Richard Pazdur, MD
The FDA has granted an accelerated approval to blinatumomab (Blincyto) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD).
The decision follows an 8 to 4 vote in favor of the indication from the FDA’s Oncologic Drugs Advisory Committee (ODAC). The panel based its recommendation on the phase II BLAST study, in which blinatumomab induced a nearly 80% complete MRD response rate in patients with MRD-positive ALL in hematologic complete remission (CR).
“This is the first FDA-approved treatment for patients with MRD-positive ALL,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.
“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD,” added Pazdur.
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 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 20120148—a 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-rank P <.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.
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 the ODAC meeting noted that the safety profile for blinatumomab in this setting was similar to what 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 was previously approved by the FDA for the treatment of adult and pediatric patients with relapsed or refractory B-cell precursor ALL. The accelerated approval of blinatumomab for MRD-positive is contingent upon confirmatory results from future studies.
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting BLA 125557 S-013 Blincyto (blinatumomab) Applicant: Amgen, Inc. Published Accessed March 29, 2018. http://bit.ly/2oV6FOq.