Amir T. Fathi, MD
Frontline treatment with the CD33-directed antibody-drug conjugate vadastuximab talirine plus a hypomethylating agent (HMA) induced deep and durable remissions for older patients with acute myeloid leukemia (AML), according to data from an ongoing phase I study presented at the 2016 European Hematology Association congress.
In the trial, the combination of vadastuximab talirine and an HMA showed an objective response rate (ORR) of 76%, which included a complete remission (CR) rate of 41%. An additional 30% of patients experienced a CR with incomplete platelet or neutrophil recovery (CRi) making the overall CR/CRi rate of 71%. There were no dose-limiting toxicities reported.
"This high of a remission rate in this traditionally high risk and difficult to treat population is very compelling," said lead investigator Amir T. Fathi, MD, Massachusetts General Hospital Cancer Center. "Response rates were higher and were achieved more quickly than would be expected from historical data with HMA therapy alone. Vadastuximab talirine and HMAs provide a favorable balance of safety, tolerability, and activity among older patients with AML."
Vadastuximab talirine works by binding to the CD33 transmembrane receptor, which is followed by internalization within the cell and the release of the DNA-binding cytotoxic dimer pyrrolobenzodiazepine. In preclinical studies, the antitumor activity of vadastuximab talirine was further enhanced by the addition of an HMA.
In the phase I study, 53 patients with CD33-positive AML were treated with vadastuximab talirine at 10 mcg/kg every 4 weeks along with azacitidine or decitabine at standard doses. A majority of patients were male (64%) and the median age was 75 years (range, 60-87). Although most patients were treatment naive, 9% had received prior low-intensity therapy for myelodysplastic syndrome (MDS).
At the time of enrollment, 36% of patients had adverse cytogenetic risk and 57% were classified as having intermediate risk cytogenetics, according to the Medical Research Council classification system. The median number of bone marrow blasts at baseline was 45.9%. Those who responded could continue to receive vadastuximab talirine until progression. After a median of 15.6 weeks, 51% of patients remained on therapy.
In 49 evaluable patients, the median time to remission was 8 weeks (2 cycles). Minimal residual disease (MRD)-negativity was induced for 42% of those who achieved a CR and for 33% of those with a CRi. Additionally, responses to the combination were similar across HMAs. For those treated with azacitidine, the CR/CRi rate was 71%. With decitabine, the CR/CRi rate was 72%.
Responses were observed in those at the highest risk. The CR/CRi rate was 73% for those with underlying MDS (n = 22). Additionally, in patients with adverse cytogenetics (n = 18), the CR/CRi rate was 83%.
"The high response rate seen with the combination was quite intriguing," said Fathi. "Vadastuximab talirine plus HMA therapy led to a composite remission rate of 71%, the majority of which were complete remissions."
Although still premature, the estimated overall survival (OS) from the first 25 patients enrolled in the study was 12.75 months with the combination. The median relapse-free survival was 7.7 months, with 51% remaining alive at the data cutoff.
"There was a low early mortality rate of 2% at 30 days and 8% and 60 days," said Fathi. "Overall survival data are promising and continue to evolve."
The most frequently observed all-grade treatment-related adverse events (AEs) were fatigue (57%), thrombocytopenia (53%), nausea (49%), febrile neutropenia (45%), constipation (42%), and anemia (42%). The most common grade 3/4 treatment-emergent AEs were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.
"During the course of this study, we determined that the combination of vadastuximab talirine and HMAs was well tolerated," said Fathi. "The most common adverse events were related to on-target effects of the drug, which manifested as low blood counts, or cytopenias. These also included febrile neutropenias. There were few off-target non-hematologic side effects."
Based on the promise of these findings, Seattle Genetics, the company developing the antibody-drug conjugate, launched a pivotal phase III study for older patients with newly diagnosed AML. If positive, results of this study could support a regulatory filing.
"AML is a lethal disease of the bone barrow and blood. It is particularly difficult to treat, with generally poor outcomes for the majority of patients. This is particularly so for older patients, in whom traditional cytotoxic chemotherapy compromises functional status," said Fathi. "This treatment may strike a balance where you can still treat patients in the out-patient setting. They can be home, for the most part, and be surrounded by their family. I do speculate that there will be some positive impact on the patient's quality of life."
The phase III trial, which is known as CASCADE and opened in May 2016, will randomize patients to receive an HMA plus vadastuximab talirine or an HMA and placebo. The primary endpoint of the study will be OS, with secondary endpoints focused on CR/CRi rates and safety. The study plans to enroll 500 patients, with an estimated primary completion date of September 2019 (NCT02785900).
Fathi A, Erba H, Lancet J, et al. SGN-CD33A in combination with hypomethylating agents: a novel, well-tolerated regimen with high remission rate in older patients with AML. Presented at: 21st Congress of the European Hematology Association; Copenhagen, Denmark; June 9-12, 2016. Abstract S503.
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