On December 10, 2023 Bristol Myers Squibb (NYSE: BMY) reported the first disclosure of primary analysis results from the high-risk, second-line cohort of 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) (Oral Presentation #602) (Press release, Bristol-Myers Squibb, DEC 10, 2023, View Source [SID1234638391]). TRANSCEND FL is 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. Additionally, the company presented long-term data from the TRANSCEND CLL 004 study evaluating Breyanzi in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) with 24-month follow-up (Oral Presentation #330). These data are being featured in oral presentations at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, from December 9-12, with the TRANSCEND FL 2L oral presentation selected as part of the 2024 Highlights of ASH (Free ASH Whitepaper) for lymphoma.
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$BMY to highlight #CARTcelltherapy data at #ASH23 in certain types of lymphoma and leukemia.
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"With additional data for Breyanzi across our TRANSCEND clinical trials, we continue to see its potential best-in-class and best-in-disease profile in follicular lymphoma, delivering clinically meaningful benefit and improved outcomes for patients with high unmet need," said Anne Kerber, M.D., senior vice president, Head of Late Clinical Development, Hematology, Oncology, Cell Therapy (HOCT), Bristol Myers Squibb. "At Bristol Myers Squibb, we have an unwavering commitment to advancing innovative treatments. The breadth of data we are presenting at ASH (Free ASH Whitepaper) this year for Breyanzi, including the first positive studies for a CD19-directed CAR T in follicular lymphoma and chronic lymphocytic leukemia, reinforces the significant progress that we are making toward bringing the promise of cell therapy to more patients."
Results from TRANSCEND FL will be discussed with health authorities. A supplemental Biologics License Application for Breyanzi in relapsed or refractory CLL based on results from TRANSCEND CLL 004 is currently under review by the U.S. Food and Drug Administration with a target action date of March 14, 2024.
Bristol Myers Squibb (BMS) has the broadest ongoing cell therapy development program in CD19-positive malignancies with Breyanzi, which also includes trials investigating its use in patients with relapsed/refractory mantle cell lymphoma (MCL). Results from the primary analysis of the MCL cohort of TRANSCEND NHL 001 were simultaneously published today in Journal of Clinical Oncology. BMS thanks the patients and investigators participating in the TRANSCEND clinical trials.
Results from TRANSCEND FL and Patient-Reported Outcomes
In the TRANSCEND FL clinical trial, 130 patients with relapsed or refractory follicular lymphoma (FL) were enrolled and treated with Breyanzi in the second-line and third-line plus settings. Patients received treatment with Breyanzi at a target dose of 100 x 106 CAR-positive viable T cells. TRANSCEND FL is the largest clinical trial evaluating a CAR T cell therapy in relapsed or refractory FL, and the first trial to report outcomes for a CAR T in second-line, high-risk FL, with results generally consistent with the efficacy and safety results observed in third-line FL.
In patients with high-risk relapsed or refractory FL treated with Breyanzi in the second-line setting who were evaluable for efficacy (n=23) with a median on-study follow-up of 18.1 months (range: 1.0–26.8), Breyanzi elicited significant responses in nearly all patients, with all responders achieving a complete response (CR).
The overall response rate (ORR), the study’s primary endpoint, and CR rate were 95.7% (n=22/23; 95% CI: 78.1-99.9; one-sided p<0.0001). With a median follow-up of 16.8 months, median duration of response (DOR) was not reached (95% CI: 19.3-NR).
The probability of patients remaining in response at 12 months was 89.8%. Median progression-free survival (PFS) was also not reached (95% CI: 20.2-NR), with a PFS rate of 91.3% at 12 months.
Breyanzi continued to exhibit a manageable and predictable 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 52.2% of patients, with no grade >3 CRS reported. Any-grade NEs were reported in 17.4% of patients, with Grade 3 NEs occurring in 4.3% of patients and no Grade 4/5 NEs reported. All cases of CRS and NEs were managed to resolution.
"Despite high initial response rates to front-line treatment, the majority of patients with follicular lymphoma relapse with prognosis worsening, leaving them in need of a treatment option that will provide significant and lasting responses," said Franck Morschhauser, M.D., Ph.D., lead investigator and Professor of Hematology at Centre Hospitalier Universitaire de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France. "Based on results from TRANSCEND FL for liso-cel as a second-line treatment option, the vast majority of patients achieved a complete response, with probability of overall responses lasting at least 12 months. Additionally, the safety profile for liso-cel continued to be manageable, showing the clinically meaningful value of using this differentiated treatment option for patients with relapsed or refractory follicular lymphoma after failure of front-line therapy."
