Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma [see Clinical Studies (14)].

2.1 Dose

See the respective Certificate of Release for Infusion (RFI Certificate) for each component, for the actual cell counts and volumes to be infused [see Dosage and Administration (2.2) and Dosage Forms and Strengths (3)].

Relapsed or Refractory LBCL After One Line of Therapy

A single dose of BREYANZI contains 90 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components), with each component supplied separately in one to four single-dose vials.

Relapsed or Refractory LBCL After Two or More Lines of Therapy

A single dose of BREYANZI contains 50 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components), with each component supplied separately in one to four single-dose vials.

2.2 Administration

BREYANZI is for autologous use only. The patient’s identity must match the patient identifiers on the BREYANZI cartons, vials and syringe labels. Do not infuse BREYANZI if the information on the patient-specific labels does not match the intended patient.

2.3 Management of Severe Adverse Reactions

5.1 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 occur in 46% (190/418), including ≥ Grade 3 CRS (Lee grading system1) 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%) [see Adverse Reactions (6.1)].

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) [see Adverse Reactions (6.1)].

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.

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)].

5.2 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 cases 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 toxicity 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%).

Monitor patients daily at least for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Manage neurologic toxicity with supportive care and/or corticosteroid as needed [see Dosage and Administration (2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].

5.3 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 [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]. 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.

5.4 Hypersensitivity Reactions

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

5.5 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 occurred in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections 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.

5.6 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.

5.7 Hypogammaglobulinemia

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

5.8 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.

5.9 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in the WARNINGS and PRECAUTIONS reflect exposure to a single dose of BREYANZI in 418 patients with relapsed or refractory (R/R) LBCL: one randomized, open-label study with 89 patients (TRANSFORM) and two open-label, single-arm studies with 61 patients (PILOT) and 268 patients (TRANSCEND).

Relapsed or Refractory LBCL After One Line of Therapy

TRANSFORM

The safety of BREYANZI was evaluated in the TRANSFORM, a randomized, open-label, multicenter study, in which patients with primary refractory LBCL or relapse within 1 year of first-line chemoimmunotherapy received BREYANZI (N=89) or standard therapy (N=91) [see Clinical Studies (14)]. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. The trial excluded patients who were ineligible for transplant or who had age > 75 years, ECOG performance status >1, history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), uncontrolled infection, CrCl < 45 mL/min, ALT > 5 times the upper limit of normal (ULN), LVEF < 40%, or absolute neutrophil count (ANC) < 1.0 × 109 cells/L or platelets < 50 × 109 cells/L in the absence of bone marrow involvement.

The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. The median age of the BREYANZI-treated population was 59 years (range: 20 to 74 years); 47% were male; 58% were white, 11% were Asian, and 5% were black.

Serious adverse reactions occurred in 38% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, sepsis, fever, febrile neutropenia, headache, aphasia, COVID-19 infection, and pulmonary embolism.

Table 3 presents selected nonlaboratory adverse reactions in patients treated with BREYANZI, and Table 4 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fever, CRS, musculoskeletal pain, headache, fatigue, nausea, constipation, and dizziness.

Other clinically important adverse reactions in < 10% of patients treated with BREYANZI included the following:

•

Immune system disorders: Hemophagocytic lymphohistiocytosis (1.1%)

•

Infections and infestations: Viral infection (9%), fungal infection (4.5%), pneumonia (2.2%)

•

Nervous system disorders: Encephalopathy (8%), aphasia (4.5%), peripheral neuropathy (4.5%), ataxia (3.4%), paresis (1.1%)

•

Psychiatric disorders: Delirium (2.2%)

•

Renal and urinary disorders: Renal failure (3.4%)

•

Respiratory, thoracic, and mediastinal disorders: Dyspnea (8%)

•

Vascular disorders: Thrombosis (8%), hypertension (7%)

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (64%), neutrophil decrease (66%), and platelet decrease (34%).

