These Highlights Do Not Include All The Information Needed To Use Lunsumio Safely And Effectively. See Full Prescribing Information For Lunsumio.

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 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.

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.

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 (mosunetuzumab-axgb) injection is a sterile, preservative-free, colorless solution for intravenous use.

Each single-dose vial contains a 1 mL solution of mosunetuzumab-axgb (1 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.

Each single-dose vial contains a 30 mL solution of mosunetuzumab-axgb (30 mg), acetic acid (12.8 mg), histidine (46.6 mg), methionine (44.8 mg), polysorbate 20 (18 mg), sucrose (2,462.4 mg), and Water for Injection, USP. The pH is 5.8.

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)].

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

Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, Grade 3 or 4 decreased lymphocytes occurred in 92%, decreased neutrophils in 38%, decreased hemoglobin in 19%, and decreased platelets in 12% of patients. Grade 4 decreased lymphocytes occurred in 71%, decreased neutrophils in 19%, and decreased platelets in 5% of patients. Febrile neutropenia occurred in 2% of patients.

Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue LUNSUMIO. Consider prophylactic granulocyte colony-stimulating factor administration as applicable [see Dosage and Administration (2.4)].

LUNSUMIO can cause serious or severe tumor flare [see Adverse Reactions (6.1)].

Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, tumor flare occurred in 4%. Manifestations included new or worsening pleural effusions, localized pain and swelling at the sites of lymphoma lesions, and tumor inflammation.

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. If compression or obstruction develops, institute standard treatment of these complications.

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

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.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of mosunetuzumab-axgb.

During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14)], using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 418) treated with LUNSUMIO developed anti-mosunetuzumab-axgb antibodies. Based on these data, the clinical relevance of anti-mosunetuzumab-axgb antibodies could not be assessed.

The efficacy of LUNSUMIO was evaluated in an open-label, multicenter, multi-cohort study (GO29781, NCT02500407) in patients with relapsed or refractory follicular lymphoma (FL) who had received at least two prior therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The study excluded patients with active infections, history of autoimmune disease, prior allogeneic transplant, or any history of CNS lymphoma or CNS disorders.

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 via intravenous infusion every 3 weeks in subsequent cycles. A treatment cycle was 21 days. LUNSUMIO was administered for 8 cycles unless patients experienced progressive disease or unacceptable toxicity. After 8 cycles, patients with a complete response discontinued therapy; patients with a partial response or stable disease continued treatment up to 17 cycles, unless patients experienced progressive disease or unacceptable toxicity.

Among the 90 patients with relapsed or refractory FL, the median age was 60 years (range: 29 to 90 years), 33% were 65 years of age or older, 61% were male, 82% were White, 9% were Asian, 4% were Black or African American, and 8% were Hispanic or Latino. A total of 77% of patients had Stage III-IV disease, 34% had bulky disease, and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 3 (range: 2 to 10), with 38% receiving 2 prior therapies, 31% receiving 3 prior therapies, and 31% receiving more than 3 prior therapies.

Seventy-nine percent of patients were refractory to prior anti-CD20 monoclonal antibody therapy, 53% were refractory to both anti-CD20 monoclonal antibody and alkylator therapy, 9% received prior rituximab plus lenalidomide therapy, 21% received prior autologous stem cell transplant, and 3% received prior CAR-T therapy. Fifty-two percent of patients had progression of disease within 24 months of first systemic therapy.

Efficacy was established on the basis of objective response rate (ORR) and duration of response (DOR) as assessed by an independent review facility according to standard criteria for NHL (Cheson 2007). The median follow-up for DOR was 14.9 months. The efficacy results are summarized in Table 12.

The median time to first response was 1.4 months (range: 1.1 to 8.9).

None.

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)]

After intravenous administration of the recommended dosage of LUNSUMIO, peripheral B-cell counts decreased to undetectable levels (< 5 cells/microliter) in most patients (95%) by Cycle 2 Day 1 and the depletion was sustained at later cycles including at Cycle 4 and Cycle 8.

