On December 20, 2022 Bristol-Myers Squibb K.K. reported that it has received approval in Japan for Breyanzi (generic name: lisocabtagene maraleucel; liso-cel), a CD19-targeting chimeric antigen receptor (CAR) T cell therapy (gene-modified autologous therapy), allowing its use in the second-line treatment of relapsed or refractory large B-cell lymphoma (LBCL), regardless of whether autologous hematopoietic stem-cell transplantation is intended (Press release, Bristol-Myers Squibb, DEC 20, 2022, View Source [SID1234625438]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This approval is based on the results of clinical trials in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma after first-line therapy, including global Phase III clinical trials (JCAR017-BCM-003) in patients intended for autologous hematopoietic stem-cell transplantation, Phase II clinical trials (017006) in the United States (U.S.) in patients not intended for autologous hematopoietic stem-cell transplantation, and cohort 2 of Phase II clinical trials (JCAR017-BCM-001) in Europe and Japan. The randomized controlled clinical trial (JCAR017-BCM003) is currently being conducted in a total of 184 patients (including nine Japanese patients) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma after first-line therapy and intended for autologous hematopoietic stem-cell transplantation who were assigned to the Breyanzi arm or the standard therapy arm (salvage chemoimmunotherapy followed by high-dose chemotherapy combined with autologous hematopoietic stem-cell transplantation in patients with a response).

The interim analysis of the JCAR017-BCM-003 clinical trial reported that the Breyanzi arm showed a statistically and clinically significant improvement in the primary endpoint of event-free survival (EFS) [HR: 0.349 95% CI: 0.229-0.530, p<0.0001] and progression-free survival (PFS) [HR: 0.406 (95% CI: 0.250-0.659), p = 0.0001]. Median PFS was 14.8 months in the Breyanzi arm (95% CI: 6.6-NE) and 5.7 months (95% CI: 3.9-9.4) in the standard therapy arm. In the Breyanzi arm, the overall safety profile of patients who had relapsed or refractory LBCL with a prior treatment history of one regimen was similar to that of such patients with a prior treatment history of two regimens or more, with no new safety signals noted.

Breyanzi has a well-established safety profile and based on results from the JCAR017-BCM-003 study, occurrences of CRS and neurologic events were generally low grade and mostly resolved quickly with standard protocols, and without the use of prophylactic steroids. In the trial, no Grade 4/5 CRS or neurologic events were reported. Any-grade CRS was reported in less than half of patients (49%; 45/92), with Grade 3 CRS reported in 1.1% of patients. Any-grade neurologic events were reported in 12% (11/92) of patients treated with Breyanzi, with Grade 3 neurologic events reported in 4% of patients.

Commenting on the approval, Makoto Sugita, Bristol Myers Squibb’s head of R&D in Japan, said, "We are very pleased that Breyanzi has been approved for use in the second-line treatment of relapsed or refractory LBCL, regardless of whether autologous hematopoietic stem-cell transplantation is intended. This approval is a major step forward for patients with refractory or relapsed LBCL who have undergone first-line therapy, as they may now benefit from a new treatment modality to bring them and their families more hope. We will continue to focus on the research and development of solutions for difficult-to-treat diseases with the aim of transforming patients’ lives through science."

About Large B-cell Lymphoma (LBCL)

LBCL includes multiple subtypes, including diffuse large B-cell lymphoma (DLBCL). The annual incidence of malignant lymphoma, including DLBCL, in Japan, is reported to be approximately 36,000 (2019), and the annual number of deaths approximately 13,000 (2020).1 Non-Hodgkin lymphomas, which account for the majority of malignant lymphomas, are generally subdivided by the differentiation status of the cell of origin (B cells, T cells, or natural killer cells) and lymphocytes,2 with approximately 70% of non-Hodgkin lymphomas in Japan classified into B-cell non-Hodgkin lymphomas.3 DLBCL is the most common type of lymphoma, accounting for 30-45% of all malignant lymphomas in Japan,3-5 especially prevalent in the elderly.1

Unmet Medical Needs for Relapsed or Refractory Large B-cell Lymphoma

Approximately 60% of patients with LBCL achieve long-term remission after first-line chemoimmunotherapy,6 whereas the rest of them are refractory to first-line therapy or relapse after a period of response. To ensure long-term disease control in patients who may undergo transplant, second-line salvage chemoimmunotherapy is required, followed by high-dose chemotherapy (HDCT) with hematopoietic stem-cell transplantation (HSCT). However, patients who are refractory to first-line therapy or relapse within 12 months are at high risk of not responding to salvage chemoimmunotherapy and therefore have difficulty obtaining long-term therapeutic benefits.7 In addition, patients who have no prospect of undergoing salvage chemoimmunotherapy followed by HDCT with HSCT have poor outcomes, with no standard therapy left for them. Therefore, there is an extremely high unmet medical need for new treatments for patients with LBCL who are refractory to first-line therapy or who relapse early.

