FDA Considering Approval Expansion for Blinatumomab in Pediatric ALL

Sean E. Harper, MD

The FDA has received a supplemental biologics license application (sBLA) to expand the approval of blinatumomab (Blincyto) to include pediatric and adolescent patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The sBLA is based on data from a single-arm phase 1/2 trial titled study 205. In the study, blinatumomab induced complete remissions (CR) in a “clinically meaningful number of pediatric patients with relapsed/refractory ALL,” according to the manufacturer of the anti-CD19 immunotherapy, Amgen.

“Children with relapsed or refractory ALL have very poor long-term outcomes and currently there are limited available therapies to induce remission,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen. “We look forward to collaborating with regulatory authorities to make Blincyto available to this ultra-orphan patient population with a high unmet medical need.”

Study 205 is a multicenter, dose-finding, efficacy trial that accrued patients aged <18 years with Ph- B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic HSCT. All patients in the trial have completed therapy and are being observed for long-term outcomes. The data will be submitted for publication, Amgen reported.

The most common serious adverse events (AEs) included pyrexia, febrile neutropenia, cytokine release syndrome, sepsis, device-related infection, overdose, convulsion, respiratory failure, hypoxia, pneumonia, and multiorgan failure. These serious AEs were comparable to those previously reported for blinatumomab.

The FDA granted blinatumomab an accelerated approval in this setting in December 2014, based on phase II data demonstrating strong clinical activity with the agent in adult patients with ALL.

In the pivotal phase II study, the CR rate was 32.4% (95% CI, 25.7-39.7), the CR with partial hematological recovery (CRh) rate was 9.2% (95% CI, 5.4-14.3), and the combined CR/CRh rate was 41.6% (95% CI, 34.4-49.1). Overall, 80% of patients who achieved a CR also responded by minimum residual disease (MRD) testing. Approximately 39% of patients who achieved a CR/CRh went on to receive an HSCT.

The most common all-grade AEs were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). In all, 3 patients experienced treatment-related grade 5 AEs: sepsis (n = 2) and candida infection (n = 1).

Neurological side effects occurred in approximately 50% of patients. Additionally, 11% experienced cytokine release syndrome. To address these side effects, the FDA approved blinatumomab with a Boxed Warning and Risk Evaluation and Mitigation Strategy (REMS).

In February, Amgen reported that the confirmatory phase III TOWER study was halted after an independent panel determined that blinatumomab improved overall survival (OS) versus standard chemotherapy in patients with Ph- relapsed/refractory B-cell precursor ALL.

The open-label phase III TOWER trial randomized patients in a 2:1 ratio to blinatumomab or investigator&rsquo;s choice of 1 of 4 standard chemotherapy regimens. The primary endpoint was OS. Secondary endpoints included CR, duration of CR, patients achieving remission with MRD, and safety. The data from TOWER will be presented at an upcoming scientific meeting, Amgen reported.