Breyanzi (Lisocabtagene Maraleucel) Medical Drug Program Summary

Breyanzi (lisocabtagene maraleucel) Medical Drug Program Summary

For patients with late stage metastatic disease (Stage IV), please refer to MP 2.373 Step Therapy Treatment in Cancer, Including Treatments for Stage Four, Advanced Metastatic Cancer and Severe Related Health Conditions for additional guidance.

FDA APPROVED INDICATIONS AND DOSAGE1 Agent(s) Indication(s) Dosage Breyanzi® • Treatment of adult BLBCL: (lisocabtagene maraleucel) patients with relapsed or A single dose of Breyanzi refractory large B-cell contains 50 to 110 X 106 Suspension for intravenous lymphoma after two or CAR-positive viable T cells infusion more lines of systemic (consisting of 1:1 CAR- therapy, including positive viable T cells of the diffuse large B-cell CD8 and CD4 components) lymphoma (DLBCL) not with each component otherwise specified supplied separately in one (including DLBCL arising to four single-dose vials. from indolent See the respective lymphoma), high-grade Certificate of Release for B-cell lymphoma, Infusion (RFI Certificate) for primary mediastinal each component for the large B-cell lymphoma, actual cell counts and and follicular lymphoma volumes to be infused grade 3B

Limitations of Use: Breyanzi is not indicated for treatment of patients with primary central nervous system lymphoma

CLINICAL RATIONALE Diffuse Large B-cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphomas (NHL). DLBCL are the most common lymphoid neoplasms in adults, accounting for approximately 30% of NHLs diagnosed annually. Immunophenotypic analysis is essential for the differentiation of the various subtypes of NHL to establish the proper diagnosis. This can be performed by flow cytometry and/or immunohistochemistry (IHC). DLBCL is a mature B cell lymphoma. All mature B cells have immunoglobulin receptors and express CD19 and CD20, but can be divided into subgroups based on expression of other surface markers.2

DLBCL coexistent with a low grade lymphoma of any kind (e.g., follicular lymphoma, gastric MALT lymphoma, or non-gastric MALT lymphoma), intravascular large-B-cell lymphoma, DLBCL-associated with chronic inflammation, anaplastic lymphoma kinase (ALK)-positive DLBCL, Epstein-Barr virus (EBV)-positive DLBCL in older patients, and t-cell/histiocyte-rich large B-cell lymphoma are also managed according to the DLBCL guidelines.2

Follicular lymphoma (FL) is another subtype of NHL. Pathologic grading according to the number of centroblasts is considered to be a clinical predictor of outcome. Clinical outcomes for patients with FL1 and FL2 are grouped under a single grade (FL1-2). The WHO

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© Copyright Prime Therapeutics LLC. 08/2021 All Rights Reserved Effective: 09/01/2021 classification mandates stratifying FL3 into either 3A (centrocytes still present) or 3B (sheets of centroblasts). Therefore, FL is divided into three grades (FL1-2, FL3A, and FL3B) based on the number of centroblasts.2

FL1-2 should be managed according to the treatment recommendations for FL. However, controversy exists regarding management of FL grade 3. There is no difference in survival outcomes between patients with FL3A and FL3B, although FL3 with > 50% diffuse component has an inferior survival outcome to that of DLBCL.2

For years, the foundations of cancer treatment were surgery, chemotherapy, and radiation therapy. But over the past several years, immunotherapy (therapies that enlist and strengthen the power of a patient’s immune system to attack tumors) has emerged as what many in the cancer community now call the “fifth pillar” of cancer treatment.3

A rapidly emerging immunotherapy approach is called adoptive cell transfer (ACT): collecting and using the patient’s own immune cells to treat their cancer. There are several types of ACT: tumor-infiltrating lymphocytes (TILs), T-Cell receptors (TCRs), and chimeric antigen receptors (CAR). TILs use immune cells that have penetrated the environment in and around the tumor. TCRs and CARs involve engineering patient’s T-cells to express a specific T-cell receptor. CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs on the other hand, use naturally occurring receptors that can also recognize antigens that are inside tumor cells. Small pieces of these antigens are then shuttled to the cell surface and “presented” to the immune system as part of a collection of proteins called the MHC complex. At this time, CAR T-cell therapy is the one that has advanced the furthest in clinical development.3