LUNSUMIO caused hypogammaglobulinemia (defined as IgG levels < 500 mg/dL). Among 67 patients with baseline IgG levels ≥ 500 mg/dL, 40% had their IgG level decreased to < 500 mg/dL after administration of the recommended dosage of LUNSUMIO.

Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured, and transient elevation of cytokines were observed at doses of 0.4 mg and above. After administration of the recommended dosage of LUNSUMIO, the highest elevation of cytokines was observed within 24 hours after the first dose on Cycle 1 Day 1 and after the first 60 mg dose on Cycle 1 Day 15. The elevated cytokine levels generally returned to baseline prior to the next infusion on Cycle 1 Day 8 and on Cycle 2 Day 1.

Mosunetuzumab-axgb PK exposure increased proportionally over a dose range from 0.2 mg to 60 mg (0.007 to 2 times the recommended treatment dosage). PK exposures for the recommended dosage of LUNSUMIO are summarized in Table 10 and Figure 1.

Figure 1. Model-Predicted Mosunetuzumab-axgb Intravenous Infusion Concentration Time Profile

Pharmacokinetic parameters (Table 11) were evaluated at the recommended dosage and are presented as geometric mean (CV%) unless otherwise specified.

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.

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)

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).

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.

Based on its mechanism of action, LUNSUMIO 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 LUNSUMIO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

• 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)

• 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):

• See Full Prescribing Information for instructions on preparation and administration. (2.5)

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

Premedication to reduce the risk of CRS and infusion-related reactions are outlined in Table 3 [see Warnings and Precautions (5.1)].

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.

Lactation: Advise not to breastfeed. (8.2)

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%).

• 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)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is LUNSUMIO for intravenous infusion. A peel-off label is provided on the LUNSUMIO Prescribing Information that should be attached to the final prepared solution. Remove the peel-off label from the Prescribing Information in the LUNSUMIO carton before discarding the carton. Affix the peel-off label to the diluted LUNSUMIO infusion bag.

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LUNSUMIO. Initiate treatment with the LUNSUMIO step-up dosing schedule to reduce the risk of CRS. Withhold LUNSUMIO until CRS resolves or permanently discontinue based on severity [see Dosage and Administration (2.1 and 2.4) and Warnings and Precautions (5.1)].

LUNSUMIO (mosunetuzumab-axgb) injection is a sterile, colorless, preservative-free solution for intravenous infusion supplied as follows:

• One 1 mg/mL single-dose vial in a carton (NDC 50242-159-01)
• One 30 mg/30 mL (1 mg/mL) single-dose vial in a carton (NDC 50242-142-01).

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.

NDC 50242-159-01

Lunsumio^®

(mosunetuzumab-axgb)

Injection

1 mg/mL

For Intravenous Infusion Only.

Single-Dose Vial.

Discard Unused Portion.

ATTENTION: Dispense the enclosed

Medication Guide to each patient.

1 vial

Rx only

Genentech

11042421

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.

LUNSUMIO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

NDC 50242-142-01

Lunsumio^®

(mosunetuzumab-axgb)

Injection

30 mg/30 mL

(1 mg/mL)

For Intravenous Infusion Only.

Single-Dose Vial.

Discard Unused Portion.

ATTENTION: Dispense the enclosed

Medication Guide to each patient.

1 vial

Rx only

Genentech

11042398

Mosunetuzumab-axgb is available in two formulations: as an injection for intravenous use (LUNSUMIO) and as an injection for subcutaneous use (LUNSUMIO VELO). Check the product labels to ensure that the correct formulation is being prescribed, dispensed, and administered to the patient [see Dosage and Administration (2.2 and 2.5)]. Do not substitute LUNSUMIO for or with LUNSUMIO VELO.

No carcinogenicity or genotoxicity studies have been conducted with mosunetuzumab-axgb.

No dedicated studies have been conducted to evaluate the effects of mosunetuzumab-axgb on fertility. No adverse effects on either male or female reproductive organs were identified in a 26-week repeat dose chronic toxicity study in sexually mature cynomolgus monkeys.

