FDA Approval: Blinatumomab

Pharmacokinetics

Blinatumomab pharmacokinetics (PK) parameters were linear over the dose range of 5 to 90 μg/m². The volume of distribution was 4.5 L, and the elimination half-life was short at 2.1 hours, but PK was highly variable. Steady-state concentrations during continuous infusion were achieved within one day. Mild and moderate renal impairment was associated with a modest decrease in clearance, but the size of the effect did not warrant modification of the starting dose. The impact of severe renal impairment or dialysis on blinatumomab PK was not assessed. There were too few cases of patients with anti-blinatumomab antibodies to allow conclusions about the impact of immunogenicity on PK.

Pharmacodynamics

The pharmacodynamic (PD) effects observed in the patient population included a rapid redistribution of T cells, NK cells, and monocytes resulting in peripheral cytopenias (with recovery in 2–7 days), and an immediate but transient increase in inflammatory cytokines, the magnitude of which appeared to be dose dependent for the initial dose. Serial measurements of serum cytokine concentrations from 186 patients treated on Protocol MT103-211 showed that, within the first 48 hours of the first infusion of blinatumomab, IL10 was elevated in 98% of patients, IL6 in 88%, IFNγ in 54%, IL2 in 27%, and TNFα in 24%.

Clinical trial overview

Protocol MT103-211 was a single-arm, open-label, two-step trial of single-agent blinatumomab for treatment of adults with Philadelphia chromosome–negative relapsed or refractory precursor B-cell ALL (R/R ALL). Eligible patients had >10% blasts in the marrow and early first relapse (first remission ≤ 12 months), second or later relapse, refractory disease, or relapse after HSCT. The primary efficacy endpoint was CR + CRh* (CR but with platelets >50 Gi/L and ANC > 0.5 Gi/L) by two cycles of therapy. The objective was to test the hypothesis that the rate of CR + CRh* was > 30%. With a sample size of 140 patients and a true response rate of 45%, the study had 96% power to exclude a 30% response rate with a one-sided type I error rate of 2.5%. Additional patients beyond the minimum sample size were accrued as prespecified in the protocol in order to allow for a supplementary analysis of clinical comparability using a modified manufacturing process.

Treatment plan

Before start of blinatumomab, cytoreduction with dexamethasone, 10 mg/m² (maximum 24 mg), daily for up to 5 days was required for patients with blasts >50% or an absolute blast count >15 Gi/L. Blinatumomab was given by continuous intravenous infusion over 4 weeks of a 6-week cycle. The treatment plan consisted of up to two cycles for induction and three cycles for consolidation. In the first cycle, the initial dose was 9 μg/day for week 1, then 28 μg/day (step dose) for the remaining 3 weeks. A dose of 28 μg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in case of adverse events. Dexamethasone, 20 mg, was given intravenously one hour before each treatment cycle and one hour before the step dose to prevent infusion reactions.

The starting dose of blinatumomab was based on the safety results of two prior studies using BSA-based dosing for patients with R/R ALL (10, 11). In these studies, initiation of treatment with 5 μg/m²/day was associated with less cytokine release syndrome, and the 5→15 μg/m²/day step-dose regimen was found to be tolerable and active. The 9→28 μg/day step-dose regimen for patients ≥45 kg was based on the PK finding of consistency of exposure when comparing fixed-dose to BSA-based dosing.

Disposition and demographics

Protocol MT103-211 accrued 189 patients internationally. At the time of the efficacy analysis, all patients had completed at least two cycles or discontinued early. Four patients with either no evidence of active ALL at enrollment or who were in late first remission were excluded from the efficacy analysis. The demographics of the remaining 185 study patients are shown in Table 1. Forty-six patients went on to allogeneic stem cell transplantation after treatment with blinatumomab.

Efficacy results

The efficacy results are shown in Table 2. In the analysis of the primary endpoint, the rate of CR + CRh* was 42% with a lower 95% confidence intervals (CI) boundary of 34%. To allow for a better understanding of the result in the context of the heterogeneity of the patient population with regard to prognostic factors, the sponsor provided a weighted analysis of patient-level data for 694 historical controls collected from 13 study groups and clinical centers (9). The analysis showed that the expected rate of CR or CR without complete hematologic recovery in some cases was 24% (95% CI, 20%–27%). This result confirmed that the target lower limit of 30% CR + CRh* in this study was reasonable for the accrued population and that the primary objective was met. The results for the primary endpoint were largely consistent across the subpopulations tested.