PILOT

The safety of BREYANZI was evaluated in the PILOT study, a single-arm open-label study in transplant-ineligible patients with R/R LBCL after one line of chemoimmunotherapy [see Clinical Studies (14)]. The study enrolled patients who were ineligible for high-dose therapy and autologous HSCT due to organ function or age, but who had adequate organ function for CAR-T cell therapy. Patients with a history of relevant CNS disorders (such as seizures or cerebrovascular ischemia), ECOG performance status > 2, or uncontrolled infection were ineligible. The trial required left ventricular ejection fraction ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, AST and ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells.

The median age was 74 years (range: 53 to 84 years), 90% were age ≥ 65 years, 61% were male. The ECOG performance status was 0 or 1 in 74% of patients and 2 in 26% of patients; 25% had CrCl < 60 ml/min; 20% had a baseline ANC < 1000/μL.

Serious adverse reactions occurred in 33% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, confusional state, gastrointestinal hemorrhage, muscular weakness, musculoskeletal pain, pulmonary embolism, and sepsis.

Table 5 presents selected nonlaboratory adverse reactions, and Table 6 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fatigue, CRS, fever, nausea, encephalopathy, hypotension, musculoskeletal pain, and edema.

Other clinically important adverse reactions in < 10% of patients included the following:

•

Blood and lymphatic system disorders: Febrile neutropenia (1.6%)

•

Eye disorders: Vision blurred (3.3%)

•

Gastrointestinal disorders: Vomiting (8%), abdominal pain (7%), gastrointestinal hemorrhage (4.9%)

•

Infections and infestations: Fungal infection (4.9%), sepsis (3.3%), viral infection (3.3%)

•

Nervous system disorders: Motor dysfunction (7%), aphasia (4.9%), ataxia (4.9%), peripheral neuropathy (4.9%)

•

Psychiatric disorders: Delirium (3.3%)

•

Renal and urinary disorders: Renal failure (7%)

•

Respiratory, thoracic, and mediastinal disorders: Hypoxia (4.9%)

•

Skin and subcutaneous tissue disorders: Rash (7%)

•

Vascular disorders: Thrombosis (7%)

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (95%), neutrophil decrease (57%), and platelet decrease (20%).

Relapsed or Refractory LBCL After Two or More Lines of Therapy

TRANSCEND

The safety of BREYANZI was evaluated in the TRANSCEND study, in which 268 adult patients with R/R LBCL after 2 or more prior lines of therapy received a single dose of CAR-positive viable T cells [see Clinical Studies (14)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median age of the study population was 63 years (range: 18 to 86 years); 65% were male. The Eastern Cooperative Oncology Group (ECOG) performance status at screening was 0 in 41% of patients, 1 in 58% of patients, and 2 in 1.5% of patients.

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.

Table 7 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 8 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 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.

Other clinically important adverse reactions in < 10% of patients included the following:

•

Cardiac disorders: Arrhythmia (6%), cardiomyopathy (1.5%)

•

Gastrointestinal disorders: Gastrointestinal hemorrhage (4.1%)

•

Infections and infestations: Pneumonia (8%), fungal infections (8%), sepsis (4.5%), urinary tract infection (4.1%)

•

Metabolism and nutrition disorders: Tumor lysis syndrome (0.7%)

•

Nervous system disorders: Ataxia or gait disturbance (7%), visual disturbance (5%), paresis (2.6%), cerebrovascular events (1.9%), seizure (1.1%), brain edema (0.4%)

•

Procedural complications: Infusion-related reaction (1.9%)

•

Respiratory, thoracic, and mediastinal disorders: Pleural effusion (7%), hypoxia (6%)

•

Vascular disorder: Thrombosis (7%)

6.2 Immunogenicity

BREYANZI has the potential to induce anti-product antibodies. The immunogenicity of BREYANZI has been evaluated using an electrochemiluminescence (ECL) immunoassay for the detection of binding antibodies against the extracellular CD19-binding domain of BREYANZI. Pre-existing anti-product antibodies were detected in 11% (28/261) of patients in TRANSCEND, 1% (1/89) of patients in TRANSFORM and 0% (0/51) of patients in PILOT. Treatment-induced or treatment-boosted anti-product antibodies were detected in 11% (27/257) in TRANSCEND, 1% (1/89) in TRANSFORM, and 2% (1/49) in PILOT, of patients, respectively. Due to the small number of patients who had anti-product antibodies, the relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics was not conclusive.

