Glofitamab

INDICATIONS AND USAGE COLUMVI is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). COLUMVI is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

DOSAGE AND ADMINISTRATION Pretreat with a single 1,000 mg dose of obinutuzumab intravenously 7 days before initiation of COLUMVI (Cycle 1 Day 1). ( 2.2 ) Administer premedications as recommended. ( 2.3 ) Administer only as an intravenous infusion. ( 2.1 ) Recommended dosage ( 2.2 ): Treatment Cycle Cycle = 21 days Day Dose of COLUMVI Day 1 Obinutuzumab 1,000 mg Cycle 1 Day 8 Step-up dose 1 2.5 mg Day 15 Step-up dose 2 10 mg Cycle 2 to 12 Day 1 30 mg Administer in a facility equipped to monitor and manage CRS. ( 2.1 , 2.2 ) Patients should be hospitalized for the 2.5 mg step-up dose and for subsequent infusions as recommended. ( 2.1 , 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.5 , 2.6 , 2.7 ) 2.1 Important Dosing Information Administer only as an intravenous infusion through a dedicated infusion line that includes a sterile 0.2-micron in-line filter. Administer COLUMVI diluted solution via intravenous bag infusion. The 2.5 mg dose may alternatively be administered via intravenous syringe infusion [see Dosage and Administration (2.5 , 2.6 , 2.7 )] . COLUMVI should only be administered by a healthcare professional with immediate access to appropriate medical support, including supportive medications to manage severe CRS [see Dosage and Administration (2.4) ] . Ensure adequate hydration before administering COLUMVI. Premedicate before each dose [see Dosage and Administration (2.3) ] . Following pretreatment with obinutuzumab, administer COLUMVI according to the step-up dosing schedule in Table 1 with appropriate premedication, including dexamethasone, to reduce the incidence and severity of CRS [see Dosage and Administration (2.3) ] . Due to the risk of CRS, patients should be hospitalized during and for 24 hours after completion of infusion of step-up dose 1 (2.5 mg on Cycle 1 Day 8) [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . Patients who experienced any grade CRS during step-up dose 1 should be hospitalized during and for 24 hours after completion of step-up dose 2 (10 mg on Cycle 1 Day 15). CRS with step-up dose 2 can occur in patients who did not experience CRS with step-up dose 1 [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . For subsequent doses, patients who experienced Grade ≥ 2 CRS with their previous infusion should be hospitalized during and for 24 hours after the completion of the next COLUMVI infusion. 2.2 Recommended Dosage Pretreatment with Obinutuzumab Pretreat all patients with a single 1,000 mg dose of obinutuzumab administered as an intravenous infusion on Cycle 1 Day 1, 7 days prior to initiation of COLUMVI (see Table 1 ) to deplete the circulating and lymphoid tissue B cells. Obinutuzumab should be administered as an intravenous infusion at 50 mg/hour. The rate of infusion can be escalated in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour. Refer to the obinutuzumab prescribing information for complete dosing information. COLUMVI Step-up Dose Schedule COLUMVI dosing begins with a step-up dose schedule. Following completion of pretreatment with obinutuzumab on Cycle 1 Day 1, administer COLUMVI as an intravenous infusion according to the step-up dose schedule in Table 1 . Administer premedications for each dose of COLUMVI as described in Table 3 [see Dosage and Administration (2.3) ]. Table 1: COLUMVI Dosing Schedule (21-Day Treatment Cycles) Treatment cycle Day Dose of COLUMVI Duration of infusion Cycle 1 Day 1 Obinutuzumab Refer to " Pretreatment with obinutuzumab " described above. Day 8 Step-up dose 1 2.5 mg 4 hours For patients who experience CRS with their previous dose of COLUMVI, the time of infusion may be extended up to 8 hours. Day 15 Step-up dose 2 10 mg Cycle 2 Day 1 30 mg 4 hours Cycle 3 to 12 Day 1 30 mg 2 hours If the patient experienced CRS with the previous dose, the duration of infusion should be maintained at 4 hours. Continue COLUMVI for a maximum of 12 cycles (inclusive of Cycle 1 step-up dosing) or until disease progression or unacceptable toxicity, whichever occurs first. Monitoring for Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Administer the COLUMVI infusions intravenously in a healthcare setting with immediate access to medical support to manage CRS, including severe CRS. For the first COLUMVI step-up dose (2.5 mg on Cycle 1 Day 8), patients should be hospitalized during and for 24 hours after completion of the COLUMVI infusion. Patients who experienced any grade CRS during step-up dose 1 should be hospitalized during and for 24 hours after completion of step-up dose 2 (10 mg on Cycle 1 Day 15). CRS with step-up dose 2 can occur in patients who did not experience CRS with step-up dose 1. For subsequent infusions (30 mg on Day 1 of Cycle 2 or subsequent cycles), patients who experienced Grade ≥ 2 CRS with their previous infusion should be hospitalized during and for 24 hours after completion of the next COLUMVI infusion. For monitoring after delayed or missed doses of COLUMVI, follow the recommendations in Table 2 . Delayed or Missed Doses If a dose of COLUMVI is delayed, restart therapy based on the recommendations made in Table 2 , then resume the treatment schedule accordingly. For repeat of the 2.5 mg dose patients should be hospitalized during and for 24 hours after completion of the COLUMVI infusion. For the repeat of the 10 mg dose, patients should be hospitalized during and for 24 hours after completion of the COLUMVI infusion if any grade CRS occurred during the most recent 2.5 mg dose. Table 2: Recommendations for Restarting COLUMVI After Dose Delay Last Dose Administered Time Since Last Dose Administered Action for Next Dose(s) Administer premedication as per Table 3 for all patients. Obinutuzumab pretreatment (Cycle 1 Day 1) ≤ 2 weeks Administer COLUMVI 2.5 mg (Cycle 1 Day 8) Patients should be hospitalized during and for 24 hours after completing infusion of the 2.5 mg dose. , then resume the planned treatment schedule. > 2 weeks Repeat obinutuzumab 1,000 mg pretreatment (Cycle 1 Day 1). Then administer COLUMVI 2.5 mg (Cycle 1 Day 8) and resume the planned treatment schedule. COLUMVI 2.5 mg (Cycle 1 Day 8) ≤ 2 weeks Administer COLUMVI 10 mg (Cycle 1 Day 15) Patients should be hospitalized during and for 24 hours after completing infusion of the 10 mg dose if CRS occurred during the most recent 2.5 mg dose. , then resume the planned treatment schedule. > 2 to ≤ 4 weeks Repeat COLUMVI 2.5 mg (Cycle 1 Day 8) . Then administer COLUMVI 10 mg (Cycle 1 Day 15) and resume the planned treatment schedule. > 4 weeks Repeat obinutuzumab 1,000 mg pretreatment (Cycle 1 Day 1) and COLUMVI 2.5 mg (Cycle 1 Day 8) . Then administer COLUMVI 10 mg (Cycle 1 Day 15) and resume the planned treatment schedule. COLUMVI 10 mg (Cycle 1 Day 15) ≤ 2 weeks Administer COLUMVI 30 mg (Cycle 2 Day 1), then resume the planned treatment schedule. > 2 to ≤ 6 weeks Repeat COLUMVI 10 mg (Cycle 1 Day 15). Then administer COLUMVI 30 mg (Cycle 2 Day 1) and resume the planned treatment schedule. > 6 weeks Repeat obinutuzumab 1,000 mg pretreatment (Cycle 1 Day 1), COLUMVI 2.5 mg (Cycle 1 Day 8) , and COLUMVI 10 mg (Cycle 1 Day 15) . Then administer COLUMVI 30 mg (Cycle 2 Day 1) and resume the planned treatment schedule. COLUMVI 30 mg (Cycle 2 onwards) ≤ 6 weeks Administer COLUMVI 30 mg, then resume the planned treatment schedule. > 6 weeks Repeat the Cycle 1 regimen described in Table 1 : obinutuzumab 1,000 mg pretreatment (Day 1), COLUMVI 2.5 mg (Day 8) , and COLUMVI 10 mg (Day 15) . Then administer COLUMVI 30 mg (Day 1 of next cycle) and resume the planned treatment schedule. 2.3 Recommended Premedication and Prophylactic Medications Premedication Administer the following premedications to reduce the risk of CRS and infusion-related reactions [see Warnings and Precautions (5.1) ] . Table 3: Premedications to be Administered for COLUMVI Infusion Day of Treatment Cycle Patients requiring

