Mosunetuzumab

LUNSUMIO 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 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 is a sterile, colorless solution for intravenous infusion available as: Injection: 1 mg/mL in a single-dose vial Injection: 30 mg/30 mL (1 mg/mL) in a single-dose vial Injection: 1 mg/mL solution in a single-dose vial. ( 3 ) 30 mg/30 mL (1 mg/mL) solution in a single-dose vial. ( 3 )

None. None. ( 4 )

Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome : Can cause serious and life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS). Monitor patients for signs and symptoms of neurologic toxicity during treatment; withhold or permanently discontinue based on severity. ( 5.2 ) Infections : Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. ( 5.3 ) Hemophagocytic Lymphohistiocytosis: Can cause serious or fatal reactions. For suspected cases, interrupt LUNSUMIO and evaluate and treat promptly. ( 5.4 ) Cytopenias : Monitor complete blood cell counts during treatment. ( 5.5 ) Tumor Flare : Can cause serious tumor flare reactions. Monitor patients at risk for complications of tumor flare. ( 5.6 ) Risk of Medication Errors with Incorrect Product Use : Ensure that the correct formulation is being prescribed, dispensed, and administered. ( 5.7 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 )

5.1 Cytokine Release Syndrome LUNSUMIO can cause CRS, including serious or life-threatening reactions [see Adverse Reactions (6.1 )] . CRS occurred in 39% of patients who received LUNSUMIO at the recommended dosage in the clinical trial, with Grade 1 CRS occurring in 28%, Grade 2 in 15%, Grade 3 in 2%, and Grade 4 in 0.5% of patients. Among 86 patients who experienced CRS, CRS recurred in 28%. Most cases of CRS occurred following doses of 1 mg on Cycle 1 Day 1 (15%), 2 mg on Cycle 1 Day 8 (5%), and 60 mg on Cycle 1 Day 15 (33%). Five percent of patients experienced CRS after receiving 60 mg on Cycle 2 Day 1 with 1% of patients experiencing CRS following subsequent dosages of LUNSUMIO. The median time to onset of CRS from the start of administration of LUNSUMIO in Cycle 1 Day 1 was 5 hours (range: 1 hour to 3 days), Cycle 1 Day 8 was 28 hours (range: 5 hours to 3 days), Cycle 1 Day 15 was 25 hours (range: 0.1 hours to 16 days), and Cycle 2 Day 1 was 46 hours (range: 12 hours to 3 days). The median duration of CRS was 3 days (range: 1 to 29 days). Clinical signs and symptoms of CRS included, but were not limited to, fever, chills, hypotension, tachycardia, hypoxia, and headache. Concurrent neurologic adverse reactions occurred in 6% of patients and included but were not limited to headache, confusional state, and anxiety. Initiate therapy according to LUNSUMIO step-up dosing schedule to reduce the risk of CRS. Administer pretreatment medications to reduce the risk of CRS, ensure adequate hydration, and monitor patients following administration of LUNSUMIO accordingly [see Dosage and Administration (2.2 and 2.3) ] . At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines and administer supportive care; withhold or permanently discontinue LUNSUMIO based on severity [see Dosage and Administration (2.4) ] . Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.2 Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome LUNSUMIO can cause serious and life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1) ] . Neurologic toxicity occurred in 39% of patients who received LUNSUMIO at the recommended dosage in the clinical trial, with Grade 3 neurologic toxicity occurring in 3% of patients. The most frequent neurologic toxicities were headache (21%), peripheral neuropathy (13%), dizziness (11%) and mental status changes (6%, including confusional state, disturbance in attention, cognitive disorder, delirium, encephalopathy, and somnolence). ICANS was reported in 1% of patients (Grade 1: 0.5%, Grade 2: 0.5%) who received LUNSUMIO at the recommended dosage in the clinical trial. Across a broader clinical trial population, ICANS or suspected ICANS occurred in 2.2% (21/949) of patients who received LUNSUMIO or LUNSUMIO VELO. The most frequent manifestations included confusional state and lethargy. Twenty patients had Grade 1-2 events and 1 patient had a Grade 3 event. The majority of cases (75%) occurred during the first cycle of treatment. The median time to onset was 17 days (range: 1 to 48 days). In total, 88% of cases resolved after a median duration of 3 days (range: 1 to 20 days). Coadministration of LUNSUMIO with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient, consider neurology evaluation as appropriate, and provide supportive therapy based on severity; withhold or permanently discontinue LUNSUMIO based on severity and follow management recommendations [see Dosage and Administration (2.4) ] . Patients who experience neurologic toxicity such as tremors, dizziness, insomnia, severe neurotoxicity, or any other adverse reactions that impair consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.3 Infections LUNSUMIO can cause serious or fatal infections [see Adverse Reactions (6.1) ] . Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, serious infections, including opportunistic infections, occurred in 17%, with Grade 3 or 4 infections in 14% and fatal infections in 0.9% of patients. The most common Grade 3 or greater infections were pneumonia, sepsis, and upper respiratory infection. Monitor patients for signs and symptoms of infection prior to and during treatment with LUNSUMIO and treat appropriately. LUNSUMIO should not be administered in the presence of active infection. Caution should be exercised when considering the use of LUNSUMIO in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Administer prophylactic antimicrobials according to guidelines. Withhold LUNSUMIO or consider permanent discontinuation of LUNSUMIO based on severity [see Dosage and Administration (2.4) ] .

