Blinatumomab Granted Full EU Approval for B-cell Precursor ALL

David M. Reese, MD

The European Commission (EC) has granted blinatumomab (Blincyto) full marketing authorization for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to Amgen, the developer of the anti-CD19 immunotherapy.

The action is based on survival data from the phase III TOWER study, in which the median overall survival (OS) with blinatumomab was 7.7 months versus 4 months with standard chemotherapy for patients with Ph-negative relapsed/refractory B-cell precursor ALL. Treatment with blinatumomab reduced the risk of death by 29% versus standard chemotherapy (HR, 0.71; 95% CI, 0.55-0.93; P = .012).^1,2 Among patients receiving blinatumomab as their first salvage treatment, the median OS was 11.1 versus 5.3 months, respectively (HR, 0.6; 95% CI, 0.39-0.91).

The EC had previously awarded the agent a conditional marketing authorization in this setting in 2015 that was contingent on data from a confirmatory trial. The full approval applies to countries in the EU, as well as Norway, Iceland, and Liechtenstein.

"Blincyto is the first single-agent immunotherapy to demonstrate superior overall survival benefit over standard of care," David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen, said in a statement.

"For decades, overall survival has been the gold standard for assessing the efficacy of treatments for blood cancers. The near doubling of median overall survival versus standard of care seen in the TOWER study is groundbreaking and reinforces Blincyto as a highly effective ALL therapy, providing physicians with a much needed, efficacious treatment option, potentially offering patients the chance to live longer," added Reese.

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

Blinatumomab was administered in 6-week cycles of 4 weeks on (continuous infusion of 9 µg/d in week 1 of cycle 1, then 28 µg/d) and 2 weeks off. Patients received dexamethasone prior to blinatumomab to prevent cytokine release syndrome. If remission was reached following 2 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 blinatumomab was 34% versus 16% with standard chemotherapy (P <.001). The combined CR/CRh/CRi rates were 44% versus 25%, respectively (P <.001). Among the overall population of patients achieving a CR/CRh/CRi, minimal residual disease (MRD)—negative status was achieved by 76% of patients receiving blinatumomab versus 48% of patients receiving standard of care. The 6-month estimated event-free survival rates were 30.7% versus 12.5%, respectively (HR, 0.55; 95% CI, 0.43-0.71).

The OS benefit with blinatumomab 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 blinatumomab (n = 267) or standard chemotherapy (n = 109). Of these patients, 57% and 25%, in the blinatumomab and chemotherapy arms, respectively, started ≥2 cycles.

The adverse event (AE) profile was similar between the 2 arms and consistent with previous studies of blinatumomab. The incidence of all-grade AEs was 99% in both treatment arms. Grade 3 AEs occurred in 37% of the blinatumomab arm and 30% of the standard chemotherapy arm. The rates of grade 4 AEs were 31% and 44%, respectively. Grade 5/fatal AEs occurred in 19% of the blinatumomab arm versus 17% of the chemotherapy arm, including grade 5 infection rates of 11% and 12%, respectively.

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

References

1. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783.
2. Topp MS, Stein A, Nicola Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER). Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract S149.