FDA Panel to Review Blinatumomab Application for MRD-positive ALL

David M. Reese, MD

The FDA’s Oncologic Drugs Advisory Committee (ODAC) is slated to review a supplemental biologics license application (sBLA) for the use of blinatumomab (Blincyto) for the treatment of patients with minimal residual disease (MRD)-positive B-cell precursor acute lymphoblastic leukemia (ALL).

The ODAC meeting is scheduled for March 7. A Prescription Drug User Fee Act target action date for the sBLA has been set for March 29.

Amgen filed the sBLA for blinatumomab based on results from the phase II BLAST trial. In findings published online in January 2018, 88 of 113 (78%) evaluable patients had a complete MRD response after 1 cycle of treatment with blinatumomab. Two more patients achieved a complete MRD response after cycle 2. Among 5 patients with Philadelphia chromosome (Ph)—positive disease who had MRD evaluations, 3 (60%) had an MRD response during cycle 1.

Investigators also found that complete MRD response was associated with significantly improved survival. Compared with nonresponders, the patients who had complete MRD response had superior relapse-free survival (RFS; 23.6 vs 5.7 months; P = .002) and overall survival (OS; 38.9 vs 12.5 months; P = .002).

David M. Reese, MD, Amgen senior vice president of Translational Sciences and Oncology, said in a press release that this is the first sBLA submitted for an MRD-positive indication.

“Currently there are no approved therapies for patients with MRD-positive ALL, representing a significant unmet need,” he said. “After achieving remission, the presence of MRD is the strongest prognostic factor for relapse in acute lymphoblastic leukemia. However, today up to half of patients remain MRD-positive after induction treatments and receive limited clinical benefit from treatments like chemotherapy or stem cell transplantation as a result of failure to identify and treat this residual disease.”

In the BLAST trial, investigators working at 46 medical centers in Europe and Russia enrolled patients into this open-label, single-arm study from November 2010 to February 2014. Patients received 15 μg/m² of blinatumomab daily by continuous intravenous infusion for up to 4 cycles. Each cycle comprised 4 weeks of blinatumomab infusion followed by a 2-week treatment-free period. Patients could receive HSCT any time after cycle 1 at the investigator’s discretion.

Adult patients with B-cell precursor ALL in first or later hematologic complete remission (CR) and with persistent or recurrent MRD ≥10⁻³ after a minimum of 3 blocks of intensive chemotherapy were eligible for inclusion. Median age was 45 years (range, 18-76). At baseline, 47% of patients had MRD ≥10⁻² and 35% were in second or later hematologic CR.

All patients completed the treatment period. Overall, 76 patients received HSCT in continuous CR after 1 cycle.

Investigators assessed the primary endpoint of complete MRD response after 1 cycle of blinatumomab in the primary endpoint full analysis set of patients with evaluable MRD markers (n = 113). Secondary endpoints of OS, RFS, and duration of hematologic remission were analyzed in the secondary endpoint full analysis set (n = 110). Overall MRD response was evaluated in the primary endpoint efficacy set (n = 103).

The primary endpoint efficacy set for analysis of overall MRD included 103 patients with hematologic CR and MRD >10⁻³ at baseline. Of these, 87% achieved any MRD response, including 80% (95% CI, 71-87) with a complete MRD response after cycle 1. Complete MRD response rates were similar between patients with MRD ≥10⁻² or <10⁻² at baseline, and between patients with first or later remission at baseline. Of 45 patients in this analysis set with treatment interruptions due to any cause during cycle 1, 82% achieved a complete MRD response.

Among the 110 patients from the full analysis set who had Ph-negative disease and <5% blasts at baseline, the Kaplan-Meier estimate for RFS was 54% (95% CI, 33-70) at 18 months, exceeding the prespecified boundary of 28%. Estimates for RFS at 18 months were similar with or without censoring for post-blinatumomab HSCT and chemotherapy.

The median RFS was 18.9 months (95% CI, 12.3-35.2) at a median follow-up of 29.9 months. Median RFS was 11.0 months among patients treated within later CR versus 24.6 months for those treated in first CR (hazard ratio, 2.09; 95% CI, 1.26-3.48; P = .004).

All patients who started cycle 1 experienced at least 1 adverse event (AE). One-third reported grade 3 AEs and 27% reported grade 4 AEs. Investigators considered 29% of grade 3 AEs and 22% of grade 4 AEs to be treatment-related. Four (3%) patients experienced cytokine release syndrome—2 grade 1 events and 2 grade 3 events, all during cycle 1.

Two patients experienced fatal AEs during the treatment period, including 1 atypical pneumonitis with H1N1 influenza that investigators determined was related to the study treatment.

Blinatumomab is currently approved for the treatment of adults and children with relapsed/refractory B-cell precursor ALL, regardless of Ph status.

Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-precursor acute lymphoblastic leukemia [published online January 22, 2018]. Blood. 10.1182/blood-2017-08-798322.

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Among the entire study population (N = 116), median OS was 36.5 months (95% CI, 19.2-not estimable).