On June 17, 2023 Bristol Myers Squibb (NYSE: BMY) reported the first disclosure of primary analysis results from two pivotal studies, TRANSCEND FL, an open-label, global, multicenter, Phase 2, single-arm study evaluating Breyanzi (lisocabtagene maraleucel; liso-cel) in patients with relapsed or refractory follicular lymphoma (FL) and the relapsed or refractory mantle cell lymphoma (MCL) cohort of TRANSCEND NHL 001, an open-label, multicenter, Phase 1, single-arm, seamless-design study evaluating Breyanzi (Press release, Bristol-Myers Squibb, JUN 17, 2023, View Source [SID1234632738]). These data were presented in late-breaking oral presentations at the 2023 International Conference on Malignant Lymphoma (ICML) on Saturday, June 17.
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"With Breyanzi, we’re dedicated to delivering a CAR T cell therapy with a differentiated profile to transform outcomes for some of the most difficult-to-treat lymphomas," said Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb. "Based on results from TRANSCEND FL and TRANSCEND NHL 001, Breyanzi continues to demonstrate the ability to elicit significant deep and durable responses alongside a manageable safety profile, potentially addressing areas of high unmet need and reinforcing our commitment to advancing innovative solutions for the broadest array of hematologic malignancies of any CD19-directed CAR T cell therapy."
Results from the TRANSCEND FL and TRANSCEND NHL 001 studies will be discussed with health authorities. Bristol Myers Squibb thanks the patients and investigators involved in the TRANSCEND clinical trials.
Results from TRANSCEND FL
TRANSCEND FL, the largest clinical trial to date to evaluate a CAR T cell therapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma, including FL, enrolled adults with relapsed or refractory disease treated with Breyanzi in the second-line and third-line plus setting. Patients received treatment with Breyanzi at a target dose of 100 x 106 CAR-positive viable T cells.
In efficacy evaluable patients with relapsed or refractory FL treated with Breyanzi in the third-line plus setting (n=101), the overall response rate (ORR) was 97% (95% CI: 91.6-99.4; one-sided p<0.0001), with 94% of patients achieving a complete response (CR; 95% CI: 87.5-97.8; one-sided p<0.0001). Responses were durable with a median duration of response not reached at a median follow-up of 16.6 months. At 12 months, 81.9% of responders had an ongoing response. Median progression-free survival (PFS) was also not reached at a median follow-up of 17.5 months, with 12-month PFS achieved in 80.7% of patients.
With a median on-study follow-up of 18.9 months in the safety set (n=130), which included patients treated in the second-line plus setting, Breyanzi exhibited a manageable safety profile, with no new safety signals observed and low rates of severe cytokine release syndrome (CRS) and neurologic events (NE). Any grade CRS occurred in 58% of patients, with Grade 3 CRS occurring in 1% of patients and no Grade 4/5 CRS reported. Any grade NEs were reported in 15% of patients, with Grade 3 NEs occurring in 2% of patients and no Grade 4/5 NEs reported.
Historically, outcomes are poor for patients with relapsed or refractory FL. Despite high initial response rates to front-line treatment, the majority of patients experience multiple relapses and prognosis often worsens with subsequent relapses. Additionally, the durability of response with available treatment options decreases with each subsequent line of therapy. There are currently no curative options.
"In the treatment of relapsed or refractory follicular lymphoma, there are few options that offer significant and lasting responses, particularly for patients with high-risk disease features and those who experience early disease progression after front-line therapy," said Franck Morschhauser, M.D., Ph.D., lead investigator and Professor of Hematology at Centre Hospitalier Universitaire de Lille, Groupe de Recherche sur les forms Injectables et les Technologies Associées, Lille, France. "In TRANSCEND FL, the overall and complete response rates achieved with liso-cel were very high, and appear mostly durable at 12 months, and, importantly, the safety profile was favorable. This data shows the potential of liso-cel as a promising treatment option for patients with relapsed or refractory follicular lymphoma."
Results from TRANSCEND NHL 001 in MCL
The MCL cohort of TRANSCEND NHL 001 enrolled adults with relapsed or refractory disease after two or more prior lines of therapy, including a BTK inhibitor. These patients were treated with Breyanzi at dose levels of either 50 x 106 or 100 x 106 CAR-positive viable T cells.
