Single-Agent Vadastuximab Talirine Active, Tolerable in AML

In a first-in-human study of patients with CD33-positive acute myeloid leukemia (AML), treatment with single-agent vadastuximab talirine (a CD33-targeted antibody-drug conjugate) resulted in a complete remission (CR) and CR with incomplete blood count recovery (CRi) rate of 28 percent. Half of patients who responded also achieved minimal residual disease (MRD) negativity.

“Responses were achieved across the spectrum of [patients with] AML, including those with traditionally poor disease risk factors, such as underlying myelodysplasia and adverse-risk cytogenetics,” wrote Eytan M. Stein, MD, of the Memorial Sloan Kettering Cancer Center in New York, and co-authors of the findings, which were published in Blood.

This phase I, dose-escalation study enrolled 131 patients (median age = 73 years; range = 26-89 years) with newly diagnosed or relapsed AML who were recruited from 14 U.S. centers between July 2013 and February 2016. Individuals with central nervous system leukemia were excluded, and antileukemic treatment (other than hydroxyurea) was prohibited within 14 days of starting study treatment.

Half of patients had underlying myelodysplasia, and 58 (44%) had disease that relapsed following a complete or partial response to the most recent therapy; 44 (34%) had refractory disease.

Using a standard 3+3 design, participants received doses ranging from 5 to 60 µg/kg. During the evaluation period for dose-limiting toxicities (DLTs; the first treatment cycle), there were no DLTs observed at the 30 µg/kg dose or in the first three patients treated at the 40 µg/kg dose. One DLT (grade 4 hypocellular marrow) was observed in 18 patients treated with the 40 µg/kg dose in the dose-escalation and -expansion phases. Given the increasing myelosuppression observed at higher doses, the researchers selected 40 µg/kg for the dose-expansion phase, despite no identification of a formal maximum tolerated dose.

Across all cohorts, the 30- and 60-day mortality rates were 8 percent and 27 percent, respectively. Most deaths were considered related to underlying disease.

Among all treated individuals, the most common any-grade and grade >3 adverse events (AEs) included febrile neutropenia, anemia, and thrombocytopenia (see TABLE). Most patients (70%) reported infections, with the most common grade ≥3 infections being lung infection (25%), sepsis (16%), and bacteremia (8%).

Thirty-four people (26%) discontinued treatment because of AEs, and, at the 40 µg/kg dose, 30 percent of doses were delayed because of neutropenia, thrombocytopenia, and febrile neutropenia.

“AEs were primarily related to on-target myelosuppression,” the researchers observed, and non-hematologic DLTs primarily occurred in the cohort of patients whose disease relapsed post-allogeneic hematopoietic cell transplantation (alloHCT).

Among 27 older, treatment-naïve patients (median age = 74 years; range = 67-89 years) who received vadastuximab talirine 40 µg/kg, two experienced DLTs (grade 3 decrease in diffusing capacity of the lungs for carbon monoxide and grade 3 hematuria). The most common AEs were decreased appetite (52%), diarrhea (48%), fatigue (48%), peripheral edema (48%), thrombocytopenia (48%), anemia (44%), dizziness (41%), and febrile neutropenia (41%). No deaths were reported within 30 days of last dose.

Treatment with vadastuximab talirine as monotherapy appeared to have a better safety profile than seen in other trials combining vadastuximab talirine with hypomethylating agents. “The optimal approach to incorporating vadastuximab talirine into a therapeutic strategy for patients with AML has not yet been determined,” Dr. Stein noted. In June 2017, Seattle Genetics, the manufacturer of vadastuximab talirine, suspended all ongoing trials involving the drug amid rising concerns about patient deaths in the phase III CASCADE trial of older patients with newly diagnosed AML.

The median treatment duration was six weeks (range = 2-50 weeks), and 20 patients (15%) remain on vadastuximab talirine in the extension phase; most are receiving vadastuximab talirine 5 µg/kg, the authors reported.

Fourteen patients (11%) went on to receive alloHCT after completing study treatment.

The CR rate (defined as CR+CRi) among all 69 patients in the dose-finding cohorts was 19 percent (CR=13%; CRi=6%). At the recommended monotherapy dose of 40 µg/kg, the CR rate among 18 efficacy-evaluable patients was 28 percent (CR=11%; CRi=17%).

The median time to neutrophil count recovery was 6.4 weeks (range = 3-9 weeks), and the median time to platelet recovery was 10.6 weeks (range = 4-25 weeks). The researchers observed a trend toward increasing blast clearance with increasing dose level: 49 percent of patients cleared marrow blasts at higher dose levels (≥30 µg/kg), compared with 32 percent at lower dose levels (p value not reported). However, the occurrence of grade 3 mucositis and sepsis led researchers to recommend a single 40 µg/kg dose.

When the investigators assessed CD33 expression in 90 bone marrow (BM) samples and 105 peripheral blood (PB) samples, they found that higher expression correlated with the likelihood of achieving blast clearance (odds ratio [OR] for PB = 3.58; 95% CI 1.10-12.6; p=0.040; and OR for BM = 4.50; 95% CI 1.31-17.0; p=0.021), but not with complete remission or MRD negativity.

Inclusion of NPM1 mutation, however, decreased the significance. “Taken together, these data suggest a possible increased potential for achieving blast clearance with higher levels of CD33 expression, but that this effect is closely linked to higher CD33 levels on blasts with NPM1 mutation, a known favorable prognostic marker,” the authors noted.

The study is limited by its small patient population in each subgroup and lack of a comparator arm.

Seattle Genetics funded the study.

The authors report financial support from Seattle Genetics.


Stein EM, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33 positive acute myeloid leukemia (AML). Blood. 2017 December 1. [Epub ahead of print]