FDA Grants Inotuzumab Ozogamicin Priority Review for ALL

Mace Rothenberg, MD

The FDA has granted a priority review designation to the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia (ALL), based on findings from the phase III INO-VATE trial.

Under the priority review program, the FDA will decide on the biologics license application for inotuzumab ozogamicin within 6 months compared with the standard 10-month review. The accelerated review timeline follows a breakthrough therapy designation for ALL received by inotuzumab ozogamicin in October 2015. Under the Prescription Drug User Fee Act (PDUFA), the FDA will make its decision on the application in August 2017.

“ALL that has recurred after, or is refractory to, first-line therapy is a rapidly progressing and deadly disease,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, the developer of the drug, said in a statement. “Based on the positive results of the INO-VATE 1022 phase III trial, we believe inotuzumab ozogamicin, if approved, represents a new treatment option for adult patients with relapsed or refractory B-cell precursor ALL.”

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.

A prior antibody-drug conjugate from Pfizer that included ozogamicin—gemtuzumab ozogamicin (Mylotarg)—was approved for acute myeloid leukemia and was subsequently withdrawn from the US market after the agent failed to show clinical benefit in confirmatory clinical trials. This agent was initially approved under the FDA's accelerated review program based on a surrogate endpoint. It was withdrawn in 2010. Pfizer is hopeful that a similar fate does not await inotuzumab ozogamicin.

In the open-label phase III trial that was instrumental in the priority review, the risk of progression or death was reduced by 55% with inotuzumab ozogamicin versus standard therapy (HR, 0.45; 97.5% CI, 0.43-0.61; P <.001). Overall survival was improved with inotuzumab ozogamicin versus chemotherapy; however, this improvement was not statistically significant (HR, 0.77; 97.5% CI, 0.58-1.03; P = .04).

Most of the patients in the investigational arm were under the age of 55 years (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 most patients with B-cell ALL.

Inotuzumab ozogamicin demonstrated a complete response (CR) or CR with incomplete platelet recovery (CRi) rate of 80.7% versus 29.4% with chemotherapy (P <.001). In those who achieved a CR/CRi, 78.4% were minimal residual disease (MRD)-negative with inotuzumab ozogamicin versus 28.1% for chemotherapy (P <.001).

For patients who were receiving their first salvage therapy, the CR/CRi rate was 87.7% with inotuzumab ozogamicin versus 28.8% with chemotherapy (P <.001). In the second salvage therapy setting, the CR/CRi rate with inotuzumab ozogamicin was 66.7% versus 30.6% with chemotherapy (P = .002).

Adverse events (AEs) 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 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. Most VOD cases were seen after SCT (n = 10). In total, there were 2 deaths associated with VOD in the inotuzumab ozogamicin arm.

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).

Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med. 2016;375:740-753.

In the phase III study, 326 patients were enrolled, with the first 218 selected for the primary analysis. One hundred and nine 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.