Lunsumio Velo

1 INDICATIONS AND USAGE LUNSUMIO VELO is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1.1 ) 1.1 Follicular Lymphoma LUNSUMIO VELO is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION LUNSUMIO VELO and LUNSUMIO have different dosage and route of administration instructions. Administer LUNSUMIO VELO only as a subcutaneous injection. ( 2.1 ) Premedicate to reduce risk of CRS. ( 2.3 , 5.1 ) Recommended dosage for LUNSUMIO VELO for subcutaneous injection ( 2.2 ): Day of Treatment Cycle length = 21 days Subcutaneous Dose of LUNSUMIO VELO Cycle 1 Day 1 5 mg Day 8 45 mg Day 15 45 mg Cycles 2+ Day 1 45 mg See Full Prescribing Information for instructions on preparation and administration. ( 2.5 ) 2.1 Important Dosing Information LUNSUMIO VELO and LUNSUMIO have different dosage and administration instructions [see Dosage and Administration (2.2) and Warnings and Precautions (5.7) ]. LUNSUMIO VELO is for subcutaneous use only. Check the product label to ensure that the correct formulation (LUNSUMIO VELO or LUNSUMIO) is being prescribed and administered. Do not substitute LUNSUMIO VELO for or with LUNSUMIO. Administer LUNSUMIO VELO to well-hydrated patients. Premedicate before each dose in Cycle 1 [see Dosage and Administration (2.3) ] . LUNSUMIO VELO should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 and 5.2) ] . 2.2 Recommended Dosage The recommended dosage for LUNSUMIO VELO subcutaneous injection is presented in Table 1 . Administer for 8 cycles unless patients experience unacceptable toxicity or disease progression. For patients who achieve a complete response, no further treatment beyond 8 cycles is required. For patients who achieve a partial response or have stable disease in response to treatment with LUNSUMIO VELO after 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless a patient experiences unacceptable toxicity or disease progression. Table 1. Recommended Dose and Schedule of LUNSUMIO VELO Subcutaneous Injection (21-Day Treatment Cycles) Day of Treatment Subcutaneous Dose of LUNSUMIO VELO Cycle 1 Day 1 5 mg Day 8 45 mg Day 15 45 mg Cycles 2+ Day 1 45 mg Table 2. Recommendations for Restarting Therapy with LUNSUMIO VELO Subcutaneous Injection After Dose Delay Last Subcutaneous Dose Administered Time Since Last Dose Administered Action for Next Subcutaneous Dose(s) 5 mg Cycle 1 Day 1 1 week to 2 weeks Administer 45 mg (Cycle 1 Day 8) Administer premedication as per Cycle 1. , then resume the planned treatment schedule. Greater than 2 weeks Repeat 5 mg (Cycle 1 Day 1) , then administer 45 mg (Cycle 1 Day 8) and resume the planned treatment schedule. 45 mg Cycle 1 Day 8 1 week to less than 6 weeks Administer 45 mg (Cycle 1 Day 15) , then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 5 mg , then administer 45 mg (Cycle 1 Day 15) 7 days later and resume the planned treatment schedule. 45 mg Cycle 1 Day 15 1 week to less than 6 weeks Administer 45 mg (Cycle 2 Day 1), then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 5 mg (Cycle 2 Day 1) , then administer 45 mg (Cycle 2 Day 8) followed by 45 mg on Day 1 of subsequent cycles. 45 mg Cycle 2 onwards 3 weeks to less than 6 weeks Administer 45 mg, then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 5 mg on Day 1 during the next cycle, then administer 45 mg on Day 8, followed by 45 mg on Day 1 of subsequent cycles. 2.3 Recommended Premedication Premedications to reduce the risk of CRS are outlined in Table 3 [see Warnings and Precautions (5.1) ] . Table 3. Premedication to be Administered Prior to LUNSUMIO VELO Subcutaneous Injection Treatment Cycle Patients Requiring Premedication Premedication Dosage Cycle 1 All patients Corticosteroid Dexamethasone 20 mg (preferred) oral or intravenous or methylprednisolone 80 mg oral or intravenous Antihistamine Antihistamine and antipyretic premedications are optional in all cycles. Diphenhydramine hydro …

