Summary Basis of Decision for Blincyto

Clinical Pharmacology

Philadelphia chromosome-negative relapsed or refractory B precursor acute lymphoblastic leukemia (ALL) is a rapidly growing type of cancer in which the bone marrow makes too many B-cell lymphoblasts (an immature type of white blood cell). Sometimes the Philadelphia chromosome, an abnormality of chromosome 22, occurs in the bone marrow cells of leukemia patients.

Blincyto (blinatumomab) is a novel bispecific antibody construct that activates endogenous T-cells to destroy B-cells.

Blinatumomab is comprised of two different single-chain antibody variable domains that bind specifically to B-lymphocyte antigen CD19 expressed on the surface of B-cells and CD3 expressed on the surface of T-cells. Blinatumomab activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on normal and malignant B-cells. The anti-tumor activity of blinatumomab is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. It is not dependent on T-cells bearing a specific TCR, or on peptide antigens presented by cancer cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumor cell, releasing proteolytic enzymes (such as perforin and granzymes) to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

The very short elimination half-life of blinatumomab requires it to be administered continuously as an intravenous infusion. It is feasible that the short half-life is typical of unprotected protein catabolism. Patients with mild or moderate renal impairment need no adjustment however, there is no information available for patients with severe renal impairment or those undergoing hemodialysis. Although blinatumomab exhibits linear pharmacokinetics, the drug is applied as a fixed dose since no clinically meaningful effects have been identified in relation to weight or body surface area.

Treatment with Blincyto dynamically changes the pharmacokinetics of T-cells, B-cells and cytokines. After the start of a Blincyto infusion, the T-cells, natural killer cells and monocytes decrease within the first 6 hours but gradually return to previous levels within 1 to 7 days. In contrast, the cytokine levels increase immediately and return to baseline levels within 1 to 2 days. This increase appears to depend on the dose and can potentially suppress the cytochrome P450 (CYP450) enzymes causing drug-drug interactions. Patients receiving concomitant CYP450 substrates should be monitored for symptoms of toxicity and their doses should be adjusted as needed.

For further details, please refer to the Blincyto Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Blincyto in adult patients with Philadelphia-negative relapsed/refractory B-precursor ALL was evaluated in a pivotal, Phase II, open-label, multicentre, single-arm study (MT103-211). Eligible patients were ≥18 years of age with relapsed/refractory disease and a first remission duration of ≤12 months in first salvage therapy, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplant (HSCT), and had ≥10% blasts in their bone marrow.

Patients received 1 to 5 cycles of Blincyto as a continuous intravenous (IV) infusion. The initial dose was 9 µg/day for the first 7 days to mitigate for potential cytokine release syndrome (CRS) and central nervous system (CNS) events associated with initial exposure to Blincyto. Starting at Week 2, the dose was escalated to the target dose of 28 μg/day and continued at that dose for the rest of Cycle 1 and all subsequent cycles. A cycle consisted of a continuous IV infusion of Blincyto at a constant flow rate over 4 weeks followed by a treatment-free interval of 2 weeks. Some patients who were unable to tolerate the target dose continued treatment at 9 μg/day. Dose adjustment was possible in case of adverse events.

Among the 189 patients who received at least 1 cycle of Blincyto, 70 were female (37%) and 119 were male (63%), the median age was 39 years (range: 18 to 79 years), 64 out of 189 (33.9%) had undergone HSCT prior to receiving Blincyto, 77 out of 189 (40.7%) had undergone one prior salvage therapy, 42 out of 189 (22.2%) had undergone two prior salvage therapies and 32 out of 189 (16.9%) had received more than two prior salvage therapies. Sixteen out of 189 (8.5%) patients were primary refractory. Thirty-one out of 189 (16.4%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2.

The primary endpoint was the complete remission (CR)/complete remission with partial hematological recovery (CRh) rate within two cycles of treatment with Blincyto. Complete remission (CR) was defined as bone marrow blasts ≤5%, no evidence of extramedullary disease, and full recovery of peripheral blood counts. Complete remission with partial hematological recovery (CRh) was included in the primary endpoint, as patients with platelets >50,000/μL and absolute neutrophil count (ANC) >500/μL are eligible for allogeneic HSCT. The unadjusted CR/CRh rate within the first two cycles of treatment with Blincyto was 42.9% [95% confidence interval (CI): 35.7% to 50.2%]. Most patients with a CR/CRh had complete response (CR = 33.3%; CRh = 9.5%). In addition, three patients who achieved a CRh response at the end of two cycles of treatment converted to CR during consolidation cycles.

Analyses of numerous secondary and exploratory endpoints were included in the study. The key secondary endpoints were relapse free survival (RFS) and overall survival (OS). However results of these endpoints and the other time-to-event endpoints were not useful without a comparator arm and adequately designed randomized studies are needed to fully characterize these endpoints. In addition, RFS was based on patients who achieved a CR/CRh during the core study. Findings from such "responder analyses", including the landmark OS analyses, are subject to bias. The duration of response, using the definition for RFS in this study, was 5.9 months (range: 0.1 - 16.5 months).

