Tapotoclax (AMG 176) demonstrated a tolerable safety profile and some anti-leukemic activity in patients with high-risk myelodysplastic syndromes (MDS) who had previously been treated with hypomethylating agents (HMAs), according to data from a phase 1 study (NCT05209152) presented at the 2024 EHA Congress. While the study showed no objective responses, it did indicate potential for blast reduction and decreased transfusion dependence, warranting further exploration in combination therapies. The trial was terminated due to lack of clinical activity during the dose-exploring phase of the study.
Study Details and Patient Characteristics
The phase 1 trial enrolled 7 adult patients with high-risk MDS who had either not responded to or relapsed after HMA therapy. The primary endpoint was safety, assessing dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included overall response rate (ORR) according to the 2006 International Working Group (IWG) criteria. Patients received tapotoclax at doses of either 120 mg/m2 (n=3) or 240 mg/m2 (n=4) once per week.
Patients had a median age of 77 years (range, 61-83), with 57% being male. A significant proportion (71%) had high- or very high–risk MDS per IPSS-R or IPSS-M. Additionally, 43% had therapy-related MDS, 29% had complex cytogenetics, and 29% harbored TP53 mutations. The median number of prior lines of therapy was 4 (range, 1-8), and the median number of cycles of prior HMA was 10 (range, 2-24). Notably, 14% of patients had received prior venetoclax.
Clinical Activity and Safety
Although no objective responses were observed among the 7 evaluable patients, 2 of 3 patients with at least 5% bone marrow blasts experienced unsustained blast reduction after at least one cycle of tapotoclax. All patients were transfusion dependent at baseline, and 71% experienced a reduction of at least 2 packed red blood cell units between cycles 1 and 2. One patient (14%) achieved transfusion independence for approximately 7 weeks.
Regarding safety, no DLTs were reported. One patient died due to an infection during cycle 2, but this was deemed unrelated to tapotoclax. Patients received a median of 3 cycles of tapotoclax (range, 2-4). One patient developed arrhythmias, possibly related to tapotoclax, which resolved without dose modifications. Common AEs included nausea (grade 1/2, 71%; grade 3, 14%), fatigue (57%; 0%), and diarrhea (29%; 0%).
Mechanism of Action and Rationale
Tapotoclax is a first-in-class small molecule that selectively inhibits MCL1, disrupting its protein-to-protein interactions within the BCL2 family and inducing apoptosis in MCL1-dependent cancer cells. Current frontline therapies for MDS often include HMAs such as azacitidine and decitabine. However, many patients eventually become refractory to or relapse after HMA treatment, highlighting the need for novel therapeutic approaches.
Expert Commentary
According to lead study author Kelly Chien, MD, assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, "Given [the] manageable toxicity profile and transitory anti-leukemic and transfusion-independent effect, the use of tapotoclax in combination with [an] HMA or other types of therapies may warrant further consideration."
