Early promising results for antibody-drug conjugate delivered with hypomethylating agents.

Older adults who are newly diagnosed with acute myeloid leukemia (AML) are often not sufficiently fit to withstand the rigors of remission induction therapy with cytarabine and an anthracycline such as daunorubicin or idarubicin. Other patients may decline to have intensive therapy due to frailty or concerns about toxicities. For these patients, clinicians in the United States often prescribe lower-intensity therapy with the hypomethylating agents decitabine and/or azacitdine, but these agents are both associated with low response rates and limited clinical benefits, according to treatment information from theNational Cancer Institute.

However, an investigational therapy consisting of a conjugated monoclonal antibody combined with hypomethylating agents (HMAs) has been shown in early clinical trials to induce high complete or near-complete remission rates in older adults with AML.

At the 2016 annual congress of the European Hematology Association, Amir T. Fathi, MD, from Massachusetts General Hospital Cancer Center in Boston, reported data from a phase I study of older adults with AML who were treated with a combination of the monoclonal antibody drug conjugate vadastuximab talirine (33A; Seattle Genetics) and either azacitdine or decitabine.

Among 49 patients evaluable for efficacy, the combined rate of complete remissions (CR) or CR with incomplete recovery of counts (CRi) was 71%.

“The high remission rate in this traditionally high-risk group and difficult-to-treat population is very compelling,” Fathi said. “Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone.”

Target: CD33

33A is a highly potent antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells. The agent is targeted to CD33 receptors that are expressed on leukemic blasts in nearly all cases of AML. The antibody is conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding to the receptors, the conjugate is internalized and transported to cellular lysosomes where the PBD dimer is released via proteolytic cleavage of the linker, resulting in a crosslinking of DNA, and leading to cell death.

The cell-killing activity of this agent had been shown in preclinical studies to be enhanced when delivered in combination with hypomethylating therapy, Fathi noted.

For the phase I trial, the combination of 33A and a hypomethylating agent was tested in 53 adults with a median age of 75. The patients all had CD33-positive AML, and all had declined to undergo an intensive chemotherapy induction regimen. Five patients had previously received low-intensity therapy for myelodysplastic syndromes, and the remaining 48 patients had not received any prior therapy for AML.

Enrollment criteria included an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Nineteen of the patients had adverse cytogenetic-risk disease, and 30 had intermediate-risk disease.

The patients received 33A in intravenous infusions of 10 mcg/kg delivered in an outpatient setting every 4 weeks on the last day of a hypomethylating therapy regimen — either azacitidine at 75 mg/m² for 7 days, or decitabine at 20 mg/m² for 5 days. Patients who had clinical benefit could be continued on treatment until disease relapse or unacceptable toxicity.

Responses were assessed by investigators according to the International Working Groupfor Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (IWG). CRi was defined as either a platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL.

The combined CR/CRi rate among the 49 patients evaluable for response at the time of data cutoff was 71%, with no difference in the rate of complete or near-complete remissions between patients treated with azacitidine or decitabine.

The overall response rate (CR, CRi, and partial responses) was 76%. Encouragingly, Fathi said, many higher-risk patients had responses, including 15 of 18 patients with adverse cytogenetics, and 16 of 22 with underlying myelodysplasia.

Eight of the 19 patients who had a CR met the criteria for minimal residual disease, as did 5 of 15 who achieved a CRi.

The overall survival results were ongoing at the time of the presentation. After a median follow-up of 12.58 months, the estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months; and as of the most recent follow-up, 27 were alive and remained on study.

The median relapse-free survival was 7.7 months; 30- and 60-day mortality rates were 2% and 8%, respectively. There were no treatment-related deaths reported.

Safety Profile

Patients generally tolerated the therapy well, Fathi said. Grade 3 or greater adverse events reported in at least 20% of patients included, in order of frequency, febrile neutropenia (47% of patients), thrombocytopenia (42%), anemia (34%), and neutropenia (28%).

Other common treatment-emergent adverse events were fatigue, nausea, constipation, decreased appetite, and peripheral edema.

Fathi noted that a phase III trial to evaluate 33A in combination with hypomethylating agents in previously untreated older AML patients is now open for enrollment.