Inotuzumab Ozogamicin Improves Response Rates Versus Chemotherapy in Phase III ALL Study

Mace Rothenberg, MD

Treatment with the antibody-drug conjugate inotuzumab ozogamicin significantly extended complete hematologic remission rates compared with chemotherapy for adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL), according to findings from the phase III INO-VATE ALL study. Pfizer, the developer of the drug, plans to continue the trial, to allow overall survival (OS) data to reach maturity.

“We are excited about the results of the INO-VATE ALL study especially since relapsed and refractory acute lymphoblastic leukemia is a particularly difficult disease to treat in adults. The top-line results show that inotuzumab ozogamicin has the potential to be an important new treatment option for patients with relapsed or refractory disease,” Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, said in a statement. “We look forward to discussing these data with the FDA and other regulatory authorities.”

The open-label phase III study enrolled 326 patients with relapsed or refractory CD22-positive ALL. Patients in the inotuzumab ozogamicin arm received intravenous treatment at 0.8-0.5 mg/m² once weekly for 3 weeks in a 21 to 28 day cycle for up to 6 cycles. In the chemotherapy arm, patients received fludarabine plus cytarabine and G-CSF, high-dose cytarabine, or cytarabine plus mitoxantrone.

The two primary endpoints of the study were OS and complete response (CR) or CR with incomplete platelet recovery (CRi). Secondary outcome measures included progression-free survival (PFS), duration of response, rate of stem-cell transplantation, and minimal residual disease.

In a preceding phase II study, 49 patients with CD22-positive relapsed/refractory ALL were treated with 1.3 to 1.8 mg/m² of inotuzumab ozogamicin every 3 to 4 weeks.¹ After promising results were demonstrated, an additional 41 patients were enrolled at a modified 0.8 mg/m² weekly dose or at a 0.5 mg/m² dose on days 8 and 15 of each cycle.

In the first 49 patients, 18% experienced a CR and 39% had a bone marrow CR for an overall response rate (ORR) of 57%. Two patients died within 4 weeks of starting treatment.

In the full 90-patient analysis, the ORR was 58%. The CR rate was 19%, the CRi rate was 30%, and the bone marrow CR rate was 9%. The median OS was 6.2 months. In the weekly dose arm, the median OS was 7.3 months. The median remission duration was 7 months. Overall, 40% of patients were able to undergo allogeneic stem cell transplantation.

The most common all-grade adverse events with inotuzumab ozogamicin were fever, hypotension, and liver-related toxicity. In the phase III study, no new or unexpected adverse events were reported. Pfizer announced plans to submit data from the investigation for presentation at an upcoming medical meeting.

Inotuzumab ozogamicin is a CD22-targeted antibody-drug conjugate 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 May 2013, a phase III study exploring inotuzumab ozogamicin as a treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) was stopped early due to futility.

In this study, inotuzumab ozogamicin was administered on a once-a-month schedule in combination with rituximab compared with investigator's choice of bendamustine plus rituximab or gemcitabine plus rituximab. During an interim analysis, an independent data monitoring committee determined that inotuzumab ozogamicin plus rituximab would not meet the primary endpoint of improving OS.

“Hematologic cancers are a complex group of diseases, with more than 70 different types of lymphomas, leukemias, or myelomas that require unique treatment options. We remain committed to evaluating inotuzumab ozogamicin in patients with hematologic malignancies,” Rothenberg said, when the NHL study was halted.

Results from a study presented at the 2014 ASH Annual Meeting of older patients with ALL showed promising findings for frontline therapy with inotuzumab ozogamicin and mini-hyper CVD.² In the 27-patient study, the CR/CRi rate was 96%. The 1-year PFS and OS rates were 81% and 78%, respectively.

In a second study presented at ASH, weekly inotuzumab ozogamicin demonstrated a CR/CRi rate of 65.7% as monotherapy in 35 adult patients with relapsed/refractory ALL.³ The median OS was 7.4 months. Common grade ≥3 adverse events included thrombocytopenia (34%), neutropenia (20%), and febrile neutropenia (20%).

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).

References

1. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013; 119(15):2728-36.
2. Jabbour E, O'Brien S, Thomas DA, et al. Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Frontline Therapy for Older Patients (≥60 years) with Acute Lymphoblastic Leukemia (ALL). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 794.
3. Advani AS, Stein AS, Kantarjian HM, et al. A Phase II Study of Weekly Inotuzumab Ozogamicin (InO) in Adult Patients with CD22-Positive Acute Lymphoblastic Leukemia (ALL) in Second or Later Salvage. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 2255.