The National Comprehensive Cancer Network (NCCN) recommends CAR T-cell therapy (if not previously given) for patients who have received ≥ 2 prior chemoimmunotherapy regimens. It should be noted that data on the efficacy of transplant in patients who have received CAR T-cell therapy are not available. HDT/ASCR is not recommended after CAR T- cell therapy. Allogenic HCT could be considered but remains investigational.2

Efficacy1 Breyanzi is a CD 19-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 (CD 137) costimulatory domain, and CD3 zeta activation domain.

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.

The efficacy of Breyanzi was evaluated in an open-label, multicenter, single-arm trial (TRANSCEND) 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 allogenic hematopoietic stem cell transplant (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 < 40%.

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. The

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© Copyright Prime Therapeutics LLC. 08/2021 All Rights Reserved Effective: 09/01/2021 overall response rate was 73% with 54% of patients showing complete response and 19% of patients showing partial response (95% CI). The median duration of response was 16.7 months (95% CI) with longer response durations in patients who achieved a CR as compared to patients with a best response of PR.

Safety Breyanzi (lisocabtagene maraleucel) has no FDA labeled contraindications but does contain the following black box warning:1 • 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

The Breyanzi REMS program includes the following components:4 • Hospitals and their associated clinics must be enrolled in the Breyanzi REMS program to be able to infuse Breyanzi • All relevant staff involved in the prescribing, dispensing, or administering of Breyanzi are trained on Breyanzi REMS program requirements and must successfully complete the Breyanzi REMS Program Knowledge Assessment and maintain records of staff training • Put processes and procedures in place to ensure that staff involved in the prescribing, dispensing, or administering of Breyanzi are retrained on Breyanzi REMS if Breyanzi has not been dispensed at least once annually for the date of certification in the Breyanzi REMS • Dispense Breyanzi only after verifying a minimum of 2 doses of tocilizumab are available on-site for each patient and are ready for immediate administration (within 2 hours) • Prior to infusion, provide patients/caregivers with the Patient Wallet Card and instruct patient to remain within 2 hours of the certified hospital and its associated clinics for at least 4 weeks following Breyanzi infusion • Ensure that, if the hospital and its associated clinics designate a replacement authorized representative (AR), the replacement AR must take the Breyanzi REMS Live Training Program (in-person or via live webcast), complete the Breyanzi REMS knowledge assessment, and complete/submit a new Breyanzi REMS Enrollment Form

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TARGET AGENT(S) Breyanzi® (lisocabtagene maraleucel)

Brand (generic) GPI HCPCS / J Multisource Code Code Breyanzi* (lisocabtagene maraleucel) 21651050401820 C9076 M, N, O, or Y

Patient individualized vials *Therapy with this agent is limited to one course per lifetime

CRITERIA FOR APPROVAL Evaluation Target Agent(s) will be approved when ALL of the following are met: 1. The patient has a diagnosis of relapsed or refractory large B-cell lymphoma, 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 (note: patient must meet all aspects of the diagnosis as indicated) AND 2. The patient does NOT have primary central nervous system lymphoma AND 3. ONE of the following: A. The patient has relapsed or has refractory large B-cell lymphoma after two or more lines of systemic therapy OR B. The patient has stage four, advanced metastatic cancer or a severe adverse health condition experienced as a result of stage four, advanced metastatic cancer AND 4. ONE of the following: A. The patient’s age is within FDA labeling for the requested agent for the requested indication OR B. The prescriber has provided information in support of the requested agent for the patient’s age for the requested indication AND 5. The patient does NOT have active uncontrolled infection including Hepatitis B, Hepatitis C, or HIV infection AND 6. The patient does NOT have any FDA labeled contraindications to the requested agent AND 7. The patient has NOT previously been treated with the requested agent or another CAR- T therapy (e.g., Kymriah, Yescarta) AND 8. The patient has NOT been treated with other gene therapy

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