Key secondary and exploratory endpoints were used to inform the regulatory decision-making process (Table 2). CR was achieved by 60 (32%) of the patients. The sponsor developed a model to project CR using a meta-analysis of summary data from multiple publications. Using this model, the projected CR rate for the accrued population treated with existing therapies was 13% (95% CI, 4%–34%), and the OR for CR using blinatumomab over existing therapies by simulation was 3.50 (95% CI, 1.63–8.40; ref. 9). For the patients who achieved CR, the median relapse-free survival (RFS) was 6.7 months, so it was concluded that the responses were reasonably durable (due to the competing risk of death in remission, RFS was used as the measure of duration of response). Finally, patients who achieved CR or CRh* were also tested for MRD using a sensitive molecular method. CR or CRh* with a reduction in MRD to less than 10⁻⁴ was achieved by 31% of the study population.

Nonclinical toxicology

Blinatumomab bound to human and chimpanzee peripheral blood mononuclear cells. In a nonterminal repeat-dose study of intravenous blinatumomab in chimpanzees and repeat-dose studies of a murine surrogate of blinatumomab in mice, test article–related changes included increased expression of T-cell activation markers and lymphocytopenia. Additional toxicologic findings in chimpanzees included expression of inflammatory cytokines, increases in body temperature and heart rate, and a decrease in blood pressure. These findings were consistent with the cytokine release syndrome observed in clinical studies.

Safety events in the intended population

Safety was assessed in 212 adults with R/R ALL treated with blinatumomab using the fixed 9→28 μg step-dose regimen or the BSA-based 5→15 μg/m² step-dose regimen. A treatment-emergent adverse event (TEAE) was experienced by >99% of patients, and the event was grade ≥3 for 78%. The most common (≥10%) TEAEs that occurred on treatment or within 30 days of the end of infusion are listed in Table 3. The most common grade ≥ 3 nonhematologic TEAEs were febrile neutropenia (23%), pneumonia (8%), pyrexia (7%), sepsis (5%), dyspnea (5%), and hypertension (5%). Four patients (2%) had hypersensitivity reaction events that could not be attributed to a cause other than blinatumomab.

The protocol did not provide specific criteria for diagnosis of cytokine release syndrome or infusion reaction. Events described by the terms “cytokine release syndrome,” “infusion reaction,” and “capillary leak syndrome” occurred in the same timeframe (median time to onset of 2 days) and with overlapping signs and symptoms, and thus, for the purposes of the safety analysis, these event terms were considered together as a grouped term (see Supplementary Table S1). Cytokine release syndrome was reported for 12% of the patients (grade ≥3 cytokine release syndrome in 2%).

A neurologic toxicity occurred in 53% of the patients. The hazard rate for the first neurologic event diminished over time, but new events were reported throughout the period of blinatumomab administration. The nature of the neurologic toxicity was variable; 72 different neurologic or psychiatric adverse event terms were reported. Grade ≥3 neurologic TEAEs that occurred in 2 or more patients were encephalopathy, headache, altered state of consciousness, aphasia, ataxia, confusional state, nervous system disorder, tremor, neurotoxicity, and seizure. Leukoencephalopathy was identified in 7 patients, including one with JC virus in the spinal fluid. Patients ≥65 years old had an increased rate of neurologic events.

Laboratory abnormalities were common, as might be expected in patients with RR ALL, but where shifts could be assessed for a worsening from grade ≤2 at baseline to grade ≥3 after start of therapy, nonhematologic abnormalities that occurred in >10% of patients included increased gamma-glutamyl-transferase, increased alanine aminotransferase, increased aspartate aminotransferase, and hyperbilirubinemia. The elevated transaminases generally occurred in the setting of cytokine release syndrome.

Blinatumomab administration was interrupted in 32% of the patients and discontinued prematurely in 17%. The most common reasons for interruption were neurologic toxicity and cytokine release syndrome. The most common reasons for permanent withdrawal included neurologic toxicity and sepsis.

One hundred and thirty deaths were reported. The majority of the deaths were considered related to active primary malignancy or complications of HSCT. Two deaths were concluded to have potentially resulted from a direct toxicity of blinatumomab, and in both cases, the clinical manifestations were attributed to or were similar to those expected for cytokine release syndrome. The rate of day-30, all-cause mortality was 8% (95% CI, 4%–12%); this was not greater than that expected based on a historical control group [14% (95% CI, 12%–16%)] as calculated by the sponsor (9).