5.4 Hemophagocytic Lymphohistiocytosis LUNSUMIO can cause fatal or serious hemophagocytic lymphohistiocytosis (HLH). HLH is a potentially life-threatening, hyperinflammatory syndrome that is independent of CRS. Common manifestations include fever, elevated ferritin, hemophagocytosis, cytopenias, coagulopathy, hepatitis, and splenomegaly. Across a broader clinical trial population, HLH occurred in 0.5% (7/1536) of patients. Most cases (5/7) were identified within the first 28 days following initiation of LUNSUMIO or LUNSUMIO VELO, with 3 cases preceded by diagnosed or suspected CRS. Of the 7 cases of HLH, 6 had fatal outcomes, with 2 deaths from HLH alone and 4 deaths with concurrent unresolved HLH. Of the 7 cases of HLH, 4 occurred in the context of concurrent EBV and/or CMV infection. Monitor for clinical signs and symptoms of HLH. Consider HLH when the presentation of CRS is atypical or prolonged, or when there are features of macrophage activation. For suspected HLH, interrupt LUNSUMIO and evaluate and treat promptly for HLH per current practice guidelines.

5.5 Cytopenias LUNSUMIO can cause serious or severe cytopenias, including lymphopenia, neutropenia, anemia, and thrombocytopenia [see Adverse Reactions (6.1) ] . […]

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%) in patients with follicular lymphoma are CRS, fatigue, rash, headache, pyrexia, musculoskeletal pain, cough, pruritus, and peripheral neuropathy. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased lymphocyte count, decreased phosphate, increased glucose, decreased neutrophil count, increased uric acid, decreased hemoglobin, and decreased platelets. ( 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to LUNSUMIO as a single agent in GO29781 in 218 patients with hematologic malignancies in an open-label, multicenter, multi-cohort study. Patients received step-up doses of 1 mg on Cycle 1 Day 1 and 2 mg on Cycle 1 Day 8, followed by 60 mg on Cycle 1 Day 15, and 60 mg on Cycle 2 Day 1, then 30 mg every 3 weeks in subsequent cycles. Each treatment cycle was 21 days. Among 218 patients who received LUNSUMIO, 52% were exposed for at least 8 cycles and 8% were exposed for 17 cycles. In this pooled safety population, the most common (≥ 20%) adverse reactions were CRS (39%), fatigue (36%), rash (34%), pyrexia (24%), and headache (21%). The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count (92%), decreased phosphate (41%), increased glucose (40%), decreased neutrophil count (38%), decreased hemoglobin (19%), increased uric acid (15%), and decreased platelets (12%). Relapsed or Refractory Follicular Lymphoma The safety of LUNSUMIO was evaluated in GO29781, an open-label, multicenter, multi-cohort study which included a cohort of 90 patients with relapsed or refractory follicular lymphoma (FL) [see Clinical Studies (14) ] . In this cohort, patients with relapsed or refractory FL were required to have received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. Patients received step-up doses of 1 mg on Cycle 1 Day 1 and 2 mg on Cycle 1 Day 8, followed by 60 mg on Cycle 1 Day 15 and 60 mg on Cycle 2 Day 1, then 30 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. The median number of cycles was 8 (range: 1 to 17). In the relapsed or refractory FL cohort, 77% were exposed for at least 8 cycles and 12% were exposed for 17 cycles. The median age was 60 years (range: 29 to 90 years), 61% were male, 82% were White, 4% were Black or African American, 9% were Asian, and 8% were Hispanic or Latino. Serious adverse reactions occurred in 47% of patients who received LUNSUMIO. Serious adverse reactions in ≥ 2% of patients included CRS, infection (including sepsis, pneumonia, urinary tract infection, EBV viremia, COVID-19, and upper respiratory tract infection), renal insufficiency, pyrexia, and tumor flare. Permanent discontinuation of LUNSUMIO due to an adverse reaction occurred in 3% of patients. Adverse reactions resulting in permanent discontinuation of LUNSUMIO included CRS and EBV viremia. Dosage interruptions of LUNSUMIO due to an adverse reaction occurred in 37% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia, infection, and CRS. Table 8 summarizes the adverse reactions in patients with relapsed or refractory FL treated with LUNSUMIO in GO29781. Table 8. Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received LUNSUMIO Intravenous Infusion in GO29781 Adverse Reaction Adverse reactions were graded based on CTCAE Version 4.0, with the exception of CRS, which was graded per ASTCT 2019 criteria. LUNSUMIO (N = 90) All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome 44