3 DOSAGE FORMS AND STRENGTHS LUNSUMIO VELO is a sterile, colorless to slightly brownish-yellow solution for subcutaneous injection available as: Injection: 5 mg/0.5 mL in a single-dose vial Injection: 45 mg/mL in a single-dose vial Injection : 5 mg/0.5 mL solution in a single-dose vial. ( 3 ) 45 mg/mL solution in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2) ] Infections [see Warnings and Precautions (5.3) ] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.4) ] Cytopenias [see Warnings and Precautions (5.5) ] Tumor Flare [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥ 20%) are injection site reactions, fatigue, rash, CRS, COVID-19 infection, musculoskeletal pain, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 15%) are decreased lymphocyte count, decreased neutrophil count, and increased uric acid. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Relapsed or Refractory Follicular Lymphoma The safety of LUNSUMIO VELO was evaluated in an open-label, multicenter study which included a cohort of 94 patients with relapsed or refractory follicular lymphoma (FL) after at least two lines of systemic therapy [see Clinical Studies (14) ] . Patients received step-up doses of 5 mg via subcutaneous injection on Cycle 1 Day 1 and 45 mg on Cycle 1 Day 8, followed by 45 mg on Cycle 1 Day 15, then 45 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. The median number of cycles was 8 (range: 1 to 17), with 78% of patients exposed for at least 8 cycles and 6% exposed for 17 cycles. The median age was 65 years (range: 35 to 84 years), 56% were male, 85% were White, 2.1% were Black or African American, 11% were Asian, and 2% were Hispanic or Latino. Serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥ 10% of patients included infection (17%, including pneumonia, other respiratory tract infections, and sepsis) and CRS (15%). Fatal adverse reactions occurred in 4.3% of patients from COVID-19 (3.2%) and HLH (1.1%). Permanent discontinuation of LUNSUMIO VELO due to an adverse reaction occurred in 7% of patients, including from COVID-19. Dosage interruptions of LUNSUMIO VELO due to an adverse reaction occurred in 40% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included COVID-19 and neutropenia. The most common adverse reactions (≥ 20%), excluding laboratory abnormalities, were injection site reactions, fatigue, rash, CRS, COVID-19 infection, musculoskeletal pain, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥ 15%) were decreased lymphocyte count, decreased neutrophil count, and increased uric acid. Grade 4 laboratory abnormalities in > 5% included lymphocyte count decreased (22%) and neutrophil count decreased (9%). Table 7 summarizes the adverse reactions. Table 7. Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received LUNSUMIO VELO Subcutaneous Injection in GO29781 Adverse Reaction LUNSUMIO VELO (N = 94) All Grades (%) Grade 3 or 4 (%) Immune system disorders The table includes a combination of grouped and ungrouped terms. Adverse reactions were graded based on CTCAE Version 4.0, with the exception of CRS, which was graded per ASTCT 2019 criteria. Cytokine release syndrome 30 2.1 General disorders and administration site conditions Injection site reactions Injection site reactions includes injection site reaction, injection site discharge, injection site erythema, injection site edema, injection site pain, injection site pruritus and injection site rash. 69 0 Fatigue Fatigue includes fatigue, asthenia, and lethargy. 39 0 Edema Edema includes edema, ed …

7 DRUG INTERACTIONS Effect of LUNSUMIO VELO on CYP450 Substrates LUNSUMIO VELO causes release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress activity of CYP450 enzymes, resulting in increased exposure of CYP450 substrates. Increased exposure of CYP450 substrates is more likely to occur after the first dose of LUNSUMIO VELO on Cycle 1 Day 1 and up to 14 days after the 45 mg dose on Cycle 1 Day 8 and during and after CRS [see Warnings and Precautions (5.1) ] . Monitor for toxicity or concentrations of drugs that are CYP450 substrates where minimal concentration changes may lead to serious adverse reactions. Consult the concomitant CYP450 substrate drug prescribing information for recommended dosage modification.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on the mechanism of action, LUNSUMIO VELO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of LUNSUMIO VELO in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with mosunetuzumab-axgb. Mosunetuzumab-axgb causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, mosunetuzumab-axgb can cause B-cell lymphocytopenia in infants exposed to mosunetuzumab-axgb in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, LUNSUMIO VELO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of mosunetuzumab-axgb in human milk, the effect on the breastfed child, or milk production. Because human IgG is present in human milk, and there is potential for mosunetuzumab-axgb absorption leading to B-cell depletion, advise women not to breastfeed during treatment with LUNSUMIO VELO and for 3 months after the last dose. 8.3 Females and Males of Reproductive Potential LUNSUMIO VELO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating LUNSUMIO VELO. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO VELO and for 3 months after the last dose. 8.4 Pediatric Use The safety and efficacy of LUNSUMIO VELO have not been established in pediatric patients. 8.5 Geriatric Use Among the 94 patients treated with LUNSUMIO VELO, 51% were 65 years of age or older. There is an insufficient number of patients 65 years of age or older to assess whether there are differences in safety or effectiveness by age group.

12.1 Mechanism of Action Mosunetuzumab-axgb is a T-cell engaging bispecific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and some healthy B-lineage cells. In vitro, mosunetuzumab-axgb activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells.

11 DESCRIPTION Mosunetuzumab-axgb is a bispecific CD20-directed CD3 T-cell engager. It is a humanized monoclonal anti-CD20xCD3 T-cell-dependent bispecific antibody of the immunoglobulin G1 (IgG1) isotype. Mosunetuzumab-axgb is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. The approximate molecular weight is 146 kDa. LUNSUMIO VELO (mosunetuzumab-axgb) injection is a sterile, preservative-free, colorless to slightly brownish-yellow solution for subcutaneous use. Each single-dose vial contains a 0.5 mL solution of mosunetuzumab-axgb (5 mg), acetic acid (0.2 mg), histidine (0.8 mg), methionine (0.7 mg), polysorbate 20 (0.3 mg), sucrose (41 mg), and Water for Injection, USP. The pH is 5.8. Each single-dose vial contains a 1 mL solution of mosunetuzumab-axgb (45 mg), acetic acid (0.4 mg), histidine (1.6 mg), methionine (1.5 mg), polysorbate 20 (0.6 mg), sucrose (82.1 mg), and Water for Injection, USP. The pH is 5.8.

16 HOW SUPPLIED/STORAGE AND HANDLING LUNSUMIO VELO (mosunetuzumab-axgb) injection is a sterile, colorless to slightly brownish-yellow, preservative-free solution for subcutaneous injection supplied as follows: One 5 mg/0.5 mL single-dose vial in a carton (NDC 50242-177-01) One 45 mg/mL single-dose vial in a carton (NDC 50242-201-01). Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.