In an 8 to 4 vote, the FDA's Oncologic Drugs Advisory Committee recommended approval of blinatumomab for the treatment of minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia.
David M. Reese, MD
In an 8 to 4 vote, the FDA's Oncologic Drugs Advisory Committee (ODAC) recommended approval of blinatumomab (Blincyto) for the treatment of minimal residual disease (MRD)-positive B-cell precursor acute lymphoblastic leukemia (ALL).
The FDA will now make its final decision on the approval, with an action date set under the Prescription Drug User Fee Act of March 29, 2018.
At the meeting, ODAC was tasked with determining whether >0.1% MRD was a valid cutoff describing a subpopulation of patients with ALL in complete remission (CR) who have a need for pre-emptive therapy. Following that, ODAC voted to determine whether, in the >0.1% MRD-positive population, the benefits of blinatumomab outweighed the risks.
Although the panel voted to recommend approval, there was no consensus on the appropriate MRD cutoff for treatment intervention.
“The positive vote from today’s ODAC [meeting] affirms the potential for Blincyto to improve outcomes in patients with B-cell precursor ALL by reducing the level of leukemic residual disease,” David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen, the manufacturer of blinatumomab, said in a statement. “If approved, an indication for the treatment of MRD-positive ALL will add an important, earlier treatment option for physicians and patients.”
Amgen submitted data from the phase II BLAST study (MT103-203; N = 211) to support the supplemental biologic license application. BLAST was a single-arm trial of up to 4 cycles of blinatumomab for treatment of patients with B-cell precursor ALL in CR or CR with partial platelet recovery and MRD >0.1%. The primary efficacy endpoint of BLAST was complete MRD response, defined as absence of detectable MRD using an assay with a sensitivity <0.01% after 1 cycle of blinatumomab.
Of 116 patients who received at least one dose of blinatumomab, the FDA identified 87 in CR with hematologic recovery and baseline MRD >0.1%, including 61 patients in CR1, 25 in CR2 and 1 in CR3. Sixty-nine patients (79.3%; 95% CI, 70.4%-87.6%) achieved a complete MRD response within the first cycle.
The full analysis set Amgen submitted from BLAST included 113 patients who were determined to be MRD-positive based on a measurement of ≥0.1% from an assay with a minimum sensitivity of 0.01% after ≥2 weeks from their last chemotherapy treatment. Among this group, 88 (77.9%; 95% CI, 69.1%-85.1%) achieved MRD CR within the first cycle.
Using the 87-patient FDA efficacy analysis set, the 18-month relapse-free survival (RFS) rate was 56%, and the estimated median RFS was 22.3 months. The estimated median RFS time in first CR at the time of treatment with blinatumomab was 25.6 months (95% CI, 18.7-not applicable), median RFS time in the second or third CR was 11.0 months (95% CI, 6.8-15.4). RFS time was numerically longer for patients in CR1 than for those in the second or third CR.
The estimated median RFS time was 23.6 months (95% CI, 17.4-not applicable) for patients with a complete MRD response and 5.7 months (95% CI, 1.6-13.6) for the MRD-nonresponders.
A propensity score analysis for the patients in first remission with or without hematopoietic recovery in BLAST and in Study 20120148a retrospective cohort study investigating the hematological RFS and overall survival (OS) in adult patients with Ph-negative BCP ALL in hematological CR with MRD—demonstrated that the RFS for the patients treated with blinatumomab was significantly greater than in the historical controls (35.2 vs 8.3 months; log-rankP<.0001).
The estimated median RFS time with propensity score weighted analyses was 35.18 months (95% CI, 24.2 to not estimable) for the blinatumomab group and 8.3 months (95% CI, 6.23-11.90) for the control group.
However, FDA staff reported that they could not confirm the estimate of the benefit of blinatumomab using this approach because the results were confounded by lack of matching for covariates that would affect the RFS endpoint, inclusion of patients with incomplete hematologic recovery rather than true CR, lack of patients in CR2 or CR3, lack of comparability between groups in the duration of follow-up, and confounding by unequal use of HSCT.
Further, the FDA noted that that the company had not demonstrated that undetectable MRD was a predictor for long-term event-free survival or OS.
Data from the safety population of 137 patients treated with blinatumomab for MRD-positive ALL came from BLAST and MT103-202, an exploratory, proof-of-concept, multicenter, open-label, single-arm trial of blinatumomab for patients in first complete hematologic remission with MRD-positive B-cell ALL.
The FDA briefing document for ODAC noted that the safety profile for blinatumomab in this setting was similar to was has been demonstrated with the treatment in patients with relapsed/refractory ALL. The median treatment exposure for the 137 patients was 55 days (range, 1-196). Ninety-one percent of patients had fever, 69% had a neurological toxicity, 7% had cytokine release syndrome, and 2% had sepsis.
Fatal adverse events occurred in 3 patients: fatal atypical pneumonia within 30 days of starting treatment; subdural hemorrhage at the site of a prior hemorrhage <30 days after the last dose of blinatumomab; and sepsis.
Blinatumomab is currently approved by the FDA the treatment of adult and pediatric patients with relapsed or refractory B-cell precursor ALL.
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting BLA 125557 S-013 Blincyto (blinatumomab) Applicant: Amgen, Inc. Published Accessed March 7, 2018. http://bit.ly/2oV6FOq.