Lunsumio

1 INDICATIONS AND USAGE 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).

2 DOSAGE AND ADMINISTRATION LUNSUMIO and LUNSUMIO VELO have different dosage and administration instructions. Administer LUNSUMIO only as an intravenous infusion. ( 2.1 ) Premedicate to reduce risk of CRS and infusion-related reactions. ( 2.3 , 5.1 ) Recommended dosage for LUNSUMIO for intravenous infusion ( 2.2 ): Day of Treatment Cycle length = 21 days Intravenous Dose of LUNSUMIO Rate of Infusion Cycle 1 Day 1 1 mg Administer over a minimum of 4 hours. Day 8 2 mg Day 15 60 mg Cycle 2 Day 1 60 mg Administer over 2 hours if infusions from Cycle 1 were well-tolerated. Cycles 3+ Day 1 30 mg See Full Prescribing Information for instructions on preparation and administration. ( 2.5 ) 2.1 Important Dosing Information LUNSUMIO and LUNSUMIO VELO have different dosage and administration instructions [see Dosage and Administration (2.2) and Warnings and Precautions (5.7) ]. LUNSUMIO is for intravenous use only. Check the product label to ensure that the correct formulation (LUNSUMIO or LUNSUMIO VELO) is being prescribed and administered. Do not substitute LUNSUMIO for or with LUNSUMIO VELO. Administer LUNSUMIO to well-hydrated patients. Premedicate before each dose in Cycle 1 and Cycle 2 [see Dosage and Administration (2.3) ] . Administer only as an intravenous infusion through a dedicated infusion line. Do not use an in-line filter to administer LUNSUMIO . Drip chamber filters can be used to administer LUNSUMIO. LUNSUMIO 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 intravenous infusion 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 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 Intravenous Infusion (21-Day Treatment Cycles) Day of Treatment Intravenous Dose of LUNSUMIO Rate of Infusion Cycle 1 Day 1 1 mg Administer over a minimum of 4 hours. Day 8 2 mg Day 15 60 mg Cycle 2 Day 1 60 mg Administer over 2 hours if infusions from Cycle 1 were well-tolerated. Cycles 3+ Day 1 30 mg Table 2. Recommendations for Restarting Therapy with LUNSUMIO Intravenous Infusion After Dose Delay Last Intravenous Dose Administered Time Since Last Dose Administered Action for Next Intravenous Dose(s) 1 mg Cycle 1 Day 1 1week to 2 weeks Administer 2 mg (Cycle 1 Day 8), then resume the planned treatment schedule. Greater than 2 weeks Repeat 1 mg (Cycle 1 Day 1), then administer 2 mg (Cycle 1 Day 8) and resume the planned treatment schedule. 2 mg Cycle 1 Day 8 1 week to 2 weeks Administer 60 mg (Cycle 1 Day 15), then resume the planned treatment schedule. Greater than 2 weeks to less than 6 weeks Repeat 2 mg (Cycle 1 Day 8), then administer 60 mg (Cycle 1 Day 15) and resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 1 Day 1) and 2 mg (Cycle 1 Day 8), then administer 60 mg (Cycle 1 Day 15) and resume the planned treatment schedule. 60 mg Cycle 1 Day 15 1 week to less than 6 weeks Administer 60 mg (Cycle 2 Day 1), then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 2 Day 1) and 2 mg (Cycle 2 Day 8), then administer 60 mg (Cycle 2 Day 15), followed by 30 mg (Cycle 3 Day 1) and then resume the planned treatment schedule. 60 mg Cycle 2 Day 1 3 weeks to less than 6 weeks Administer 30 mg (Cycle 3 Day 1), then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 3 D…

5 WARNINGS AND PRECAUTIONS 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 [see Dosage and Administration (2.3) ] . Administer pretreatment medications to reduce the risk of CRS, ensure adequate hydration, and monitor patients following administration of LUNSUMIO accordingly. 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…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 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.

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.

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%) 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 dos…