Vadastuximab Talirine Shows Early Signs of Efficacy in Patients With AML

Harry P. Erba, MD, PhD

With treatment for newly diagnosed acute myeloid leukemia (AML) remaining essentially unchanged over the last 4 decades, researchers are hopeful that the addition of the investigational agent vadastuximab talirine to standard 7+3 induction therapy may improve survival for these patients.

Early signals of efficacy from a phase Ib study suggest that it might, according to lead investigator Harry P. Erba, MD, PhD, a professor of medicine and director of the UAB Hematology Malignancy Program, who reported the findings during a press briefing at the 2016 ASH Annual Meeting.

Vadastuximab talirine is an antibody drug conjugate (ADC) that works by binding to the CD33 transmembrane receptor expressed in approximately 90% of patients with AML. Erba noted that randomized clinical trials in the United Kingdom and France have shown improved outcomes with the addition of another ADC that binds to the CD33 protein—gemtuzumab ozogamicin (Mylotarg)—to intensive chemotherapy. The agent, currently approved in the US for investigational use only, also demonstrated a lower risk of relapse among children when it was incorporated into their treatment regimen in a study led by the Children’s Oncology Group.

Researchers on this phase Ib study hypothesized that the addition of vadastuximab talirine to 7+3 could induce deeper minimal residual disease (MRD)-negative remissions, leading to reduced relapse rates and improved overall survival. Additionally, previous studies have demonstrated a correlation between better survival and MRD remission after induction.

Forty-two patients have been treated thus far in this ongoing study (NCT02326584) enrolling newly diagnosed patients with AML aged 18-65 years. The median age of patients in the study up to now is 45.5 years with an ECOG performance status of 0-1; 17% of patients had secondary AML, 50% had intermediate-risk karyotypes and 36% adverse karyotypes, which Erba explained is a very important prognostic factor of remission.

Patients received escalating doses of vadastuximab talirine in combination with 7+3 induction (cytarabine 100 mg/m²and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle, and responses were assessed on days 15 and 28. A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine. The primary objectives of the study were to assess safety, tolerability and any early signs of antileukemic activity, Erba said.

The investigators observed no evidence of increased toxicity or mortality with the addition of vadastuximab talirine, and the rates of adverse events (AEs) were similar to what would be expected with standard chemotherapy alone. Erba noted that hematologic events such as neutropenia are expected in AML patients receiving intensive chemotherapy, but the incidence of grade 3/4 hematologic events was no higher than typical in patients receiving the 7+3 regimen alone.

No patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage, although grade ≥3 liver function test abnormalities were observed in 1 patient. The most commonly reported grade 1/2 nonhematologic AEs were nausea (55%), diarrhea (33%), and constipation (31%).

Researchers said the outcomes with vadastuximab talirine were also encouraging from an efficacy standpoint. “Seventy-six percent of patients achieved a response,” Erba reported, with 60% achieving complete remission and 17% achieving remission with incomplete blood count recovery.

Erba said that although a 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, this study offered hints of additional benefit conferred by the investigational agent that warrant further examination in a phase II trial.

“The first hint was that 30 out of the 32 patients required only 1 round of chemotherapy to achieve that remission,” Erba said. “This also suggested that we might be getting deeper remissions.” Additionally, when MRD was assessed utilizing a very sensitive flow cytometric assay, 25 of those 32 complete remissions were actually complete remissions that were MRD-negative. “Going back to our hypothesis, if we can get patients to an MRD-negative state, maybe the outcomes could improve,” he continued.

A randomized phase II trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.

“I think we can safely give vadastuximab talirine in combination with chemotherapy,” said Erba. “The next question to study is whether the agent improves long-term disease-free survival. There’s much reason to be hopeful that such an investigation will have positive results.”

Reference:

Erba HP, Levy MY, Vasu S, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 906.