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.

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 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.

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.

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 (mosunetuzumab-axgb) injection is a sterile, preservative-free, colorless solution for intravenous use.

Each single-dose vial contains a 1 mL solution of mosunetuzumab-axgb (1 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.

Each single-dose vial contains a 30 mL solution of mosunetuzumab-axgb (30 mg), acetic acid (12.8 mg), histidine (46.6 mg), methionine (44.8 mg), polysorbate 20 (18 mg), sucrose (2,462.4 mg), and Water for Injection, USP. The pH is 5.8.

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)].

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

Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, Grade 3 or 4 decreased lymphocytes occurred in 92%, decreased neutrophils in 38%, decreased hemoglobin in 19%, and decreased platelets in 12% of patients. Grade 4 decreased lymphocytes occurred in 71%, decreased neutrophils in 19%, and decreased platelets in 5% of patients. Febrile neutropenia occurred in 2% of patients.

Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue LUNSUMIO. Consider prophylactic granulocyte colony-stimulating factor administration as applicable [see Dosage and Administration (2.4)].

LUNSUMIO can cause serious or severe tumor flare [see Adverse Reactions (6.1)].

Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, tumor flare occurred in 4%. Manifestations included new or worsening pleural effusions, localized pain and swelling at the sites of lymphoma lesions, and tumor inflammation.

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. If compression or obstruction develops, institute standard treatment of these complications.

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

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.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of mosunetuzumab-axgb.

During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14)], using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 418) treated with LUNSUMIO developed anti-mosunetuzumab-axgb antibodies. Based on these data, the clinical relevance of anti-mosunetuzumab-axgb antibodies could not be assessed.

The efficacy of LUNSUMIO was evaluated in an open-label, multicenter, multi-cohort study (GO29781, NCT02500407) in patients with relapsed or refractory follicular lymphoma (FL) who had received at least two prior therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The study excluded patients with active infections, history of autoimmune disease, prior allogeneic transplant, or any history of CNS lymphoma or CNS disorders.

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 via intravenous infusion every 3 weeks in subsequent cycles. A treatment cycle was 21 days. LUNSUMIO was administered for 8 cycles unless patients experienced progressive disease or unacceptable toxicity. After 8 cycles, patients with a complete response discontinued therapy; patients with a partial response or stable disease continued treatment up to 17 cycles, unless patients experienced progressive disease or unacceptable toxicity.

Among the 90 patients with relapsed or refractory FL, the median age was 60 years (range: 29 to 90 years), 33% were 65 years of age or older, 61% were male, 82% were White, 9% were Asian, 4% were Black or African American, and 8% were Hispanic or Latino. A total of 77% of patients had Stage III-IV disease, 34% had bulky disease, and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 3 (range: 2 to 10), with 38% receiving 2 prior therapies, 31% receiving 3 prior therapies, and 31% receiving more than 3 prior therapies.

Seventy-nine percent of patients were refractory to prior anti-CD20 monoclonal antibody therapy, 53% were refractory to both anti-CD20 monoclonal antibody and alkylator therapy, 9% received prior rituximab plus lenalidomide therapy, 21% received prior autologous stem cell transplant, and 3% received prior CAR-T therapy. Fifty-two percent of patients had progression of disease within 24 months of first systemic therapy.

Efficacy was established on the basis of objective response rate (ORR) and duration of response (DOR) as assessed by an independent review facility according to standard criteria for NHL (Cheson 2007). The median follow-up for DOR was 14.9 months. The efficacy results are summarized in Table 12.

The median time to first response was 1.4 months (range: 1.1 to 8.9).

None.

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)]

After intravenous administration of the recommended dosage of LUNSUMIO, peripheral B-cell counts decreased to undetectable levels (< 5 cells/microliter) in most patients (95%) by Cycle 2 Day 1 and the depletion was sustained at later cycles including at Cycle 4 and Cycle 8.

