LUNSUMIO VELO

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.

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).

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 hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine Antipyretic Oral acetaminophen (500 mg to 1,000 mg) Cycles 2+ Patients who experienced any grade CRS with the previous dose Corticosteroid Dexamethasone 20 mg (preferred) oral or intravenous or methylprednisolone 80 mg oral or intravenous Antihistamine Diphenhydramine hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine Antipyretic Oral acetaminophen (500 mg to 1,000 mg) 2.4 Dosage Modifications for Adverse Reactions See Tables 4 and 5 for the recommended dosage modifications for adverse reactions of CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity (ICANS). See Table 6 for the recommended dosage modifications for other adverse reactions following administration of LUNSUMIO VELO. Dosage Modifications for Cytokine Release Syndrome Identify CRS based on clinical presentation [see Warnings and Precautions (5.1) ] . Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold LUNSUMIO VELO until CRS resolves, manage according to the recommendations in Table 4 and per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Table 4. Recommendations for Management of Cytokine Release Syndrome with LUNSUMIO VELO Subcutaneous Administration Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS. Presenting Symptoms Actions If CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis. Grade 1 Fever ≥ 100.4°F (38°C) Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines. Ensure CRS symptoms are resolved prior to the next dose of LUNSUMIO VELO. Refer to Table 2 for information on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2) ] . Administer premedication Refer to Table 3 for additional information on premedication. prior to next dose of LUNSUMIO VELO and monitor patient more frequently. Grade 2 Fever ≥ 100.4°F (38°C) with: Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO VELO. Hypotension not requiring vasopressors Administer premedication prior to next dose of LUNSUMIO VELO. and/or For the next dose of LUNSUMIO VELO, monitor more frequently and consider hospitalization. hypoxia requiring low-flow oxygen Low-flow oxygen defined as oxygen delivered at < 6 L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute. by nasal cannula or blow-by. Recurrent Grade 2 CRS Manage per Grade 3 CRS. Grade 3 Fever ≥ 100.4°F (38°C) with: Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO VELO. Hypotension requiring a vasopressor (with or without vasopressin) Administer premedication prior to next dose of LUNSUMIO VELO. and/or For the next dose of LUNSUMIO VELO, monitor more frequently and hospitalize for the next dose. hypoxia requiring high flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask. If CRS occurred after the 5 mg or 45 mg dose, administer 5 mg as the next dose. Resume treatment schedule after recovery. If the 5 mg dose is tolerated without grade 3 CRS, resume subsequent doses at 45 mg. Recurrent Grade 3 CRS Permanently discontinue LUNSUMIO VELO. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Grade 4 Fever ≥ 100.4°F (38°C) with: Permanently discontinue LUNSUMIO VELO. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation). Dosage Modifications for Neurologic Toxicity, including ICANS Management recommendations for neurologic toxicity, including ICANS, are summarized in Table 5 . At the first sign of neurologic toxicity, including ICANS, consider neurology evaluation and withholding of LUNSUMIO VELO based on the type and severity of neurotoxicity. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care. Table 5. Recommendations for Management of Neurologic Toxicity (including ICANS) Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. , Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS. Actions Neurologic Toxicity (including ICANS ) Grade 1 Continue LUNSUMIO VELO and monitor neurologic toxicity symptoms. If ICANS, manage per current practice guidelines. Grade 2 Withhold LUNSUMIO VELO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours. See Table 2 for recommendations on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2) ] . Provide supportive therapy, and consider neurologic evaluation. If ICANS, manage per current practice guidelines. Grade 3 Withhold LUNSUMIO VELO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours. Provide supportive therapy, which may include intensive care, and consider neurology evaluation. If ICANS, manage per current practice guidelines. If recurrence of ICANS, permanently discontinue LUNSUMIO VELO. Grade 4 Permanently discontinue LUNSUMIO VELO. Provide supportive therapy, which may include intensive care, and consider neurology evaluation. If ICANS, manage per current practice guidelines. Other Adverse Reactions Table 6. Recommended Dosage Modification for Other Adverse Reactions Adverse Reactions Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. Severity Actions Infections [see Warnings and Precautions (5.3) ] Grades 1 – 4 Withhold LUNSUMIO VELO in patients with active infection until the infection resolves. See Table 2 for recommendations on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2) ] . For Grade 4, consider permanent discontinuation of LUNSUMIO VELO. Neutropenia [see Warnings and Precautions (5.4) ] Absolute neutrophil count less than 0.5 × 10 9 /L Withhold LUNSUMIO VELO until absolute neutrophil count is 0.5 × 10 9 /L or higher. Other Adverse Reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] Grade 3 or higher Withhold LUNSUMIO VELO until the toxicity resolves to Grade 1 or baseline. Permanently discontinue LUNSUMIO VELO if a Grade 4 injection site reaction occurs. 2.5 Preparation and Administration If the LUNSUMIO VELO dose is not administered immediately, refer to "Storage of Prepared Syringe" section below. To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is LUNSUMIO VELO for subcutaneous administration. A peel-off label is provided on the LUNSUMIO VELO Prescribing Information that should be attached to the final prepared syringe. Remove the peel-off label from the Prescribing Information in the LUNSUMIO VELO carton before discarding the carton. Affix the peel-off label to the prepared LUNSUMIO VELO syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is discolored, or cloudy, or if foreign particles are present. Each LUNSUMIO VELO 5 mg/0.5 mL and 45 mg/mL vial are supplied as ready-to-use solution that do not need dilution prior to subcutaneous administration. LUNSUMIO VELO vials are for one-time use in one patient only. No incompatibilities between LUNSUMIO VELO and polypropylene or polycarbonate syringe material, stainless-steel transfer and injection needles, and polyethylene or polypropylene syringe closing caps have been observed. Preparation of the Syringe Use aseptic technique to prepare LUNSUMIO VELO. Select the appropriate strength vial based on the prescribed dose. Withdraw the required volume of LUNSUMIO VELO solution from the vial with a syringe and an appropriately sized transfer needle (18G to 21G recommended). The smallest syringe that can accurately deliver the injection volume should be used. Discard any unused portion left in the vial. Remove the transfer needle and attach an appropriately sized injection needle (25G to 30G recommended). Apply peel-off label from the Prescribing Information to the prepared drug product. Once transferred from the vial to the syringe, LUNSUMIO VELO solution for injection should be injected immediately because LUNSUMIO VELO solution for injection does not contain any antimicrobial-preservative. Administration Inject the required volume of LUNSUMIO VELO into the subcutaneous tissue of the abdomen or thigh, changing the site of injection with each dose. Do not inject into tattoos, moles, scars or areas where the skin is red, bruised, tender, hard, or not intact. The dose should be administered subcutaneously over approximately 30 seconds to 1 minute. Storage of Prepared Syringe The prepared syringe should be used immediately. If not used immediately, replace the transfer needle with a syringe closing cap. Do not attach an injection needle. The capped syringe can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 32 hours protected from light and/or at 9°C to 25°C (37°F to 77°F) for up to 8 hours at ambient light. Once removed from refrigerated storage, the solution can be equilibrated to ambient temperature up to 25°C (77°F) prior to administration. Do not warm LUNSUMIO VELO in any other way.

