Updated Results from a Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML

Background

Leukemic stem cells have high expression of CD123 compared to normal hematopoietic stem cells. CD123 is therefore an attractive therapeutic target in myeloid neoplasms including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Vibecotamab is a CD3-CD123 bispecific engaging antibody with clinical activity in relapsed/refractory AML, particularly in low-blast disease. We therefore sought to evaluate vibecotamab in other low-blast states: MDS or CMML after hypomethylating agent (HMA) failure and MRD-positive AML.

Methods

In this phase II study, adults with MDS (IPSS-R intermediate or higher risk) or CMML (CMML-1 or CMML-2) after HMA failure or AML in first or second morphologic remission with MRD at a level of ≥0.1% by flow cytometry were eligible. CD123 expression ≥20% on aberrant myeloid blasts was required. Vibecotamab was given IV in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7µg/kg. Patients (pts) received up to 4 cycles of vibecotamab in 28-day cycles. The primary endpoints were response rate (CR + mCR + PR + HI + clinical benefit) in the MDS/CMML cohort and MRD negativity rate (sensitivity: 0.01%) in the AML MRD cohort.

Results

Between 5/2022 and 3/2024, 37 pts were treated (19 MDS/CMML, 18 AML MRD).

In the MDS/CMML cohort (16 MDS, 3 CMML), 9 pts (47%) received ≥2 prior lines of therapy, 11 pts (58%) had prior venetoclax exposure, and 2 pts (11%) had prior stem cell transplant (SCT). 11 MDS pts (69%) were IPSS-R high or very high risk. The median percentage of blasts expressing CD123 was 78% (range, 40%-99%).

Of the 19 MDS/CMML pts, 13 responded (68%), with 12 (63%) achieving marrow complete remission (mCR) and 1 (5%) achieving hematologic improvement (HI) per IWG 2006 criteria. Among the 16 MDS pts, 9 (56%) achieved mCR, 4 of whom (31%) also achieved HI, and 1 (6%) achieved HI only. Per revised IWG 2023 MDS criteria, 9/16 MDS pts (56%) achieved CR with limited count recovery (CR_L). 4/8 MDS pts (50%) with TP53 mutations achieved CR_L. All 3 CMML pts achieved mCR, 2 of whom also achieved HI. Among 17 pts with baseline bone marrow blasts ≥5% at enrollment, 12 (71%) achieved mCR, with or without HI. Best response occurred after the first cycle in all pts. The degree of CD123 expression was not associated with likelihood of response. Of the 13 responders, 2 are in ongoing response (6.4 and 11.4 months), 3 died in CR_L, and 8 relapsed. 6 of 8 (75%) relapses occurred after completion of intended protocol therapy. Among responders, the median duration of response was 5.2 months and the overall survival was 10.3 months.

In the AML MRD cohort, 9 pts (50%) received ≥2 prior lines of therapy, 15 pts (83%) had prior venetoclax, and 7 pts (39%) had prior SCT. 14 pts (78%) were ELN 2022 adverse risk. The median percentage of blasts expressing CD123 was 84% (range, 49%-99%), and the baseline MRD was 0.8% (range, 0.1%-3.9%).

Of the 18 AML MRD pts, 5 (28%) achieved MRD negativity, all of which occurred after 1 cycle. Among the 5 responders, 4 were ELN adverse risk, 4 had prior venetoclax, 3 had prior SCT, 1 had TP53 mutation, and 1 had inv(3).The median MRD in responders was 0.2% (range 0.1%-1.0%) vs 1.4% (range 0.3%-3.9%) in non-responders (P=0.009). The degree of CD123 expression was not associated with likelihood of response. At last follow-up, 2 responders relapsed following completion of protocol therapy (1.2 and 5.6 months after completion) and 3 are still in MRD-negative remission (durations of responses: 4.1, 24.6 and 25.6 months).

Vibecotamab was well-tolerated with no pts requiring dose reductions or taken off study due to adverse events. The most common related adverse event was infusion reactions: grade 1 in 1 pt (3%), grade 2 in 22 pts (60%), and grade 3 in 2 pts (5%). Myelosuppression was minimal, consistent with previous studies of vibecotamab.

Conclusion

Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 68% in MDS/CMML after HMA failure and 27% in MRD-positive AML. Across both cohorts, 8 of the 10 relapses occurred after completion of protocol therapy. The protocol has now been amended for vibecotamab to be given indefinitely to responders. The clinical activity of vibecotamab, including in high-risk pts and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.