Blincyto Granted FDA Approval for Leukemia Subset

Blincyto (blinatumomab) was granted full approval by the Food and Drug Administration (FDA) to treat both children and adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), regardless of Philadelphia chromosome (Ph) status, according to the developer of the anti-CD19 immunotherapy, Amgen.

The approval was based on data from the phase 3 TOWER study, in which the median overall survival (OS) with Blincyto was 7.7 versus four months with standard chemotherapy for patients with Ph-negative relapsed/refractory B-cell precursor ALL. Treatment with Blincyto reduced the risk of death by 29 percent versus standard chemotherapy.

The application also contained data from the phase 2 ALCANTARA trial, which demonstrated the efficacy of Blincyto in patients with Ph-positive relapsed/refractory B-cell precursor ALL. The median OS in this single-arm, open-label study was 7.1 months. Sixteen of 45 patients (36 percent) achieved a complete response (CR) or CR with partial hematological recovery (CRh) during the first two cycles of therapy, including four of 10 patients with a T315I mutation. MRD-negative status was achieved by 88 percent of CR/CRh responders.

"For researchers and physicians, overall survival is the primary goal of treatment and the gold standard of outcomes, demonstrating a clear value to patients," TOWER study investigator Anthony Stein, M.D., co-director of the Gehr Family Center for Leukemia Research, City of Hope, said in a statement. "Data from the TOWER study support the use of this single agent bispecific T cell engager immunotherapy, the first to demonstrate superior overall survival in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL, offering a much needed alternative with significantly improved outcomes over standard of care chemotherapy."

The open-label phase 4 TOWER trial randomized 405 patients in a 2-1 ratio to Blincyto (271 patients) or investigator’s choice of one of four standard chemotherapy regimens (134 patients). The median patient age was 37 years in both arms. Other baseline characteristics were also well balanced in the Blincyto versus the standard chemotherapy arm, including median bone marrow blasts (80 percent vs 79 percent), prior salvage therapy (56 percent vs 52 percent) and prior allogeneic stem cell transplant (alloSCT; 35 percent vs 34 percent).

Blincyto was administered in six-week cycles of four weeks on (continuous infusion of 9 µg/d in week 1 of cycle 1, then 28 µg/d) and two weeks off. Patients received dexamethasone prior to Blincyto to prevent cytokine release syndrome. If remission was reached following two induction cycles, patients could receive treatment until relapse. OS was the primary efficacy endpoint. Complete remission (CR) and combined CR, CRh or CR with incomplete hematologic recovery (CRi) were secondary outcome measures.

The CR rate with Blincyto was 34 percent versus 16 percent with standard chemotherapy. The combined CR/CRh/CRi rates were 44 percent versus 25 percent, respectively. Among the overall population of patients achieving a CR/CRh/CRi, minimal residual disease (MRD)—negative status was achieved by 76 percent of patients receiving Blincyto versus 48 percent of patients receiving standard of care. The 6-month estimated event-free survival rates were 30.7 percent versus 12.5 percent, respectively.

The OS benefit with Blincyto was observed across prespecified patient subgroups based on age, prior salvage therapy, or allogenic stem cell transplant. The study was halted early for efficacy based on the recommendation of an independent data monitoring committee.

The safety analysis for TOWER was based on 376 patients who received at least 1 dose of Blincyto (267 patients) or standard chemotherapy (109 patients). Of these patients, 57 percent and 25 percent, in the Blincyto and chemotherapy arms, respectively, started at least two cycles.

The adverse event (AE) profile was similar between the two arms and consistent with previous studies of Blincyto. The incidence of all-grade AEs was 99 percent in both treatment arms. Grade 3 AEs occurred in 37 percent of the Blincyto arm and 30 percent of the standard chemotherapy arm. The rates of grade 4 AEs were 31 percent and 44 percent, respectively. Grade 5/fatal AEs occurred in 19 percent of the Blincyto arm versus 17 percent of the chemotherapy arm, including grade 5 infection rates of 11 percent and 12 percent, respectively.

Grade 3 or higher AEs of interest included neutropenia (38 percent in the Blincyto arm vs 58 percent in the standard chemotherapy arm), infection (34 percent vs 52 percent), neurologic events (9 percent vs 8 percent) and cytokine release syndrome (5 percent vs 0).

"Relapsed or refractory ALL is often a lethal disease, with a median overall survival of just four months on standard of care chemotherapy," Bijal D. Shah, M.D., medical oncologist, Moffitt Cancer Center, said in a statement. "As a physician, my goal is to identify treatments that improve response rates in patients with aggressive hematologic malignancies. Blincyto is an option that has been shown to help these high-risk patients fight their disease."

The FDA initially granted an accelerated approval Blincyto as a treatment for patients with Ph- relapsed/refractory B-precursor ALL in December 2014, based on findings from a phase II trial. Prior to this decision, the agent had received a breakthrough therapy designation. The Blincyto label includes a boxed warning regarding cytokine release syndrome and neurotoxicity. Additionally, the FDA requires completion of a risk evaluation and mitigation strategy (REMS) program prior to use of the anti-CD19 agent.