Blinatumomab Displays Impressive CR Rates in ALL Studies

FDA Grants Priority Review for Crizotinib for mNSCLC

Nicola Gökbuget, MD

Blinatumomab (Blincyto) as a single agent showed high complete remission (CR), or CR with partial hematological recovery (CRh), in adult patients with Philadelphia chromosome (Ph)-positive and -negative B-cell precursor acute lymphoblastic leukemia (ALL), says data from two phase II trials presented at the 2015 ASH Annual Meeting.

In the first study, data shows blinatumomab's CR/CRh rate was 36% in patients with relapsed/refractory Philadelphia chromosome (Ph)-positive ALL. Of those with a CR/CRh, 88% tested negative for minimal residual disease (MRD). A fourth of patients then received subsequent stem cell transplant, with the median overall survival (OS) being 7.1 months.

In the second study, data shows the MRD-negative CR rate was 80% for blinatumomab in 103 patients withh Ph-negative ALL experiencing an MRD-positive hematologic CR. Median OS with blinatumomab was 36.5 months and 67% of patients were able to receive a stem cell transplant.

“This is a proof-of-principle study with a new compound in an MRD-positive population with an MRD-based endpoint in which blinatumomab induced a high complete MRD response rate of 80%,” said lead investigator Nicola Gökbuget, MD, Department of Medicine, Goethe University, Frankfurt, Germany. “MRD response was associated with improved overall survival, relapse-free survival, and response duration.”

Blinatumomab has a dual affinity for CD3 and CD19, which is a highly specific B-cell marker expressed in more than 90% of B-cell malignancies. On December 3, 2014, the FDA granted an accelerated approval to the novel immunotherapy as a treatment for patients with Ph-negative relapsed/refractory B-precursor ALL.

In first phase II study presented at ASH, 45 patients received blinatumomab as a continuous intravenous infusion in a 6-week treatment cycle. The immunotherapy was administered for 4 weeks followed by a 2-week treatment-free duration. For the first week of treatment blinatumomab was administered at 9 μg/day followed by a gradual dose escalation from day 8 through 29 to a final dose of 28 μg/day, which was the dose used for subsequent cycles.

Patients enrolled in the study had greater than 5% blasts in their bone marrow with an ECOG PS ≤2. All patients were relapsed or refractory to at least one second-generation TKI or were intolerant/refractory to imatinib or second-generation TKIs, prior agents included dasatinib (87%), imatinib (56%), ponatinib (51%), and nilotinib (51%).

The primary endpoint of the study was CR/CRh within 2 cycles of treatment, with secondary outcome measures focused on MRD, duration of response, OS, and safety. Other outcome measures of the study were focused on MRD and the efficacy of blinatumomab against specific BCR-ABL mutations.

CR/CRh rates were similar across patient groups. In 27 patients who received ≥2 prior second-generation TKIs, the CR/CRh rate was 41%. Additionally, in those with T315I resistance mutations (n = 10), the CR/CRh rate was 40%.

Responses where the same in patients &ge;55 and for those 18 to <55 years of age (36% and 35%, respectively). After a median follow-up of 8.8 months, the median relapse-free survival (RFS) duration was 6.7 months in those &ge;55 years old and 5.5 months in those <55.

&ldquo;Equivalent CR/CRh and RFS was observed in patients less than 55 and over 55 years of age," said lead investigator Giovanni Martinelli, MD, Institute of Hematology, S.Orsola-Malpighi University Hospital, Bologna, Italy. "Hematologic and molecular responses were independent of mutational status, including presence of the T315I mutation."

Treatment-related grade &ge;3 adverse events (AEs) were seen in 44% of patients treated with blinatumomab. The most frequently observed grade &ge;3 AEs were febrile neutropenia (11%), alanine aminotransferase increase (11%), aspartate aminotransferase increase (9%), anemia (9%), thrombocytopenia (7%), and pyrexia (7%).

Neurologic AEs were seen in 47% of patients treated with blinatumomab, regardless of causality. The most common of these AEs, all of which were grade 1/2, were paresthesia (13%), confusional state (11%), dizziness (11%), and tremor (9%).

&ldquo;There were no grade 4 or 5 neurologic events or cytokine release syndrome observed,&rdquo; said Martinelli. &ldquo;Adverse events were consistent with previous blinatumomab treatment experience in the setting of Ph-negative relapsed/refractory ALL.&rdquo;

In the second phase II study, 103 of 116 patients at a median age of 45 years were evaluable for the primary endpoint of complete MRD response. Secondary endpoints included MRD response, OS, and safety. Patients who had previously undergone stem-cell transplant were excluded from the trial.

Blinatumomab was administered at 15 &mu;g/m2 per day for 4 weeks with 2 weeks treatment-free. Those ineligible for allogeneic transplant could receive as many as three additional cycles of blinatumomab. Transplant-eligible patients could also receive as many as three additional cycles while awaiting a suitable donor.

Analysis of the primary endpoint showed an 80% response rate in the efficacy cohort, and 78% in the full-analysis cohort (N = 113). The median relapse-free survival (RFS) with blinatumomab was 29.9 months. The 18-month RFS rate was 54%. When censoring for transplant, the median RFS was not yet reached.

Patients in their first CR had a median RFS of 24.6 versus 11.0 months for those in their second or third CR (P= .004). &ldquo;Patients treated in first remission had improved RFS and response duration compared to those treated in subsequent remission,&rdquo; explained G&ouml;kbuget.

Those with an MRD-negative CR after 1 cycle of treatment had a median OS of 38.9 versus 12.5 months in the MRD-positive group (P= .002). The median duration of response was not reached in the MRD-negative group versus 17.2 months in those who remained MRD-positive (P= .049).

Serious AEs were seen in 63% of patients across the full study population (N = 116). Grade 3/4 AEs were experienced by 60% of patients, with 2 patients experiencing a fatal event.

Treatment interruptions were required for 31% of patients, primarily due to pyrexia (8%), chills (3%), alanine aminotransferase or aspartate aminotransferase increase (3%), overdose (3%), tremor (3%), aphasia encephalopathy (3%). Following a dose interruption, treatment was resumed at a lower dose of 5 &mu;g/m2 per day.

Ten percent and 3% of patients experienced grade 3 and 4 neurologic AEs, respectively. All-grade neurologic AEs were seen in 53% of patients, the most common being tremor (30%), aphasia (13%), dizziness (8%), ataxia (6%), paresthesia (6%), and encephalopathy (5%). Neurologic AEs leading to discontinuation included tremor (4%), aphasia (3%), encephalopathy (3%), and seizure (3%).

&ldquo;Among patients who experienced neurologic events on study, most had an event of grade less than 2,&rdquo; said G&ouml;kbuget. &ldquo;Twelve patients interrupted or discontinued treatment due to grade 3 or greater neurologic events.&rdquo;

Blinatumomab continues to be assessed across a variety of settings, including an open-label phase III study comparing the immunotherapy with chemotherapy for patients with relapsed or refractory B-precursor ALL. The primary endpoint of this study is overall survival.

References

1. Martinelli G, Dombret H, Chevallier P, et al. Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 679.
2. G&ouml;kbuget N, Dombret H, Bonifacio M, et al. Long-Term Outcomes after Blinatumomab Treatment: Follow-up of a Phase 2 Study in Patients (Pts) with Minimal Residual Disease (MRD) Positive B-Cell Precursor Acute Lymphoblastic Leukemia (ALL). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 680.