LUNSUMIO caused hypogammaglobulinemia (defined as IgG levels < 500 mg/dL). Among 67 patients with baseline IgG levels ≥ 500 mg/dL, 40% had their IgG level decreased to < 500 mg/dL after administration of the recommended dosage of LUNSUMIO.

Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured, and transient elevation of cytokines were observed at doses of 0.4 mg and above. After administration of the recommended dosage of LUNSUMIO, the highest elevation of cytokines was observed within 24 hours after the first dose on Cycle 1 Day 1 and after the first 60 mg dose on Cycle 1 Day 15. The elevated cytokine levels generally returned to baseline prior to the next infusion on Cycle 1 Day 8 and on Cycle 2 Day 1.

Mosunetuzumab-axgb PK exposure increased proportionally over a dose range from 0.2 mg to 60 mg (0.007 to 2 times the recommended treatment dosage). PK exposures for the recommended dosage of LUNSUMIO are summarized in Table 10 and Figure 1.

Figure 1. Model-Predicted Mosunetuzumab-axgb Intravenous Infusion Concentration Time Profile

Pharmacokinetic parameters (Table 11) were evaluated at the recommended dosage and are presented as geometric mean (CV%) unless otherwise specified.

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.

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)

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).

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.

Based on its mechanism of action, LUNSUMIO 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 LUNSUMIO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

• 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)

• 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):

• See Full Prescribing Information for instructions on preparation and administration. (2.5)

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

Premedication to reduce the risk of CRS and infusion-related reactions are outlined in Table 3 [see Warnings and Precautions (5.1)].

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.

Lactation: Advise not to breastfeed. (8.2)

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%).

• 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)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is LUNSUMIO for intravenous infusion. A peel-off label is provided on the LUNSUMIO Prescribing Information that should be attached to the final prepared solution. Remove the peel-off label from the Prescribing Information in the LUNSUMIO carton before discarding the carton. Affix the peel-off label to the diluted LUNSUMIO infusion bag.

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LUNSUMIO. Initiate treatment with the LUNSUMIO step-up dosing schedule to reduce the risk of CRS. Withhold LUNSUMIO until CRS resolves or permanently discontinue based on severity [see Dosage and Administration (2.1 and 2.4) and Warnings and Precautions (5.1)].

LUNSUMIO (mosunetuzumab-axgb) injection is a sterile, colorless, preservative-free solution for intravenous infusion supplied as follows:

• One 1 mg/mL single-dose vial in a carton (NDC 50242-159-01)
• One 30 mg/30 mL (1 mg/mL) single-dose vial in a carton (NDC 50242-142-01).

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.

NDC 50242-159-01

Lunsumio^®

(mosunetuzumab-axgb)

Injection

1 mg/mL

For Intravenous Infusion Only.

Single-Dose Vial.

Discard Unused Portion.

ATTENTION: Dispense the enclosed

Medication Guide to each patient.

1 vial

Rx only

Genentech

11042421

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.

LUNSUMIO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

NDC 50242-142-01

Lunsumio^®

(mosunetuzumab-axgb)

Injection

30 mg/30 mL

(1 mg/mL)

For Intravenous Infusion Only.

Single-Dose Vial.

Discard Unused Portion.

ATTENTION: Dispense the enclosed

Medication Guide to each patient.

1 vial

Rx only

Genentech

11042398

Mosunetuzumab-axgb is available in two formulations: as an injection for intravenous use (LUNSUMIO) and as an injection for subcutaneous use (LUNSUMIO VELO). Check the product labels to ensure that the correct formulation is being prescribed, dispensed, and administered to the patient [see Dosage and Administration (2.2 and 2.5)]. Do not substitute LUNSUMIO for or with LUNSUMIO VELO.

No carcinogenicity or genotoxicity studies have been conducted with mosunetuzumab-axgb.

No dedicated studies have been conducted to evaluate the effects of mosunetuzumab-axgb on fertility. No adverse effects on either male or female reproductive organs were identified in a 26-week repeat dose chronic toxicity study in sexually mature cynomolgus monkeys.

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.