Inotuzumab Ozogamicin Shows High MRD-negative CR Rate in ALL

Daniel J. DeAngelo, MD, PhD

Treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin demonstrated a complete response (CR) or CR with incomplete platelet recovery (CRi) rate of 80.7% in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), according to findings from a phase III study presented at the 20th Congress of the European Hematology Association (EHA).

In the trial, inotuzumab ozogamicin was compared with standard chemotherapy. The dual primary endpoint was CR/CRi and overall survival (OS). In the chemotherapy arm, the CR/CRi rate was 33.3%, representing more than a doubling in response with inotuzumab ozogamicin (P <.0001). In patients who achieved a CR/CRi, 78.4% were minimal residual disease (MRD)-negative (<0.01% cells by central flow cytometry). OS data were not yet mature at the time of the analysis.

“The results of a large global phase III study have demonstrated that inotuzumab ozogamicin was superior to standard chemotherapy in patients with relapsed acute lymphoblastic leukemia,” lead investigator Daniel J. DeAngelo, MD, PhD, director of Clinical and Translational Research, Adult Leukemia, Institute Physician at the Dana-Farber Cancer Institute, told OncLive. “Inotuzumab ozogamicin showed a higher overall response rate as well as a higher rate of achieving an MRD-negative status.”

In the open-label phase III study, 326 patients were enrolled, with the first 218 selected for the primary analysis that was presented at EHA. For this analysis, 109 patients received inotuzumab ozogamicin at a starting dose of 1.8 mg/m² each cycle, which consisted of a 0.8 mg/m² dose on day 1 followed by 0.5 mg/m² on day 8 and day 15. 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 OS being analyzed in all 326 individuals. Secondary endpoints included duration of remission (DOR), MRD-negativity in those with CR/CRi, and stem cell transplantation (SCT) rate.

In the analysis presented at EHA, the majority of the patients in the investigational arm were under the age of 55 (61%). The clinical trial represented the first salvage therapy for 67% of patients in the inotuzumab ozogamicin arm versus 63% in the comparator. All patients enrolled in the phase III study were CD22-positive, which is expressed in the majority of patients with B-cell ALL.

For patients who were receiving their first salvage therapy, the CR/CRi rate was 87.7% with inotuzumab ozogamicin versus 31.3% with chemotherapy (P <.0001). In the second salvage therapy setting, the CR/CRi rate with inotuzumab ozogamicin was 66.7% versus 37.9% with chemotherapy (P = .0104). In complete responders, MRD-negativity was achieved in 78.4% versus 28.1%, with inotuzumab ozogamicin and chemotherapy, respectively (P <.0001).

The duration of first complete remission was ≥12 months in 43% of patients treated with inotuzumab ozogamicin compared with 35% in the chemotherapy arm. The median DOR was 4.6 months with inotuzumab ozogamicin compared with 3.1 months for chemotherapy (P = .0169).

"Although the analysis is ongoing as we wait for the overall survival data, hopefully this study will translate into improved options for patients with relapsed ALL," DeAngelo said.

Side effects were assessed in 259 patients from the full study population. This analysis consisted of those who received ≥1 dose of inotuzumab ozogamicin (n = 139) or chemotherapy (n = 120). The median duration of treatment in the inotuzumab ozogamicin arm was 8.3 weeks versus 0.9 weeks with chemotherapy.

Eighty-three percent of patients in the inotuzumab ozogamicin arm discontinued treatment over the course of the study versus 89% in the chemotherapy arm. The most common cause of discontinuation in the inotuzumab ozogamicin arm was CR (35%) compared with resistant disease in the chemotherapy arm (40%). The number of patients receiving SCT was doubled in the inotuzumab ozogamicin arm (n = 48) compared with chemotherapy (n = 20).

The most frequently observed grade ≥3 adverse events (AEs) in both arms were hematologic cytopenias. Grade ≥3 hepatobiliary AEs were seen in 9% of patients treated with inotuzumab ozogamicin versus 3% with chemotherapy. All grade veno-occlusive liver disease (VOD) occurred in 15 patients (13 were grade ≥3) in the inotuzumab ozogamicin arm versus 1 in the chemotherapy arm. The majority of VOD cases were seen after SCT (n = 10). In total, there were 2 deaths associated with VOD in the inotuzumab ozogamicin arm.

Analysis of the phase III study remains ongoing. Based on the initial assessment of the trial, Pfizer, the company developing the drug, has entered into discussions with the FDA and other regulatory authorities.

"We are currently in discussions with regulatory authorities to determine how to bring this important new therapy to patients as soon as possible," Mark Shapiro, MD, PhD, Global Medical Affairs Lead, Hematology Programs at Pfizer, told OncLive.

Inotuzumab ozogamicin 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.

Clinical trials continue to assess inotuzumab ozogamicin as a treatment for patients with hematologic malignancies. A phase I/II study is looking at the drug as a treatment for elderly patients with ALL (NCT01371630). Additionally, another phase I/II study is exploring the agent in patients with CD22-positive lymphoid malignancies (NCT01664910).

DeAngelo DJ, Stelljes M, Martinelli G, et al. Efficacy and safety of inotuzumab ozogamicin (InO) vs standard of care (SOC) in salvage 1 or 2 patients with acute lymphoblastic leukemia (ALL): an ongoing global phase 3 study. Presented at: 20th Congress of the European Hematology Association (EHA); Sunday, June 14, 2015; Vienna, Austria. Abstract #LB2073.