With a median on-study follow-up of 16.1 months, the ORR in patients evaluated for efficacy in the primary analysis set (n=74) was 86.5% (95% CI: 76.5-93.3; one-sided p<0.0001), with 74.3% of patients achieving a CR (95% CI: 62.8-83.8; one-sided p<0.0001).
In the safety set (n=88), Breyanzi was well-tolerated and no new safety signals were observed. Any grade CRS occurred in 61% of patients, with Grade 3/4 CRS occurring in 1% of patients and no Grade 5 CRS reported. Any grade NEs were reported in 31% of patients, with Grade 3/4 NEs occurring in 9% of patients and no Grade 5 NEs reported.
There are currently no curative options for MCL and relapse is common, with many patients developing resistance to initial treatment. With each additional line of therapy, both response rates and duration of response tend to decrease, and prognosis worsens.
"Despite advances in treatment, there remains a critical unmet need for additional therapies that offer deep and durable responses in patients with high-risk, aggressive relapsed or refractory mantle cell lymphoma," said Michael Wang, M.D., lead investigator and Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas. "Liso-cel offers the potential for complete responses with a one-time infusion and a manageable safety profile, representing a potential new treatment option for these patients."
About TRANSCEND FL
TRANSCEND FL (NCT04245839) is an open-label, global, multicenter, Phase 2, single-arm study to determine the efficacy and safety of Breyanzi in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma, including follicular lymphoma and marginal zone lymphoma. The primary outcome measure is overall response rate. Secondary outcome measures include complete response rate, duration of response, and progression-free survival.
About TRANSCEND NHL 001
TRANSCEND NHL 001 (NCT02631044) is an open-label, multicenter, pivotal, Phase 1, single-arm, seamless-design study to determine the safety, pharmacokinetics and antitumor activity of Breyanzi in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma. The primary outcome measures are treatment-related adverse events, dose-limiting toxicities and overall response rate. Secondary outcome measures include complete response rate, duration of response and progression-free survival.
About FL
Follicular lymphoma (FL) is the second most common, slow-growing form of non-Hodgkin lymphoma (NHL), accounting for 20 to 30 percent of all NHL cases. Most patients with FL are over 50 years of age when they are diagnosed. FL develops when white blood cells cluster together to form lumps in a person’s lymph nodes or organs. It is characterized by periods of remission and relapse, and the disease becomes more difficult to treat after relapse or disease progression.
About MCL
Mantle cell lymphoma (MCL) is an aggressive, rare form of non-Hodgkin lymphoma (NHL), representing roughly 3% of all NHL cases. MCL originates from cells in the "mantle zone" of the lymph node. MCL occurs more frequently in older adults with an average age at diagnosis in the mid-60s, and it is more often found in males than in females. In MCL, relapse after initial treatment is common, and for most, the disease eventually progresses or returns.
About Breyanzi
Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment. Breyanzi is approved by the U.S. Food and Drug Administration (FDA) for the 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 LBCL, 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 transplant due to comorbidities or age, or relapsed or refractory disease after two or more lines of systemic therapy. Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.
Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding cytokine release syndrome and neurotoxicity.
Breyanzi is also approved in Japan and Europe for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, 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 lymphoma and leukemia. For more information, visit clinicaltrials.gov.
U.S. Important Safety Information and Indication
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the 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.
BOXED 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 (CRS)
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 two or more lines of therapy for LBCL, CRS occurred in 46% (122/268), including ≥ Grade 3 CRS in 4.1% of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 98% with a median duration of 5 days (range: 1 to 17 days).
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%) 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 two or more lines of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 35% (95/268), including ≥ Grade 3 in 12% of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of neurotoxicity was 8 days (range: 1 to 46 days). Neurologic toxicities resolved in 85% with a median duration of 12 days (range: 1 to 87 days).
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, 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, 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 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, 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%) are fever, CRS, fatigue, musculoskeletal pain, and nausea.
The most common Grade 3-4 laboratory abnormalities (≥ 30%) include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.
Please see full Prescribing Information , including Boxed WARNINGS and Medication Guide .