Vadastuximab talirine induces modest benefit for acute myeloid leukemia

The addition of vadastuximab talirine to a hypomethylating agent led to a high complete remission rate among older patients with CD33-positive acute myeloid leukemia, according to a phase 1 study.

However, the combination therapy led to more hematologic toxicities than historical data for hypomethylating agent monotherapy.

“Outcomes for patients with AML remain poor, particularly in older patients who are more likely to have adverse disease features and may not be candidates for aggressive induction and consolidative approaches including stem cell transplant,” Amir T. Fathi, MD, assistant professor of medicine at Massachusetts General Hospital Cancer Center and Harvard Medical School, and colleagues wrote. “Hypomethylating agents, decitabine or 5-azacitidine, are now increasingly used in this population as lower intensity therapy but are associated with low rates of remission.

“The development of novel, well-tolerated therapies to enhance the efficacy of hypomethylating agents could meaningfully improve the standard of care for older patients with AML,” they added.

Fathi and colleagues assessed the combination of vadastuximab talirine (SGN-CD33A, Seattle Genetics) — a CD33-targeted antibody-drug conjugate — and azacitidine or decitabine among 53 patients (median age, 75 years) with AML. Exclusion criteria included previous treatment with hypomethylating agents. However, prior low-intensity treatment was allowed.

Thirty-eight percent of patients had adverse cytogenic risk and 62% had intermediate risk. Forty-five percent of patients had secondary AML.

Patients received IV 10 g/kg vadastuximab talirine on the last day of hypomethylating agent infusion in 4-week cycles.

Median treatment duration was 19.3 weeks

Researchers observed a 30-day mortality rate of 2% and a 60-day mortality rate of 8%.

The complete remission rate, which included complete remission with incomplete blood count recovery, was 70%. Researchers observed 51% of remissions were minimal residual disease negative on flow cytometry.

Researchers noted high complete remission rates persisted among patients with secondary AML (75%), those aged 75 years or older (62%), and those with adverse cytogenic risk (80%).

Median RFS was 7.7 months (95% CI, 4.9-15.4) and median OS was 11.3 months (95% CI, 8.8-13.2).

Researcher did not observe any dose-limiting toxicities or infusion related reactions.

The most common treatment-related adverse events included fatigue (62%), thrombocytopenia (62%), nausea (53%), anemia (49%), febrile neutropenia (49%), constipation (47%), decreased appetite (45%), neutropenia (45%), peripheral edema (42%), dyspnea (34%), pyrexia (32%), diarrhea (28%), dizziness (28%), vomiting (28%), hypotension (25%), cough (23%), headache (21%) and insomnia (21%).

Fifty-seven percent of patients experiencing grade 3 or higher thrombocytopenia.

Researchers observed no grade 3 or higher bleeding events. The most common bleeding events of any grade included epistaxis (19%), contusion (11%) and petechiae (11%).

Infections of any grade occurred among 79% of patients, including grade 3 or higher lung infections (34%), sepsis (11%) and bacteremia (11%).

The safety profile appeared similar regardless of whether patients received azacitidine or decitabine, except for febrile neutropenia, which occurred among 23% of patients treated with azacitidine compared with 59% of those treated with decitabine.

Adverse events delayed 43% of all doses of vadastuximab talirine.

Following the results of this phase 1 trial, researchers launched the global, randomized, placebo-controlled phase 3 CASCADE trial of vadastuximab talirine with hypomethylating agents compared with hypomethylating agents alone. However, the trial was terminated early due to increased deaths on the combination arm.

“Though the data from the CASCADE trial remain under analysis, lack of success on the phase 3 study may demonstrate the difficulties inherent in translating promising phase 1 results to a much larger, global study of an older population of hypomethylating agent-eligible AML patients who are more susceptible to toxicity,” the researchers wrote.

“Future studies with myelosuppressive novel agents in this population, many of whom develop potentially lethal cytopenias, may require more strict protocol-defined guidelines for supportive care and monitoring, including criteria for hospitalization, which would include clinical developments such as fever, severe or progressive bleeding, progressive dyspnea or hypoxia among others, as well as mandated use of prophylactic antimicrobials,” they added. – by Cassie Homer

Disclosures: Seattle Genetics funded the study. Fathi reports consultant and steering committee roles with Seattle Genetics. Please see the study for all other authors’ relevant financial disclosures.