Other statistical issues were identified, including the potential for informative censoring, ad-hoc analyses, and sub-group analyses (due to very small numbers in many subgroups). It is anticipated that results from the ongoing confirmatory Phase III, randomized study will be more reliable for establishing the benefit of Blincyto over current therapies, and for characterizing factors that may be associated with the primary endpoint.

One supportive dose-escalation study (MT103-206) was submitted. The study enrolled 36 adult patients with relapsed/refractory B-precursor ALL. Dosing was on a body surface area basis and ranged from 5 to 30 µg/m²/day. The overall complete remission rate was considerably higher than the response rate observed in the pivotal study. However, Study MT103-206 included patients with blasts in bone marrow as low as 5% and also enrolled patients with late-relapse (>12 months). Thus, the lower disease burdens and less aggressive disease may partially account for the increased remission rate.

Historical data from a retrospective study and a model-based meta-analysis were provided to support the results obtained in the pivotal study MT103-211. However, there were several limitations with the historical data, including different definitions for response/remission, different enrolment criteria, and changes in standard of care/medical practice over time. Such substantial differences between published studies are reflected in the large range of response rates (24% to 70%). Therefore, objective comparisons could not be made between the results of the pivotal study and the historical studies.

In conclusion, the results of the pivotal study demonstrated promising evidence of the clinical effectiveness of Blincyto in the treatment of patients with relapsed/refractory ALL, and particularly for those who have no other treatment options. Anticipated data from the ongoing Phase III, randomized study, comparing Blincyto to standard of care, may provide further evidence to establish the benefit of Blincyto over current therapies.

For more information, refer to the Blincyto Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Blincyto (blinatumomab) was evaluated in the two adult relapse/refractory ALL studies described in the Clinical Efficacy section. A total of 225 patients (189 in Study MT103-211 and 36 in Study MT103-206) received 1 to 5 cycles of Blincyto as a continuous IV infusion. By study, the median exposure duration was 42.2 days in Study MT103-211, and 55.6 days across dose groups in Study MT103-206. Due to differences in study design, patient characteristics and the limited number of patients in Study MT103-206, the safety profile of Blincyto is largely based on safety data from the pivotal study, Study MT103-211. The safety profile of Blincyto in Study MT103-206 was generally consistent with that observed in the pivotal study and reinforced the relevant safety concerns for Blincyto in B-precursor ALL.

In the pivotal study, almost all patients experienced at least one treatment-emergent adverse event (TEAE) and 88% of patients had TEAEs related to Blincyto. The most commonly reported TEAEs were infections (63%), pyrexia (60%), headache (34%), febrile neutropenia (28%), peripheral oedema (26%), nausea (24%), hypokalemia (24%), constipation (21%), anemia (20%), diarrhea (18%), tremors (18%), and neutropenia (18%). Eighty-two percent of patients experienced Grade 3-5 TEAEs; febrile neutropenia, infections, neutropenia, and anemia were the most commonly reported events. Fatal events related to Blincyto were sepsis, encephalopathy, Candida infection, and Escherichia sepsis (one report each). The most common TEAEs leading to discontinuation of Blincyto included sepsis and encephalopathy.

Important identified safety risks for Blincyto are neurologic events, cytokine release syndrome (CRS), tumour lysis syndrome (TLS), infections, overdose, elevated liver enzymes, neutropenia/febrile neutropenia, decreased immunoglobulins, capillary leak syndrome, and infusion reactions. Important potential safety risks are thromboembolic events (including disseminated intravascular coagulation and venous thrombosis), leukoencephalopathy, and lymphopenia.

Cytokine release syndrome (CRS) and infusion reactions, which may be indistinguishable from CRS, can occur during the first cycle of Blincyto. Serious adverse events that may be associated with CRS include pyrexia, asthenia, headache, hypotension, total bilirubin increased, elevation of liver enzymes, and nausea. In the pivotal study, CRS events, including cytokine storm, were reported in 13% of patients and TEAEs that may be symptomatic of CRS were reported by 94% of patients.

Tumor lysis syndrome (TLS) includes hyperkalemia, hyperphosphatemia, hyperuricemia, hyperuricosuria, and hypocalcemia, which results from the breakdown products of rapidly dying cancer cells. Tumor lysis syndrome was reported in 4.2% of patients in the pivotal study and possibly in 5 additional patients based on a broad search strategy for TEAEs suggestive of TLS. The median time to first onset of events was 2.0 days. The majority of patients who experienced adverse events suggestive of TLS had high tumor burden (blast >50% at baseline). As TLS can potentially cause lethal cardiac arrhythmias and/or renal failure, appropriate prophylactic measures should be used and fluid balance should be closely monitored during the first 48 hours. Current guidelines for the management of TLS recommend offering aggressive hydration and antihyperuricemic therapies (such as allopurinol or rasburicase) to patients with higher risk factors such as high tumor burden, increased age, and pre-existing renal impairment. Monitoring of fluid status and laboratory results (for changes in levels of uric acid, potassium, phosphate, and calcium) is also recommended.

