Introduction

Glofitamab-gxbm, a bispecific CD20-directed CD3 T-cell engager, is an antineoplastic agent.

Uses for Glofitamab

Glofitamab-gxbm has the following uses:

Glofitamab-gxbm 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Glofitamab Dosage and Administration

General

Glofitamab-gxbm is available in the following dosage form(s) and strength(s):

• Injection concentrate: 2.5 mg/2.5 mL (1 mg/mL) in a single-dose vial for IV infusion after dilution.

• Injection concentrate: 10 mg/10 mL (1 mg/mL) in a single-dose vial for IV infusion after dilution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer by a healthcare professional with immediate access to appropriate medical support, including supportive medications to manage severe cytokine release syndrome (CRS).

• Patients should be hospitalized for the 2.5 mg step-up dose and for subsequent infusions as recommended.

• Pretreat all patients with a single 1,000 mg dose of obinutuzumab administered as an IV infusion 7 days before initiation of glofitamab-gxbm (Cycle 1 Day 1).

• Administer premedications (e.g., dexamethasone, acetaminophen, antihistamine) as recommended.

• Administer glofitamab-gxbm only as an IV infusion.

• Recommended dosage is as follows (see Table 1). Initiate therapy according to the step-up dosing schedule to reduce the incidence and severity of CRS. Administer the drug in 21-day cycles. Continue treatment for a maximum of 12 cycles (inclusive of Cycle 1 step-up dosing) or until disease progression or unacceptable toxicity, whichever occurs first.

• See Full Prescribing Information for instructions on preparation and administration of glofitamab-gxbm, and for dosage modification recommendations for adverse reactions.

Cycle = 21 days

For patients who experience CRS with their previous dose of glofitamab-gxbm, the time of infusion may be extended up to 8 hours

If the patient experienced CRS with the previous dose, the duration of infusion should be maintained at 4 hours

Contraindications

• None.

Warnings/Precautions

Cytokine Release Syndrome

Glofitamab can cause serious and fatal cytokine release syndrome (CRS).

Among 145 patients who received glofitamab-gxbm, 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 glofitamab-gxbm, 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 glofitamab-gxbm, 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 glofitamab-gxbm, 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 glofitamab-gxbm in a facility equipped to monitor and manage CRS. Initiate therapy according to the step-up dosing schedule to reduce the risk of CRS, administer pretreatment medications, and ensure adequate hydration. 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 glofitamab infusion.

At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue glofitamab based on severity.

Neurologic Toxicity

Glofitamab can cause serious and fatal neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS).

Among 145 patients who received glofitamab-gxbm, 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 glofitamab 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 glofitamab based on severity.

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.

Serious Infections

Glofitamab can cause serious or fatal infections.

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.

Glofitamab should not be administered to patients with an active infection. Administer antimicrobial prophylaxis according to guidelines. Monitor patients before and during glofitamab-gxbm treatment for infection and treat appropriately. Withhold or consider permanent discontinuation of glofitamab-gxbm based on severity.

Tumor Flare

Glofitamab can cause serious tumor flare. 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 glofitamab-gxbm, 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 the drug. 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 glofitamab until tumor flare resolves.

Embryo-fetal Toxicity

Based on its mechanism of action, glofitamab 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 glofitamab and for 1 month after the last dose.

Specific Populations

Pregnancy

Based on its mechanism of action glofitamab may cause fetal harm when administered to a pregnant woman. There are no available data on the use of glofitamab-gxbm in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with glofitamab-gxbm.

Glofitamab 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, glofitamab can cause B-cell lymphocytopenia in infants exposed to the drug in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, glofitamab 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% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of glofitamab-gxbm in human milk or the effects on the breastfed child or milk production. Because human IgG is present in human milk, and there is potential for drug absorption leading to B-cell depletion, advise women not to breastfeed during treatment with glofitamab and for 1 month after the last dose of the drug.

Females and Males of Reproductive Potential

Glofitamab may cause fetal harm when administered to a pregnant woman

Verify pregnancy status in females of reproductive potential prior to initiating the drug.

Advise female patients of reproductive potential to use effective contraception during treatment with glofitamab and for 1 month after the last dose of the drug.

Pediatric Use

The safety and efficacy of glofitamab-gxbm in pediatric patients have not been established.

Geriatric Use

Of the 145 patients with relapsed or refractory large B-cell lymphoma (LBCL) who received glofitamab-gxbm in study NP30179, 55% were 65 years of age or older, and 23% were 75 years of age or older. There was a higher rate of fatal adverse reactions, primarily from COVID-19, in patients 65 years of age or older compared to younger patients. No overall differences in efficacy were observed between patients 65 years of age or older and younger patients.

Common Adverse Effects

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 decreased lymphocyte count, decreased phosphate, decreased neutrophil count, decreased uric acid, and decreased fibrinogen.

General

Glofitamab-gxbm is available in the following dosage form(s) and strength(s):

• Injection concentrate: 2.5 mg/2.5 mL (1 mg/mL) in a single-dose vial for IV infusion after dilution.

• Injection concentrate: 10 mg/10 mL (1 mg/mL) in a single-dose vial for IV infusion after dilution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer by a healthcare professional with immediate access to appropriate medical support, including supportive medications to manage severe cytokine release syndrome (CRS).

• Patients should be hospitalized for the 2.5 mg step-up dose and for subsequent infusions as recommended.

• Pretreat all patients with a single 1,000 mg dose of obinutuzumab administered as an IV infusion 7 days before initiation of glofitamab-gxbm (Cycle 1 Day 1).

• Administer premedications (e.g., dexamethasone, acetaminophen, antihistamine) as recommended.

• Administer glofitamab-gxbm only as an IV infusion.

• Recommended dosage is as follows (see Table 1). Initiate therapy according to the step-up dosing schedule to reduce the incidence and severity of CRS. Administer the drug in 21-day cycles. Continue treatment for a maximum of 12 cycles (inclusive of Cycle 1 step-up dosing) or until disease progression or unacceptable toxicity, whichever occurs first.

• See Full Prescribing Information for instructions on preparation and administration of glofitamab-gxbm, and for dosage modification recommendations for adverse reactions.

Cycle = 21 days

For patients who experience CRS with their previous dose of glofitamab-gxbm, the time of infusion may be extended up to 8 hours

If the patient experienced CRS with the previous dose, the duration of infusion should be maintained at 4 hours