly 7 weeks.
The trial’s primary end point focused on safety, including the incidence of dose-limiting toxicities (DLTs). No DLTs were observed, and while 1 patient experienced a fatal infection during the second cycle, it was deemed unrelated to tapotoclax.
Other adverse effects (AEs) included nausea (85%), fatigue (57%), and diarrhea (29%), most of which were grade 1 or 2. One patient experienced mild arrhythmias linked to the treatment, which were managed without dose adjustments. Additionally, 1 patient experienced QTc prolongation, but this was consistent with prior conditions.
Study Design and Background
Tapotoclax is a first-in-class small molecule that selectively inhibits MCL1. This disrupts its protein-to-protein interactions within the BCL2 family and induces apoptosis in MCL1-dependent cancer cells.
In the phase 1 trial, tapotoclax’s safety and potential efficacy was explored when given as a treatment for patients with MDS following HMA therapy.2 Patients received a median of 3 treatment cycles (range, 2-4), with bone marrow aspirations and biopsies performed at baseline, after cycles 1 and 2, and then every other cycle.
The study involved 7 adult patients with high-risk MDS who had previously undergone HMA therapy, either failing to respond after 4 cycles or relapsing.1 The median age was 77 years (range, 61-83), with 57% male patients. Most patients (71%) were classified as high or very high risk based on IPSS-R or IPSS-M scores. Additionally, 43% had therapy-related MDS, 29% had complex cytogenetics, and 29% harbored TP53 mutations. All patients had received multiple prior treatments, with a median of 4 lines (range, 1-8), and had completed an average of 10 cycles of HMA therapy (range, 2-24).1
The primary end point assessed was safety, including the incidence of DLTs and AEs. Secondary end points consisted of overall response rate according to 2006 International Working Group criteria.
Due to the lack of clinical activity observed during the dose-exploring phase, the trial was eventually terminated. Reasons for treatment discontinuation included disease progression or lack of response (57%), as well as unrelated factors such as allogeneic stem cell transplant (14%) and patient preference for hospice (14%).
Next Steps
While frontline HMA therapies like azacitidine and decitabine remain standard for MDS, patients who become refractory or relapse face limited options. This study’s findings highlight the ongoing need for innovative treatments in high-risk MDS.
Although tapotoclax demonstrated tolerable safety, its limited efficacy suggests that further exploration is needed to enhance treatment outcomes for this patient population.