7.1 Drug-Laboratory Test Interactions

HIV and the lentivirus used to make BREYANZI have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received BREYANZI.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of BREYANZI have not been established in pediatric patients.

8.5 Geriatric Use

In clinical trials of BREYANZI, 111 (41%) of 268 patients with two or more prior lines of therapy for LBCL, and 89 (59%) of 150 patients with one prior line of therapy for LBCL, were 65 years of age or older; 27 (10%) and 28 (19%) were 75 years of age or older, respectively. No clinically important differences in safety or effectiveness of BREYANZI were observed between patients aged ≥ 65 and younger patients.

12.1 Mechanism of Action

BREYANZI is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion and persistence of BREYANZI.

CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells.

12.2 Pharmacodynamics

Following BREYANZI infusion, pharmacodynamic responses were evaluated over a 4-week period by measuring transient elevation of soluble biomarkers such as cytokines, chemokines, and other molecules. Peak elevation of soluble biomarkers was observed within the first 14 days after BREYANZI infusion and returned to baseline levels within 28 days.

B-cell aplasia, defined as CD19+ B cells comprising less than 3% of peripheral blood lymphocytes, is an on-target effect of BREYANZI. B-cell aplasia was observed in the majority of patients for up to 1 year following BREYANZI infusion.

12.3 Pharmacokinetics

Following infusion, BREYANZI exhibited an initial expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood occurred 10-12 days after infusion. BREYANZI was present in peripheral blood for an estimated median of 12.1 months (range: 0.1+ to 24.2+ months).

Among patients who received two or more prior lines of therapy for LBCL (TRANSCEND), responders (N=135) had a 2.3-fold higher median Cmax than nonresponders (N=37) (35,335 vs. 15,527 copies/µg). Responders had a 1.8-fold higher median AUC0-28d than nonresponders (273,552 vs. 155,240 day*copies/µg).

In TRANSCEND, patients with higher CAR-T cell expansion tended to have higher rates of CRS and neurologic toxicities. Patients treated with tocilizumab (N=49) had a 3.6-fold and 3.7-fold higher median Cmax and AUC0-28d, respectively, compared to patients who did not receive tocilizumab (N=189). Similarly, patients who received corticosteroids (N=50) had a 3.8-fold and 3.7-fold higher median Cmax and AUC0-28d, respectively, compared to patients who did not receive corticosteroids (N=188).

Patients < 65 years old (N=142) had a 3.1-fold and 2.3-fold higher median Cmax and AUC0-28d, respectively, compared to patients ≥ 65 years old (N=96). Sex, race, ethnicity, and body weight did not show clear relationships to Cmax and AUC0-28d.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with BREYANZI. No studies have been conducted to evaluate the effects of BREYANZI on fertility. In vitro studies with BREYANZI manufactured from healthy donors and patients showed no evidence for transformation and/or immortalization and no preferential integration near genes associated with oncogenic transformation.

Relapsed or Refractory LBCL After One Line of Therapy

TRANSFORM

A randomized, open-label, multicenter trial evaluated the efficacy of BREYANZI in adult patients with relapsed or refractory LBCL after first-line chemoimmunotherapy (TRANSFORM; NCT03575351). Patients had not yet received treatment for relapsed or refractory lymphoma, were potential candidates for autologous HSCT, and were required to have primary refractory disease or relapse within 12 months from complete response (CR) to initial chemoimmunotherapy. Eligibility criteria required adequate organ function and blood counts for HSCT.