WARNINGS AND PRECAUTIONS Neurologic Toxicity : Can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Monitor for neurologic toxicity; withhold or permanently discontinue based on severity. ( 5.2 ) Serious Infections : Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Tumor Flare : Can cause serious tumor flare reactions. Monitor patients at risk for complications of tumor flare. ( 5.4 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Cytokine Release Syndrome COLUMVI can cause serious and fatal cytokine release syndrome (CRS) [see Adverse Reactions (6.1) ] . Among 145 patients who received COLUMVI, CRS occurred in 70%, with Grade 1 CRS developing in 52% of all patients, Grade 2 in 14%, Grade 3 in 2.8%, and Grade 4 in 1.4%. The most common manifestations of CRS included fever, tachycardia, hypotension, chills, and hypoxia. CRS occurred in 56% of patients after the 2.5 mg dose of COLUMVI, 35% after the 10 mg dose, 29% after the initial 30 mg target dose, and 2.8% after subsequent doses. With the first step-up dose of COLUMVI, the median time to onset of CRS (from the start of infusion) was 14 hours (range: 5 to 74 hours). CRS after any dose resolved in 98% of cases, with a median duration of CRS of 2 days (range: 1 to 14 days). Recurrent CRS occurred in 34% of all patients. CRS can first occur with the 10 mg dose; of 135 patients treated with the 10 mg dose of COLUMVI, 15 patients (11%) experienced their first CRS event with the 10 mg dose, of which 13 events were Grade 1, 1 event was Grade 2, and 1 event was Grade 3. Administer COLUMVI in a facility equipped to monitor and manage CRS. Initiate therapy according to the COLUMVI step-up dosing schedule to reduce the risk of CRS, administer pretreatment medications, and ensure adequate hydration [see Dosage and Administration (2.3) ] . Patients should be hospitalized during and for 24 hours after completing infusion of the 2.5 mg step-up dose. Patients who experienced any grade CRS during the 2.5 mg step-up dose should be hospitalized during and for 24 hours after completion of the 10 mg step-up dose. For subsequent doses, patients who experienced Grade ≥ 2 CRS with the previous infusion should be hospitalized during and for 24 hours after the next COLUMVI infusion [see Dosage and Administration (2.1 and 2.2) ] . At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue COLUMVI based on severity [see Dosage and Administration (2.4) ] . If CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis. 5.2 Neurologic Toxicity COLUMVI can cause serious and fatal neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS) [see Adverse Reactions (6.1) ] . Among 145 patients who received COLUMVI, the most frequent neurologic toxicities of any grade were headache (10%), peripheral neuropathy (8%), dizziness or vertigo (7%), and mental status changes (4.8%, including confusional state, cognitive disorder, disorientation, somnolence, and delirium). Grade 3 or higher neurologic adverse reactions occurred in 2.1% of patients and included somnolence, delirium, and myelitis. Cases of ICANS of any grade occurred in 4.8% of patients. Coadministration of COLUMVI with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Optimize concomitant medications and hydration to avoid dizziness or mental status changes. Institute fall precautions as appropriate. Monitor patients for signs and symptoms of neurologic toxicity, evaluate, and provide supportive therapy; withhold or permanently discontinue COLUMVI based on severity [see Dosage and Administration (2.4) ] . Evaluate patients who experience neurologic toxicity such as tremors, dizziness, or adverse reactions that may impair cognition or consciousness promptly, including potential neurology evaluation. Advise affected patients to refrain from driving and/or engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurologic toxicity fully resolves. 