None. None. ( 4 )

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 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, edema peripheral, face edema, pulmonary edema, fluid overload, and related terms. 13 0 Pyrexia 11 1.1 Chills 11 0 Skin and subcutaneous tissue disorders Rash Rash includes rash, injection site rash, erythema, dermatitis, palmar-plantar erythrodysesthesia, erythema multiforme, urticaria, and related terms. 35 3.2 Dry skin 11 0 Nervous system Headache 17 0 Peripheral neuropathy Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, dysesthesia, hypoesthesia, burning sensation, and neuralgia. 11 0 Dizziness Dizziness includes dizziness and vertigo. 10 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, back pain, myalgia, musculoskeletal chest pain, and neck pain. 20 0 Arthralgia 13 0 Respiratory, thoracic, and mediastinal disorders Cough 13 0 Dyspnea 11 0 Gastrointestinal disorders Diarrhea 20 0 Nausea 14 0 Constipation 14 0 Abdominal pain 13 0 Infections COVID-19 Adverse reaction with fatal outcome. , Grade 5 COVID-19 occurred in 3.2% of patients. 27 4.3 Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, rhinovirus infection, and related terms. 15 2.1 Pneumonia Pneumonia includes lung consolidation and specific types of pneumonia including COVID-19 pneumonia. 13 4.3 Psychiatric disorder Insomnia 15 0 Clinically relevant adverse reactions in < 10% of patients who received LUNSUMIO VELO included pruritus, skin exfoliation, herpes zoster infection, tremor, sepsis, cytomegalovirus (CMV) infection, ICANS, febrile neutropenia, capillary leak syndrome, tumor flare, and HLH . Table 8 summarizes select laboratory abnormalities. Table 8. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received LUNSUMIO VELO Subcutaneous Injection in GO29781 Laboratory Abnormality LUNSUMIO VELO The denominator used to calculate the rate varied from 85 to 94 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocyte count decreased 84 69 Hemoglobin decreased 60 10 Neutrophils decreased 50 26 Platelets decreased 33 6.4 Chemistry Phosphate decreased 48 11 Alanine aminotransferase increased 34 1.1 Gamma-glutamyl transferase increased 31 1.1 Uric acid increased 28 28 Aspartate aminotransferase increased 28 2.1 Potassium decreased 27 0 Magnesium decreased 25 2.1 Clinically relevant laboratory abnormalities in < 20% of patients included glucose increased.

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.

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.