In total, 184 patients were randomized in a 1:1 ratio to receive a single infusion of BREYANZI (planned dose, 100 × 106 CAR-positive viable T cells) or to receive standard therapy consisting of 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained CR or PR. All patients underwent leukapheresis prior to randomization.

Patients randomized to BREYANZI were to receive lymphodepleting chemotherapy consisting of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days followed by BREYANZI infusion 2 to 7 days after completion of lymphodepleting chemotherapy. Bridging chemotherapy was permitted between leukapheresis and the start of lymphodepleting chemotherapy. BREYANZI was administered in the inpatient (79%) and outpatient (21%) setting.

In the overall study population, the median age was 59 years (range: 20 to 75 years), 57% were male, 59% were white, 10% were Asian, and 4% were black. Diagnoses included de novo DLBCL NOS (55%), high-grade B-cell lymphoma (23%), primary mediastinal large B-cell lymphoma (10%), and DLBCL arising from indolent lymphoma (8%). Of these patients, 73% had primary refractory disease to last therapy and 27% had relapsed disease within 12 months of achieving CR to first-line therapy.

Of 92 patients randomized to receive BREYANZI, 89 (97%) received BREYANZI. The median time from leukapheresis to product availability was 26 days (range: 19 to 84 days), and the median time from leukapheresis to product infusion was 36 days (range: 25 to 91 days). Fifty-eight (63%) patients received bridging therapy. One patient received a nonconforming product (manufacturing failure; 1.1%).

Of the 92 patients randomized to receive standard therapy, 91 started treatment and 43 (47%) received high-dose therapy and HSCT. The most common reason for not receiving HSCT was lack of efficacy of the salvage chemotherapy.

The primary efficacy measure was event-free survival (EFS) as determined by an independent review committee (IRC). Other efficacy measures included progression-free survival. Efficacy is summarized in Table 9 and Figure 1. The estimated 1-year EFS was 45% [95% CI: 29, 59] in the BREYANZI arm and 24% [95% CI: 14, 35] in the standard therapy arm.

Of the 92 patients in the BREYANZI arm, the estimated median DOR was not reached (95% CI: 7.9 months, NR) in patients who achieved CR (N=61) and 2.3 months (95% CI: 2.1, NR) in patients who achieved a best response of PR (N=18).

An interim analysis of overall survival was conducted at the time of the primary EFS analysis. The interim analysis of overall survival did not meet the criteria for statistical significance. Forty-six patients randomized to the standard therapy arm (50%) subsequently received BREYANZI on protocol.

Figure 1: Kaplan-Meier Plot of IRC-Assessed Event-Free Survival (Intention-to- Treat Analysis)

PILOT

The efficacy of BREYANZI was evaluated in a single-arm, open-label, multicenter trial (PILOT; NCT03483103) in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy. The study enrolled patients who were not eligible for high-dose therapy and autologous HSCT due to organ function or age, while also having adequate organ function for CAR-T cell therapy. The study required at least one of the following criteria: age ≥ 70 years, adjusted diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 60%; LVEF < 50%; creatinine clearance < 60mL/min; AST or ALT greater than 2 × ULN, or ECOG performance status of 2. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. Bridging therapy for disease control was permitted between leukapheresis and the start of lymphodepleting chemotherapy. Of the 61 patients treated with BREYANZI, 32 (53%) received bridging therapy.

BREYANZI was administered two to seven days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient (67%) and outpatient (33%) setting.

Of 74 patients who underwent leukapheresis, 61 (82%) received BREYANZI and comprise the main efficacy population; 1 (1.4%) received CAR-positive T cells that did not meet the product specifications for BREYANZI (manufacturing failure); and 12 (16%) did not receive CAR-positive T cells for other reasons.

