Currently no targeted therapies are approved for the treatment of relapsed/refractory Philadelphia Chromosome-negative (Ph-) acute lymphocytic leukemia (ALL). Moreover, given the toxicities associated with the available chemotherapy options, less than half of patients are treated with second-line therapy.1
Blinatumomab is an investigational bispecific T-cell-engaging antibody developed using Micromet’s “BiTE” (bispecific T-cell engager) technology. The concept behind the bispecific antibody is that by binding the tumor cell through CD19 ― which is expressed by nearly all tested B-lineage ALL cells (including ALL blasts) ― and T-cells through CD3, the antibody brings the T-cells into closer contact with the tumor cells, thereby promoting T-cell mediated lysis of the tumor cells. In a previous Phase II study conducted in 36 relapsed/refractory B-cell ALL patients, treatment with blinatumomab achieved a complete hematologic remission (CR)/CRh (CR with partial hematologic recovery) rate of 69% (25/36), a median relapse free survival (RFS) of 7.6 months and a median overall survival (OS) of 9.8 months.2 Micromet (now Amgen) sought to confirm the antileukemic activity of single-agent blinatumomab in the difficult-to-treat population with relapsed/refractory ALL with the Phase II trial that was reported Tuesday at ASCO in the leukemia oral session.
This was a large Phase II study (MT103-211; NCT01466179) of blinatumomab in Ph-, relapsed/refractory ALL.3 This confirmatory open-label, single-arm trial was initiated in October 2011. Eligible patients had primary refractory disease; early relapse (duration of first remission was12 months or less); relapse within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT); or any relapsed or refractory disease after first salvage therapy. The primary endpoint was rate of CR / CRh within the first two treatment cycles. Secondary endpoints included rates of CR and CRh, proportion of patients eligible for allogeneic HSCT after CR/CRh rate, relapse-free survival, overall survival, time to hematological relapse, event-free survival, pharmacokinetics, and safety. The trial completed enrollment by November 2013. Before its purchase by Amgen, Micromet initiated the trial with an estimated enrollment of 61 patients. By January 2013, the planned enrollment had been tripled to 180 patients, and Amgen subsequently guided that this will be a pivotal trial to support regulatory approval in this unmet need population.
The single-arm MT103-211trial enrolled 189 patients who were treated with blinatumomab (28 µg/day, continuous IV, four weeks on, two weeks off; Days 1-7 of Cycle 1 only, 9 µg/day) for a median of two cycles (range = 1–5 cycles). Treatment with blinatumomab resulted in 43% CR/CRh rate during the first two cycles of therapy, and 80% of CR/CRh occurred within the first cycle. Median RFS was 5.9 months and median OS was 6.1 months. Adverse events were consistent with previously reported adverse events. The most frequent Grade 3 or higher adverse events were febrile neutropenia (25%), neutropenia (16%); anemia (14%), nervous system/psychiatric disorders (13%) and pneumonia (9%). Grade 3 or higher nervous system/psychiatric disorders included encephalopathy (3%), ataxia (2%) and confusional state (2%). Fatal adverse events were only seen in patients with uncontrolled leukemia.
This large Phase II study confirmed the antileukemia activity of single-agent blinatumomab in a difficult-to-treat population with relapse/refractory ALL. The only other approved agent for relapsed/ refractory B-cell ALL is Marqibo® (vincristine sulfate liposome, Talon Therapeutics), which was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of Ph- ALL patients who have relapsed after two or more prior therapies. If we compare the outcomes of these two trials, blinatumomab appears to offer better outcomes than Marqibo (CR/CRh 43% and 15%, respectively) and overall survival (6.0 months and 4.6 months, respectively).4,5 However, the patient demographics are different between these two studies, making comparison difficult; specifically, the blinatumomab trial enrolled a large portion of patients in earlier relapse than the Marqibo trial, which could explain the difference in response rate and survival. Randomized data is not available for either drug, which further limits the ability to assess their clinical merits, but the single-arm Phase II data certainly is encouraging.
In late 2013, Amgen initiated a Phase III trial (00103311; NCT02013167) that will randomize relapsed/refractory Ph- B-cell ALL patients to either blinatumomab or physician’s choice of chemotherapy. The endpoint of this trial is OS and will most likely serve the need to convert an anticipated accelerated approval (based on the Phase II data reported today) to a full FDA approval; it also will support regulatory filings outside the U.S. An approval will not come fast enough for this setting with high unmet need. The data from this important Phase II trial ushers in the era of targeted immune therapy as a new treatment option for ALL patients.
By Stephanie Hawthorne, Ph.D., Senior Director, and Greg Wolfe, Ph.D., Senior Consultant, Kantar Health
 Kantar Health CancerMPact® Treatment Architecture, United States and Western Europe, accessed June 3, 2014
 Topp, et al., Bone Marrow Transplant, 2013
 Topp, et al., Abstract 7005, ASCO 2014
 Marqibo FDA label, accessed June 3, 2014
 O’Brien, et al., J Clin Oncol, 2012