Besponsa Gains FDA Approval to Treat Acute Lymphoblastic Leukemia

Richard Pazdur, MD

Besponsa (inotuzumab ozogamicin) was granted FDA approval for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) after a phase 3 trial -- INO-VATE — proved the drug to be beneficia.

It should be noted, the approval comes with a boxed warning for hepatotoxicity and warning of an increased risk of death following certain types of stem cell transplant.

In the phase 3 study, 326 patients were enrolled, with the approval based on data from the first 218 selected for the primary analysis. At this analysis, the complete remission (CR) rate was 35.8 percent in the Besponsa compared with 17.4 percent with chemotherapy. Of those who achieved a CR, 89.7 percent in the Besponsa were minimal residual disease (MRD)-negative versus 31.6 percent with chemotherapy.

“For adult patients with B-cell ALL whose cancer has not responded to initial treatment or has returned after treatment, life expectancy is typically low,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “These patients have few treatments available and today’s approval provides a new, targeted treatment option.”

Besponsa is composed of a humanized IgG4 anti-CD22 antibody covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazide (CalichDMH). Upon binding to B cell-specific CD22 receptors, the drug is internalized causing the release of CalichDMH within the cell. The cytotoxic agent CalichDMH causes double-strand DNA breaks and apoptosis.

In the phase 3 study, 326 patients were enrolled, with the first 218 selected for the primary analysis. One hundred and nine patients received Besponsa at a starting dose of 1.8 mg/m2 each cycle, which consisted of a 0.8 mg/m² dose on day one followed by 0.5 mg/m² on day eight and day 15, which is the FDA recommended dose. In the chemotherapy arm, 109 patients received physicians’ choice of fludarabine plus cytarabine with G-CSF, high-dose cytarabine or cytarabine plus mitoxantrone.

The study was designed to assess response from the first 218 patients, with overall survival (OS) being analyzed in all 326 individuals. During this review, the risk of progression or death was reduced by 55 percent with Besponsa versus standard therapy. OS was improved with Besponsa versus chemotherapy; however, this improvement was not statistically significant.

The most common adverse reactions occurring in greater than 20 percent of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased and hyperbilirubinemia. The most common (more than 2 percent) adverse reactions reported as the reason for permanent discontinuation were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased and hemorrhage.