About Breyanzi

Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi has been designated as an orphan regenerative medicine product by the MHLW for aggressive Bcell non-Hodgkin lymphoma, and was approved in Japan in March 2021 for the treatment of patients with R/R large B-cell lymphoma and R/R follicular lymphoma after two or more lines of therapy. Breyanzi is also approved in the U.S. as second-line therapy, and in the U.S., European Union, Switzerland and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphomas and leukemias. For more information, visit clinicaltrials.gov.

Breyanzi U.S. FDA-Approved Indication

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
Relapsed or refractory disease after two or more lines of systemic therapy.
Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma

U.S. Important Safety Information

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Among patients receiving BREYANZI for LBCL (N=418), CRS occurred in 46% (190/418), including ≥ Grade 3 CRS (Lee grading system) in 3.1% of patients.

In patients receiving BREYANZI after one line of therapy for LBCL, CRS occurred in 45% (68/150), including Grade 3 CRS in 1.3% of patients. The median time to onset was 4 days (range: 1 to 63 days). CRS resolved in all patients with a median duration of 4 days (range: 1 to 16 days).

The most common manifestations of CRS (≥10%) from 3 clinical studies included fever (94%), hypotension (42%), tachycardia (28%), chills (23%), hypoxia (16%), and headache (12%).

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.

Of the 418 patients who received BREYANZI for LBCL, 23% received tocilizumab and/or a corticosteroid for CRS, including 10% who received tocilizumab only and 2.2% who received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In patients receiving BREYANZI after one line of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 27% (41/150) of patients, including Grade 3 cases in 7% of patients. The median time to onset of neurologic toxicities was 8 days (range: 1 to 63 days). The median duration of neurologic toxicity was 6 days (range: 1 to 119 days).

In all patients combined receiving BREYANZI for LBCL from 3 clinical studies, neurologic toxicities occurred in 33% (136/418), including ≥ Grade 3 cases in 10% of patients. The median time to onset was 8 days (range: 1 to 63), with 87% of cases developing by 16 days. Neurologic toxicities resolved in 85% of patients with a median duration of 11 days (range: 1 to 119 days). Of patients developing neurotoxicity, 77% (105/136) also developed CRS.

The most common neurologic toxicities (≥ 5%) included encephalopathy (20%), tremor (13%), aphasia (8%), headache (6%), dizziness (6%), and delirium (5%).

CRS and Neurologic Toxicities Monitoring

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-888-423-5436.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion.

In patients receiving BREYANZI for LBCL from 3 clinical studies, infections of any grade occurred in 36% with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections occurred in 4.3%, viral infections in 1.9% and fungal infections in 0.5%.

Febrile neutropenia developed after BREYANZI infusion in 8% of patients with LBCL. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Avoid administration of BREYANZI in patients with clinically significant active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells.

In patients who received BREYANZI for LBCL, 15 of the 16 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion.

Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion from 3 clinical studies in 36% of patients with LBCL and included thrombocytopenia in 28%, neutropenia in 21%, and anemia in 6%.

Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI.

In patients receiving BREYANZI for LBCL from 3 clinical studies, hypogammaglobulinemia was reported as an adverse reaction in 11% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 28% of patients.

Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

Adverse Reactions

The most common nonlaboratory adverse reactions (incidence ≥ 30%) from 3 clinical studies are fever, CRS, fatigue, musculoskeletal pain, and nausea.

The most common Grade 3-4 laboratory abnormalities (≥ 30%) from 3 clinical studies include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

Product Overview

Brand Name

BREYANZI for intravenous infusion

Generic Name

lisocabtagene maraleucel; liso-cel

Date of Partial Change Approval

December 20, 2022

Indications or Performance

The following types of relapsed or refractory large B-cell lymphoma

Diffuse large B cell lymphoma
Primary mediastinal large B cell lymphoma
Transformed indolent non-Hodgkin lymphoma
High-grade B cell lymphoma
Relapsed or refractory follicular lymphoma
(Note: only for patients who have no prior history of treatment with a CD19 antigen-directed chimeric antigen receptor T cell transfusion therapy.)

Precautions Related to Indications or Performance

For patients with follicular lymphoma, BREYANZI must be administered only to those who have been diagnosed as being Grade 3B by pathologists with adequate experience.
Selection of eligible patients must be done based on thorough familiarity with the information presented in "CLINICAL STUDIES" section on the histologic types, prior treatment histories, and other features of the patients who were enrolled in the clinical studies, and based on a thorough understanding of the efficacy and safety of BREYANZI.
Marketing Authorization Holder

Bristol-Myers Squibb K.K.

References

Cancer Information Service "Statistical Information by Cancer Type Malignant Lymphoma" (As of November, 2022) View Source
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
Muto R, Miyoshi H, Sato K, et al. Epidemiology and secular trends of malignant lymphoma in Japan: Analysis of 9426 cases according to the World Health Organization classification. Cancer Med. 2018;7(11):5843-58.
Aoki R, Karube K, Sugita Y, et al. Distribution of malignant lymphoma in Japan: analysis of 2260 cases, 2001-2006. Pathol Int. 2008;58(3):174-82.
Chihara D, Ito H, Matsuda T, et al. Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol. 2014;164(4):536-45.
Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005;23(18):4117-26.
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-90.