2.2 General disorders and administration site conditions Fatigue Fatigue includes fatigue, asthenia, and lethargy. 42 0 Pyrexia 29

1.1 Only Grade 3 adverse reactions occurred. Edema Edema includes edema, edema peripheral, peripheral swelling, face edema, swelling face, pulmonary edema, fluid overload, and fluid retention. 17

1.1 Chills 13

1.1 Skin and subcutaneous tissue disorders Rash Rash includes rash, rash erythematous, exfoliative rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, erythema, palmar erythema, dermatitis, and dermatitis acneiform. 39

4.4 Pruritus 21 0 Dry skin 16 0 Skin exfoliation 10 0 Nervous system Headache Headache includes headache and migraine. 32

1.1 Peripheral neuropathy Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, paresthesia, dysesthesia, hypoesthesia, burning sensation, and neuralgia. 20 0 Dizziness Dizziness includes dizziness and vertigo. 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, back pain, myalgia, musculoskeletal chest pain, and neck pain. 28

1.1 Arthralgia 11 0 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough, productive cough, and upper airway cough syndrome. 22 0 Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 11

1.1 Gastrointestinal disorders Diarrhea 17 0 Nausea 17 0 Abdominal pain Abdominal pain includes abdominal pain, lower abdominal pain, and abdominal discomfort. 12

1.1 Infections Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, and rhinovirus infection. 14

2.2 Urinary tract infection Urinary tract infection includes urinary tract infection and acute pyelonephritis. 10

1.1 Psychiatric disorder Insomnia 12 0 Clinically relevant adverse reactions in < 10% of patients who received LUNSUMIO included pneumonia, sepsis, COVID-19, EBV viremia, mental status changes, tumor lysis syndrome, renal insufficiency, anxiety, motor dysfunction (including ataxia, gait disturbance and tremor), tumor flare, ICANS, and Pneumocystis jirovecii pneumonia. Table 9 summarizes the laboratory abnormalities in patients with relapsed or refractory FL treated with LUNSUMIO in GO29781. Table 9. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received LUNSUMIO Intravenous Infusion in GO29781 Laboratory Abnormality LUNSUMIO The denominator used to calculate the rate varied from 72 to 90 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 100 98 Hemoglobin decreased 68 12 Neutrophils decreased 58 40 Platelets decreased 46 10 Chemistry Phosphate decreased 78 46 Glucose increased 42 42 Aspartate aminotransferase increased 39

4.4 Gamma-glutamyl transferase increased 34 9 Magnesium decreased 34 0 Potassium decreased 33 6 Alanine aminotransferase increased 32 7 Uric acid increased 22 22

Effect of LUNSUMIO on CYP450 Substrates LUNSUMIO 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 on Cycle 1 Day 1 and up to 14 days after the 60 mg dose on Cycle 2 Day 1 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.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on the mechanism of action, LUNSUMIO 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 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 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 and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential LUNSUMIO 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. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO and for 3 months after the last dose.

8.4 Pediatric Use The safety and efficacy of LUNSUMIO have not been established in pediatric patients.

8.5 Geriatric Use Among the 90 patients with relapsed or refractory follicular lymphoma treated with LUNSUMIO, 33% were 65 years of age or older, and 8% were 75 years of age or older. There is an insufficient number of patients 65 years of age or older and 75 years of age or older to assess whether there are differences in safety or effectiveness in patients 65 years of age and older compared to younger adult patients.

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.