PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has granted approval for Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy. This approval covers all European Union (EU) member states.*

The approval is based on results from the pivotal Phase 3 TRANSFORM trial in which Breyanzi demonstrated statistically significant and clinically meaningful improvements in the study’s primary endpoint of event-free survival (EFS), and key secondary endpoints of complete responses (CR) and progression-free survival (PFS) compared to standard therapy (consisting of salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant [HSCT]), along with a manageable and well-established safety profile.

“With Breyanzi, people in Europe living with relapsed or refractory DLBCL now have a differentiated CAR T cell therapy option earlier in the treatment paradigm that provides long-term clinical benefit,” said Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb. “This marks the approval of our third indication in Europe for our CAR T cell therapy portfolio, underscoring our continued drive to deliver the promise of cell therapy with curative potential for more patients.”

In DLBCL, the most common form of non-Hodgkin lymphoma, up to 40% of patients have disease that is refractory to or relapses following initial therapy. The standard therapy for these patients consists of intensive salvage immunochemotherapy followed by high-dose chemotherapy and HSCT for those whose disease responds to the salvage therapy and are eligible for transplant. However, only an estimated 25% of patients are considered eligible for transplant and experience long-term clinical benefit, leaving a continued unmet need for second-line treatment options with curative potential.

“Based on results of the TRANSFORM trial, Breyanzi provides significantly improved outcomes compared to the standard of care that has been in place for decades, along with a well-established safety profile, demonstrating the benefit of using a CAR T cell therapy earlier for patients with relapsed or refractory DLBCL,” said Bertram Glass, M.D., TRANSFORM trial investigator and Chief Physician of the Department of Hematology and Stem Cell Transplantation, Helios Klinikum, Berlin, Germany. “This approval represents a significant milestone for patients with continued progress toward transforming second-line treatment practice to provide a personalized treatment option that offers the potential for durable remission.”

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

TRANSFORM Clinical Trial Results

In the TRANSFORM study, Breyanzi more than quadrupled median EFS compared to standard therapy (10.1 months vs. 2.3 months [HR: 0.349; 95% CI (0.229-0.530) p<0.0001]) at the time of prespecified interim analysis with a median follow-up of 6.2 months. Results of the primary analysis, with a median follow-up of 17.5 months were consistent with the interim analysis, with median EFS not reached for Breyanzi (95% CI: 9.5-NR) vs. 2.4 months for standard therapy (95% CI: 2.2-4.9). With Breyanzi, the majority (73.9%) of patients achieved a CR compared to less than half (43.5%) of those who were treated with standard therapy. Median PFS was not reached (95% CI: 12.6-NR) with Breyanzi vs. 6.2 months (95% CI: 4.3-8.6) with standard therapy (HR: 0.400; 95% CI: 0.261-0.615; p<0.0001).

The safety profile of Breyanzi is well-established, and in the TRANSFORM study, occurrences of cytokine release syndrome (CRS) and neurologic events were generally low-grade, and mostly resolved quickly with standard protocols and without the use of prophylactic steroids. Any-grade CRS was reported in less than half of patients (48.9%), with Grade 3 CRS reported in 1% of patients. The median time to onset of CRS was five days (range: 1 to 63) and median duration of CRS was four days (range: 1 to 16). Any-grade neurologic events were reported in 10.9% of patients treated with Breyanzi, with Grade 3 neurologic events reported in 4.3% of patients. The median time to onset of neurologic events was 11 days (range: 7 to 17 days). The median duration of neurologic toxicities was 4.5 days (range: 1 to 30 days). For full details on the Special Warnings and Precautions for Use and Adverse Reactions (including appropriate management), please refer to the EU Summary of Product Characteristics (SmPC).

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard of care (platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopietic stem cell transplant [HSCT] in patients responding to salvage chemotherapy) in patients with large B-cell lymphoma that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy. Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy (HDCT) and auto-HSCT. The primary endpoint of the study was event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first. Complete response rate was a key secondary endpoint. Other efficacy endpoints included progression-free survival, overall survival, overall response rate and duration of response.

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 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 for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed or 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 leukemia. For more information, visit clinicaltrials.gov.

Full European Summary of Product Characteristics for Breyanzi is available from the EMA website at www.ema.europa.eu .

U.S. Important Safety Information

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)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) 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 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). 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. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients. Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

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. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI infusion and 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.

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. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

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 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) 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 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, during this initial period.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

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

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Learn more about the science behind cell therapy and ongoing research at Bristol Myers Squibb here.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that the outcome of pricing and reimbursement negotiations in individual countries in Europe may delay or limit the commercial potential of Breyanzi(lisocabtagene maraleucel) for the indication described in this release, that continued approval of such product candidate for such indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials, and whether such product candidate for such indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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