5.3 Serious Infections COLUMVI can cause serious or fatal infections [see Adverse Reactions (6.1) ] . Serious infections were reported in 16% of patients, including Grade 3 or 4 infections in 10%, and fatal infections in 4.8% of patients. Grade 3 or higher infections reported in ≥ 2% of patients were COVID-19 infection (6%), including COVID-19 pneumonia, and sepsis (4.1%). Febrile neutropenia occurred in 3.4% of patients. COLUMVI should not be administered to patients with an active infection. Administer antimicrobial prophylaxis according to guidelines. Monitor patients before and during COLUMVI treatment for infection and treat appropriately. Withhold or consider permanent discontinuation of COLUMVI based on severity [see Dosage and Administration (2.4) ] . 5.4 Tumor Flare COLUMVI can cause serious tumor flare [see Adverse Reactions (6.1) ] . Manifestations include localized pain and swelling at the sites of the lymphoma lesions and/or dyspnea from new pleural effusions. Tumor flare was reported in 12% of patients who received COLUMVI, including Grade 2 tumor flare in 4.8% of patients and Grade 3 tumor flare in 2.8%. Recurrent tumor flare occurred in two (12%) of the affected patients. Most tumor flare events occurred during Cycle 1, with a median time to first onset of 2 days (range: 1 to 16 days) after the first dose of COLUMVI. The median duration was 3.5 days (range: 1 to 35 days). Patients with bulky tumors or disease located in close proximity to airways or a vital organ should be monitored closely during initial therapy. Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare, and institute appropriate treatment. Withhold COLUMVI until tumor flare resolves [see Dosage and Administration (2.4) ] . 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, COLUMVI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

CONTRAINDICATIONS None. None. ( 4 )

DRUG INTERACTIONS For certain CYP substrates where minimal concentration changes may lead to serious adverse reactions, monitor for toxicities or drug concentrations of such CYP substrates when coadministered with COLUMVI. Glofitamab-gxbm causes the release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress the activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of COLUMVI on Cycle 1 Day 8 and up to 14 days after the first 30 mg dose on Cycle 2 Day 1 and during and after CRS [see Warnings and Precautions (5.1) ] .

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurologic Toxicity [see Warnings and Precautions (5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Tumor Flare [see Warnings and Precautions (5.4) ] The most common (≥ 20%) adverse reactions, excluding laboratory abnormalities, are cytokine release syndrome, musculoskeletal pain, rash, and fatigue. The most common (≥ 20%) Grade 3 to 4 laboratory abnormalities are lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased. ( 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 DLBCL, NOS or LBCL Arising from Follicular Lymphoma Study NP30179 The safety of COLUMVI was evaluated in Study NP30179, a multi-cohort, multicenter, single-arm clinical trial that included 154 adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy [see Clinical Studies (14.1) ] . The trial required an ECOG performance status of 0 or 1, absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 75,000/µL independent of transfusion, serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CLcr) ≥ 50 mL/min, and hepatic transaminases ≤ 3 × ULN. The trial excluded patients with active or previous central nervous system (CNS) lymphoma or CNS disease, acute infection, recent infection requiring intravenous antibiotics, or prior allogeneic hematopoietic stem cell transplantation (HSCT). Patients received pretreatment with a single dose of obinutuzumab on Day 1 of Cycle 1 (seven days prior to start of COLUMVI). Following premedication, COLUMVI was administered by intravenous infusion according to the step-up dosing schedule with 2.5 mg on Day 8 of Cycle 1, and 10 mg on Day 15 of Cycle 1. Patients received the 30 mg COLUMVI dose by intravenous infusion on Day 1 of subsequent cycles for a maximum of 12 cycles (including step-up dosing). Each cycle was 21 days. Patients were hospitalized during and for 24 hours following completion of at least the first