FDA Grants Priority Review to sBLA for Full Approval of Blinatumomab in ALL

Sean E. Harper, MD

The FDA has granted a priority review to a supplemental biologics license application (sBLA) supporting the conversion of the accelerated approval of blinatumomab (Blincyto) to a full approval as a treatment for patients with Philadelphia chromosome-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

The sBLA for the anti-CD19 agent is based on the phase III TOWER trial, in which treatment with blinatumomab led to a median overall survival (OS) of 7.7 months versus 4 months with standard chemotherapy.^1,2 The application also provides data supporting the use of blinatumomab in patients with Philadelphia chromosome-positive (Ph+) relapsed/refractory B-cell precursor ALL.

Under the priority designation, the FDA will review the sBLA within 6 months from the acceptance of the filing, compared with the standard 10 months. The FDA is scheduled to make its final decision by August 14, 2017.

"Patients with relapsed or refractory ALL generally have a very poor prognosis. The median OS on standard of care chemotherapy is just 4 months," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the developer of blinatumomab, said in a statement. “Blincyto is the first-and-only approved bispecific immunotherapy with superior OS results versus standard of care chemotherapy, nearly doubling the median OS for patients with this form of ALL. We look forward to making this important potential new option available to patients with all forms of relapsed or refractory B-cell ALL.

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 were allowed to receive treatment until relapse. OS was the primary efficacy endpoint. Complete remission (CR) and combined CR or CR with partial or incomplete hematologic recovery (CR/CRh/CRi) were secondary outcome measures.

Treatment with blinatumomab reduced the risk of death by 29% versus standard chemotherapy (HR, 0.71; 95% CI, 0.55-0.93; P = .012). The OS benefit with blinatumomab was observed across prespecified patient subgroups based on age, prior salvage therapy, or alloSCT. The study was halted early for efficacy based on the recommendation of an an independent data monitoring committee.

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 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).

The application also included data from the open-label phase II ALCANTARA study, which evaluated the efficacy and tolerability of blinatumomab in adult patients with Ph+ relapsed or refractory B-cell precursor ALL.³

Sixteen of 45 patients (36%) achieved a CR/CRh during the first 2 cycles of therapy, including 4 of 10 patients with a T315I mutation. MRD-negative status was achieved by 88% of CR/CRh responders. Seven responders (44%) received allogeneic hematopoietic stem-cell transplantation. The median OS was 7.1 months.

The FDA granted an accelerated approval to blinatumomab in 2014 as a treatment for patients with Ph- relapsed/refractory B-precursor ALL, based on findings from a phase II trial.

According to Amgen, the Blincyto label includes a Boxed Warning regarding cytokine release syndrome and neurological toxicities.

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.
3. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome—positive b-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study (published online March 29, 2017). J Clin Oncol. doi:10.1200/JCO.2016.69.3531.

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.