APVO436 Achieves Anti-Neoplastic Activity With Tolerable Safety in R/R AML/MDS

APVO436 appears to be safe and effective for the treatment of acute myeloid leukemia or myelodysplastic syndrome.

Phase 1 results show that patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) had favorable survival and responses to the investigational bispecific antibody APVO436, and the agent demonstrated was tolerable according to updated findings from an ongoing phase 1 trial (NCT03647800) presented during the ASH Annual Meeting and Exposition 2021.

Regarding safety, APVO436 was found to have an acceptable tolerability profile with manageable adverse effects (AEs) in patients with AML/MDS. The most common grade 3 or higher AEs observed that were suspected to be related to APVO436 included cytokine release syndrome (CRS; n = 4/46; 8.7%), anemia (n = 2/26; 4.3%), and infusion-related reactions (n = 2/26; 4.3%). No hematologic dose-limiting toxicities (DLTs) were observed with ABVO436 across cohorts.

Serious AEs (SAEs) were observed in 28.3% of patients (n = 13/46); 15.2% (n = 7/13) of these were from CRS and 6.5% (n = 3/17) were from infusion-related reactions. The remaining 3 SAEs included one case each of sepsis, which was possibly related to ABVO436, generalized weakness, and grade 1 neurotoxicity. These events resolved within 5 days, 28 days, and 2 days, respectively.

Notably, regarding efficacy, the median overall survival (OS) was 338.5 days among the 8 patients who obtained favorable responses compared with 100 days for nonresponders (n = 31; log-rank, 5.298; P = .0213). Across all patients (n = 39), the median OS was 178 days.

“The off-the-shelf availability of APVO436 combined with its single-agent, anti-leukemic activity, favorable safety profile, ease of administration not requiring continuous infusion but weekly short infusions that can be administered in out-patient settings makes it an attractive option as a bispecific T-cell engager [BiTE] against AML,” lead study author Justin M. Watts, MD, an associate professor of medicine in the Division of Hematology and chief of the Leukemia Section of the Sylvester Comprehensive Cancer Center of the University of Miami Health System, and coauthors wrote in the poster.

APVO436 is a humanized, glycosylated homodimeric bispecific antibody targeted against CD123 CD3ε. The agent is comprised of 2 binding domain sets linked to a human immunoglobulin G1 Fc domain.

“APVO436 is a CD3/CD123-targeted BiTE antibody that brings cytotoxic T lymphocytes [CTLs] into proximity with CD123-expressing AML blasts and leukemic stem cells to allow for increased CTL-mediated cell killing,” said Watts in a presentation of the data.

The phase 1b dose-escalation study utilized a 3+3 design to evaluate multiple doses of APVO436 in patients with relapsed/refractory AML and high-risk MDS.

Overall, the study screened 58 patients with relapsed/refractory AML and MDS. Of these patients, 12 failed screening and the remaining 46 patients were deemed eligible for enrollment to the trial. Patients were enrolled 7 to 39 days following documentation of progressive leukemia or leukemic relapse.

Patients in cohort 1 were started on a 0.3-mcg dose of APVO436, which equated to approximately 0.005 mcg/kg for a patient weighing 60 kg. Moreover, this dose was the Minimum Anticipated Biological Effect Level of APVO436 based on T-cell activation assays.

Cohorts were assigned weekly target dose levels of 1 mcg, 3 mcg, 9 mcg, 18 mcg, 12 mcg, 24 mcg, 36 mcg, 48 mcg, and 60 mcg, respectively.

The maximum tolerated dose was not reached at a weekly flat dose of 60 mcg (cohort 10; n = 4). All patients in cohort 10 tolerated APVO436 and no DLTs or grade 3 or 4 AEs were observed.

The recommended phase 2 dose (RP2D), which served as the primary end point of the study, was identified at 18 mcg as a single, flat dose. This dose level, which was given to cohort 6 and equated to approximately 0.2 mcg/kg based on the body weight of the patients enrolled, comprised 30% of the dose level given to patients in cohort 10.

The cumulative incidence of grade 3 or 4 AEs and SAEs, and the incidence of AEs of interest (≥grade 2: CRS, infusion-related reactions, cardiac toxicity, and neurotoxicity as complications of CRS) were also evaluated. Efficacy served as the secondary end point and included the incidence of composite complete responses (CRs) and the incidence of patients who are able to achieve minimal residual disease–negative CRs and undergo hematopoietic stem cell transplant as post-protocol therapy.

Patients were a median age of 69 years (range, 18-82) and most were White (73.9%) males (52.2%). Regarding diagnosis, 84.8% of patients had AML, including primary AML (56.5%), secondary AML (19.6%), or treatment-related AML (8.7%). The remaining 15.2% of patients had MDS. Patients received a median of 2.5 prior lines of chemotherapy (range, 1-8); 34.8% of patients received 4 or more prior lines.

Patients received a median of 7 APVO436 treatments (standard error, 11±2).

Further safety findings showed that transient neurotoxicity related to APVO436 occurred in 10.9% of patients (n = 5/46). The onset of symptoms occurred during cycle 1 in 4 patients and cycle 8 in 1 patient. Mild, grade 1 symptoms, including headache, tremor, dizziness, lethargy, insomnia, memory loss, and confusion, were observed.

One patient in cohort 7 experienced grade 3 confusion on the first day of treatment; the AE was resolved within 1 day.

Moreover, the incidence of neurotoxicity was not found to be dose-dependent, or predicted by gender, race, age, absolute lymphocyte count, or percentage of lymphocytes in peripheral blood.

Neurotoxicity occurred in 3 patients who did not develop CRS; 7 patients who developed CRS did not experience neurotoxicity.

One grade 5 event of fatal acute renal failure occurred in 1 patient who initially developed grade 2 CRS.

Further efficacy findings revealed that, among responders, the median time to progression was 177 days (range, 87-238). One of 8 responders had clearance of peripheral blasts with a more than 50% decrease in bone marrow blast percentage.

Of 34 of 39 evaluable patients, 64.7% (n = 22) achieved stable disease (SD) as their best overall response with ABVO436. Of responders, 8 patients (23.5%) achieved SD within 31 to 75 days after study entry, and disease stability lasted for more than 3 months; 7 patients had progression on 2 to 4 prior lines of anti-AML therapy.

Two patients with primary AML, more than 25% bone marrow blasts, and unfavorable cytogenetics and/or adverse risk group genomic mutations achieved a partial response (PR) at 58 days and 75 days, respectively. These PRs deepened into complete responses (CRs) with full hematologic recovery at 92 days and 113 days, respectively.

The first patient achieved a CR with full hematologic recovery on day 1 of cycle 5. They relapsed 85 days later but continued to have SD until cycle 10 of treatment. The second patient was in a CR on day 1 of cycle 5 but relapsed 57 days later.

Of the 7 patients with MDS enrolled, 6 patients were evaluated for response. All patients had SD without a significant hematological improvement as their best overall response.

The time to progression among patients with MDS was 104 days, more than 106 days, 138 days, more than 147 days, 211 days, and 321 days. Moreover, 3 patients obtained a bone marrow CR with ABVO346.

“In the open-label, multi-center, dose-expansion phase of the study, we will evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities,” Watts and coauthors concluded.


Watts JM, Lin TL, Mims AS, et al. Tolerability and single agent anti-neoplastic activity of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory AML or MDS. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Poster 3415