step-up dose. Of the 154 patients who initiated study treatment, 145 received COLUMVI; nine patients (6%) did not receive COLUMVI due to infection, progressive disease, or patient decision. Patients received a median of 5 cycles of COLUMVI with 30% receiving all 12 cycles of COLUMVI. Of patients who received COLUMVI, the median age was 66 years (range: 21 to 90 years); 66% were male; 77% were White, 4.8% were Asian, 1.4% were Black or African American, 6% were Hispanic or Latino. The main diagnoses were DLBCL, NOS and LBCL arising from follicular lymphoma. Serious adverse reactions occurred in 48% of patients who received COLUMVI. Serious adverse reactions in ≥ 2% of patients included CRS, COVID-19 infection, sepsis, and tumor flare. Fatal adverse reactions occurred in 5% of patients from COVID-19 infection (3.4%), sepsis (1.4%), and delirium (0.6%). Adverse reactions led to permanent discontinuation of COLUMVI in 7% of patients, including from infection, delirium, neutropenia, and CRS. Adverse reactions led to dose interruptions of COLUMVI in 19% of patients, most frequently (≥ 2%) from neutropenia and thrombocytopenia. The most common (≥ 20%) adverse reactions, excluding laboratory terms, were CRS, musculoskeletal pain, rash, and fatigue. The most common Grade 3 to 4 laboratory abnormalities (≥ 20%) were lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased. Table 9 summarizes adverse reactions observed in Study NP30179. Table 9: Select Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179 Adverse Reactions COLUMVI N=145 All grades (%) Grade 3 or 4 (%) The table includes a combination of grouped and ungrouped terms. Adverse reactions were graded using NCI CTCAE version 4.03, with the exception of CRS, which was graded per ASTCT consensus criteria in most cases. Immune system disorders Cytokine release syndrome 70 4.1 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes musculoskeletal pain, back pain, bone pain, flank pain, myalgia, neck pain, and pain in extremity. 21 2.1 General disorders Fatigue Includes fatigue and asthenia. 20 1.4 Pyrexia 16 0 Edema Includes edema, edema peripheral, swelling face, and face edema. 10 0 Skin and subcutaneous tissue disorders Rash Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative, erythema, palmar erythema, pruritus, and rash erythematous. 20 1.4 Gastrointestinal disorders Constipation 14 0 Diarrhea 14 0 Nausea 10 0 Abdominal pain Includes abdominal pain, abdominal discomfort, and abdominal pain upper. 10 0 Neoplasms Tumor flare 12 2.8 Neurologic Disorders Headache 10 0 Clinically relevant adverse reactions occurring in < 10% of patients who received COLUMVI included infusion-related reaction, peripheral neuropathy, pneumonia, mental status changes, vomiting, tumor lysis syndrome, febrile neutropenia, upper respiratory tract infection, sepsis, herpes zoster infection, gastrointestinal hemorrhage, tremor, myelitis, and colitis. Table 10 summarizes laboratory abnormalities in Study NP30179. Table 10: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179 Laboratory Abnormality COLUMVI The denominator used to calculate the rate varied from 137 to 145 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 90 83 Hemoglobin decreased 72 8 Neutrophils decreased 56 26 Grade 4 neutrophil decrease occurred in 9% of patients. Platelets decreased 56 8 Chemistry Fibrinogen decreased 84 21 Phosphate decreased 69 28 Sodium decreased 49 7 Calcium decreased 48 2.1 Gamma-glutamyl transferase increased 33 9 Potassium decreased 32 6 Uric acid increased 23 23 Clinically relevant adverse reactions occurring in other clinical trials: Immune system disorders : Hemophagocytic Lymphohistiocytosis

Mechanism of Action Glofitamab-gxbm is a bispecific antibody that binds to CD20 expressed on the surface of B cells, and to CD3 receptor expressed on the surface of T cells. Glofitamab-gxbm causes T-cell activation and proliferation, secretion of cytokines, and the lysis of CD20-expressing B cells. Glofitamab-gxbm showed anti-tumor activity in vivo in mouse models of DLBCL.