Of the 61 patients who received BREYANZI, the median age was 74 years (range: 53 to 84 years), 61% were male, 89% were white, 3% were Asian, and 2% were black. Diagnoses included de novo DLBCL NOS (51%), high-grade B-cell lymphoma (33%), and DLBCL arising from follicular lymphoma (15%). Of these patients, 53% had primary refractory disease, 23% had relapse within 12 months of completing first-line therapy, and 25% had relapse >12 months after first-line therapy.

Efficacy was based on complete response (CR) rate and duration of response (DOR), as determined by an independent review committee (IRC) using 2014 Lugano criteria (Tables 10 and 11). The median time to CR was 1 month (range 0.8 to 6.9 months).

Relapsed or Refractory LBCL After Two or More Lines of Therapy

TRANSCEND

The efficacy of BREYANZI was evaluated in an open-label, multicenter, single-arm trial (TRANSCEND; NCT02631044) in adult patients with relapsed or refractory large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. The study included patients with ECOG performance status ≤ 2, prior autologous and/or allogeneic HSCT, and secondary CNS lymphoma involvement. The study excluded patients with a creatinine clearance of less than 30 mL/min, alanine aminotransferase > 5 times the upper limit of normal, or left ventricular ejection fraction (LVEF) < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy, including intrathecal chemotherapy or radiation therapy for treatment of CNS involvement with lymphoma.

BREYANZI was administered two to seven days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient and outpatient setting.

Of 299 patients who underwent leukapheresis for whom BREYANZI was manufactured in the dose range of 50 to 110 × 106 CAR-positive viable T cells:

•

44 (15%) did not receive CAR-positive T cells either due to manufacturing failures (n=2), death (n=29), disease complications (n=6), or other reasons (n=7).

•

204 (68%) received BREYANZI in the intended dose range, of whom 192 were evaluable for efficacy (main efficacy population); 12 were not evaluable due to absence of PET positive disease at study baseline or after bridging therapy.

•

51 (17%) either received BREYANZI outside of the intended dose range (n=26) or received CAR-positive T cells that did not meet the product specifications for BREYANZI (manufacturing failures; n=25).

Of the 192 patients in the main efficacy population, the median age was 63 years (range: 18 to 86 years), 69% were male, 84% were white, 6% were black, and 4.7% were Asian. The median number of prior therapies was 3 (range: 1 to 8). Diagnoses were de novo DLBCL (53%), DLBCL transformed from indolent lymphoma (25%), high-grade B-cell lymphoma (14%), primary mediastinal large B-cell lymphoma (7%), follicular lymphoma, grade 3B (1.0%). Of these patients, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior HSCT and 2.6% had CNS involvement.

Efficacy was based on complete response (CR) rate and duration of response (DOR), as determined by an independent review committee (IRC) using 2014 Lugano criteria (Tables 12 and 13). The median time to first response (CR or partial response [PR]) was 1.0 month (range: 0.7 to 8.9 months). The median time to first CR was 1.0 month (range 0.8 to 12.5 months). Of the 104 patients who achieved CR, 23 initially had stable disease (6 patients) or PR (17 patients), with a median time to improvement of 2.2 months (range: 0.7 to 11.6 months).

CI=confidence interval.

DOR=duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached

Response durations were longer in patients who achieved a CR, as compared to patients with a best response of PR (Table 13). Of the 104 patients who achieved CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months.

Of the 287 patients who underwent leukapheresis and had radiographically evaluable disease, 27 additional patients achieved a response, apart from the responses noted in Table 12. The IRC-assessed overall response rate in the leukapheresed population (n=287) was 59% (95% CI: 53, 64), with a CR rate of 43% (95% CI: 37, 49) and PR rate of 15% (95% CI: 11, 20). These efficacy results include responses that may have been contributed solely by bridging therapy, responses after receipt of product outside of the intended dose range, and responses to product that did not meet release specifications.