Neurologic TEAEs, including serious and fatal events, were reported in 52% of patients, and included ten reports of encephalopathy. Of the eight cases that were related to the study drug, six were Grade ≥3. There was one report of metabolic encephalopathy which had a fatal outcome. Elderly patients (≥65 years of age) experienced a higher rate of serious neurologic events (including encephalopathy) compared to the younger patients. The median time to onset of a neurologic event was 9 days. Patients should receive a neurological assessment prior to starting Blincyto, and be closely monitored for CNS toxicity during treatment. Patients may also require prophylactic treatment to prevent CNS ALL relapse. There is a potential risk of an increase in neurologic events in patients with pre-existing or history of CNS pathology, however no data is available as these patients were excluded from the pivotal study.

Leukoencephalopathy was reported in one patient treated with Blincyto in the pivotal study. This case was Grade 3 in severity and considered related to study drug. One other case of leukoencephalopathy was reported in a non-pivotal study. Progressive multifocal leukoencephalopathy (PML) is a well-known risk of B-cell depletion therapies with anti-CD20 antibodies. Based on the limited safety data, the risk of PML in patients treated with Blincyto cannot be excluded. Therefore patients should be monitored for signs and symptoms consistent with PML. In the case of suspected PML, magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid sampling for presence of John Cunningham (JC) virus should be conducted in consultation with a neurologist.

Infection events including sepsis, bacteremia, septic shock, opportunistic infections and catheter site infections, were reported in 63% of patients. Half of the infection events were serious and in some cases fatal. Serious infections included pneumonia, sepsis, opportunistic infections, device-related infection, and bacteremia. Fatal infection events considered related to Blincyto treatment were sepsis, Escherichia coli sepsis, and Candida infection. The types and severity of infections are expected in this patient population; however Blincyto treatment may also be a factor in development of infections due to its mechanism of action.

Neutropenia and febrile neutropenia, including serious and life-threatening cases, were commonly reported in patients with relapsed or refractory ALL who were treated with Blincyto. Laboratory parameters for neutropenia including white blood cell count and neutrophil count should be monitored during Blincyto treatment in these patients.

Overdose events were reported and the majority of cases were due to errors in drug preparation or infusion rate. Adverse events (AEs) resulting from overdose were pyrexia, tremors and headache; which are also common AEs observed at the recommended dosages. There is a substantial risk for errors in reconstitution and administration of Blincyto, therefore clear instructions and training must be provided to healthcare professionals.

Analysis of TEAEs by subpopulations found a difference in incidence rates between elderly patients and patients <65 years of age. In the elderly cohort, a higher incidence of AEs overall, as well as serious AEs, were reported. In particular, serious TEAEs reported in the CNS System Order Class (SOC), such as cognitive disorder, encephalopathy, and state of confusion were reported with a greater than 5% difference. Encephalopathy was reported with a >10% difference.

The Integrated Safety Summary provided analysis of safety data from all clinical studies of Blincyto in various indications (including adult relapse/refractory B-precursor ALL), with a total of 475 patients. The safety data from the other clinical studies generally support the safety profile of Blincyto as characterized in the pivotal study. However, the incidence of febrile neutropenia (all grades and Grade ≥3) is substantially higher in Study MT103-211 than in other studies; and the incidence of TEAEs under the Infections and Infestations SOC (all grades and Grade ≥3) was substantially higher in the R/R ALL studies than in the other studies. The incidence of pneumonia (all grades and Grade ≥3) was higher in the R/R ALL studies compared to the other studies. In a pediatric dose-finding study dose, limiting toxicities were observed at doses ≥15 µg/m²/day and included instances of CRS including one case that was fatal.

Supporting data were provided in United States Food and Drug Administration (FDA) 120-day Update and post-marketing reports. Rates of serious events such as neurologic events (including encephalopathy), CRS, infections, and TLS were similar to those reported in the pivotal study.

Overall, the safety data from the clinical studies indicate that Blincyto is associated with high rates of AEs, including serious, life-threatening and fatal events. However this assessment is based mainly on data from the single-arm study in a R/R ALL patient population that is heavily pre-treated with chemotherapy and immunosuppressive therapy. Therefore, the safety profile of Blincyto needs to be further characterized in context with a control group in a randomized study such as the ongoing confirmatory study (Study 00103311) in which the efficacy and safety of Blincyto is compared to standard-of-care chemotherapy regimens.

Most identified serious risks such as CRS, infusion reaction, TLS and neurological toxicity can be managed with close monitoring, prophylactic medications, immediate treatment, dose adjustment, interruption or discontinuation of Blincyto. Appropriate warnings and precautions are in place in the approved Blincyto Product Monograph to address all identified safety concerns. Warnings regarding CRS, infusion reactions, TLS, neurological events including encephalopathy, and serious infections have been included in a Serious Warnings and Precautions box. All identified and potential risks are well described in the Risk Management Plan (RMP) for risk mitigation and post-marketing surveillance.

For more information, refer to the Blincyto Product Monograph, approved by Health Canada and available through the Drug Product Database.