Patient-reported outcomes (PROs) from TRANSCEND FL are also being presented (Oral Presentation #668), representing the first disclosure of PRO data for a CAR T cell therapy in relapsed or refractory FL. Based on an exploratory analysis, the majority of patients with second- or third-line relapsed or refractory FL reported clinically significant improvements in quality of life, disease symptoms, and functioning after being treated with Breyanzi. Those receiving Breyanzi in the second-line setting generally demonstrated greater and faster meaningful improvements in most primary domains, compared to those who received Breyanzi in the third-line setting, including role and cognitive functioning, fatigue, pain, and Functional Assessment of Cancer Therapy Lymphoma scores.
Results from the third-line-plus treatment cohort of TRANSCEND FL were previously presented at the 2023 International Conference on Malignant Lymphoma in June 2023.
Results from TRANSCEND CLL 004
TRANSCEND CLL 004 is the first pivotal, multicenter study of a CD19-directed CAR T cell therapy for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) after progression on a BTK inhibitor (BTKi) and BCL-2 inhibitor (BCL2i). The study included a broad population of patients with relapsed or refractory CLL or small lymphocytic leukemia (SLL) with high unmet need who had received at least two prior lines of therapy, including a BTKi (n=118), to be treated with Breyanzi. Results from the primary analysis of TRANSCEND CLL 004, with a median follow-up of 21.1 months, were previously presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2023.
With a longer-term median (range) follow-up of 23.5 months (0.4-59.6) in the prespecified primary efficacy analysis set (PEAS; n=50), which consisted of a subset of patients who had experienced disease progression following treatment with a BTKi and failure of BCL2i-based regimens and who were treated with the target dose of 100 x 106 CAR-positive viable T-cells of Breyanzi, patients derived statistically significant CR rate of 20% (95% CI: 10.0-33.7), the study’s primary endpoint.
The high rates of undetectable minimal residual disease (uMRD) observed with Breyanzi were maintained with longer-term follow-up, with a uMRD rate 64% in the blood (95% CI: 45.2-77.1) and 60% in the bone marrow (95% CI: 45.2-73.6). The ORR increased to 44% (95% CI: 30.0-58.7), with a median (range) DOR of 35.3 months (11.01-NR). One patient who had a best overall response of partial response at the primary analysis experienced a deepening of response at 18 months, achieving a CR without any additional therapy. Of 9 patients who had achieved a CR at primary analysis, 8 had ongoing CRs and one completed the study with the last assessment as a CR.
"For patients with relapsed or refractory CLL, current treatment options rarely provide complete responses, and durability of response is limited," said Tanya Siddiqi, M.D., lead investigator and associate professor in the Department of Hematology and Hematopoietic Cell Transplantation and Director of the CLL program at City of Hope National Medical Center. "With long-term follow-up from TRANSCEND CLL 004, the complete and lasting responses achieved with liso-cel are unprecedented in this patient population, with a deepening of responses observed over time and a manageable and predictable safety profile. Based on these results, liso-cel has the potential to be a significant advance in the treatment of relapsed or refractory CLL."
Among all treated patients (n=118), Breyanzi exhibited a manageable safety profile, with any grade CRS observed in 85% of patients, with Grade 3 CRS occurring in 8% of patients and no Grade 4/5 CRS reported. Any grade NEs were reported in 45% of patients, with Grade 3 NEs occurring in 18% of patients, Grade 4 NEs occurring in 1% of patients, and no Grade 5 NEs reported.
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 CLL 004
TRANSCEND CLL 004 (NCT03331198) is a Phase 1/2 open-label, single-arm, multicenter study evaluating Breyanzi in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The Phase 1 dose escalation portion of the study assessed the safety and recommended dose for the subsequent Phase 2 expansion cohort. The Phase 2 portion of the study is evaluating Breyanzi at the recommended dose from the Phase 1 monotherapy arm. The primary endpoint of the Phase 2 portion of the study is complete response rate, including complete remission with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines.
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 CLL and SLL
Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes, and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. Small lymphocytic lymphoma (SLL) also affects the lymphocytes, with cancer cells found mostly in the lymph nodes. While there are several treatments available for CLL and SLL, there is a need for additional effective therapies as there is no standard of care for relapsed or refractory CLL or SLL after prior therapy with targeted agents. Patients with relapsed or refractory disease have limited treatment options and generally experience shorter periods of response with each subsequent treatment.
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 in the U.S., 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.