Author: [AUTHOR] Published on 8/4/2023 6:00:00 AM

FDA Approves COLUMVI (glofitamab-gxbm) for the Treatment of Adult Patients with Selected Relapsed or Refractory Large B-cell Lymphomas

On June 15, 2023, the US Food and Drug Administration (FDA) approved COLUMVI (glofitamab-gxbm) 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).

Following a single 1,000 mg dose of obinutuzumab on Cycle 1 Day 1 to deplete circulating and lymphoid tissue B cells, glofitamab-gxbm is administered by intravenous (IV) infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length is 21 days. Due to the risk of CRS, patients should be hospitalized for the 2.5 mg step-up dose and for subsequent doses as recommended. Additional details about administration and managing adverse reactions can be found in the prescribing information below.

Cytokine Release Syndrome (CRS), including serious or fatal reactions, can occur in patients receiving COLUMVI. COLUMVI should only be administered by a healthcare professional with immediate access to appropriate medical support, including supportive medications to manage severe CRS. Pre-medicate before each dose, and initiate treatment with the COLUMVI step-up dosing schedule to reduce the risk of CRS. Withhold COLUMVI until CRS resolves or permanently discontinue based on severity.

Based on its mechanism of action, COLUMVI may cause fetal harm. Advise pregnant women of the potential risk to the fetus. Advise women not to breastfeed during treatment with COLUMVI and for 1 month after the last dose of COLUMVI. Advise female patients of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose of COLUMVI.

Additional information regarding dosage and administration as well as warnings and precautions about CRS, neurologic toxicity, serious infections, tumor flare, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 
MOA: 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.

General PK: The PK of glofitamab-gxbm was determined following pretreatment with a single dose of obinutuzumab of 1,000 mg. Glofitamab-gxbm exposure increased dose-proportionally over the dose range from 0.005 to 30 mg (0.000167 to 1 times the recommended treatment dosage). Glofitamab-gxbm exposure parameters are summarized in Table 1 for the approved recommended dosage.

Table 1: Exposure Parameters of Glofitamab-gxbm Following Pretreatment with a Single Dose of Obinutuzumab of 1,000 mg

	AUCtau (day∙mcg/mL)	Cmax (mcg/mL)	Ctrough (mcg/mL)
First full 30 mg dose	44.5 (55%)	9.41 (27%)	0.52 (83%)
Steady state1 30 mg dose	48.6 (33%)	9.44 (26%)	0.59 (67%)

Data presented as geometric mean (CV%). AUCtau = area under the concentration-time curve over one 21-day cycle; C_max = maximum glofitamab-gxbm concentration; C_trough = glofitamab-gxbm concentration prior to next dose; CV = geometric coefficient of variation.
¹ Steady state values are approximated at Cycle 6 (week 18).

Distribution: The glofitamab-gxbm total volume of distribution is 5.6 L (24%).

Elimination: At steady state, the glofitamab-gxbm terminal half-life is 7.6 days (24%) and the clearance is 0.617 L/day (33%). Glofitamab-gxbm is expected to be metabolized into small peptides by catabolic pathways.

PD:

• Circulating B Cell Count: Peripheral B cell counts decreased to undetectable levels (< 5 cells/microliter) in 86.5% of patients by Cycle 1 Day 7 after obinutuzumab pretreatment of 1,000 mg on Cycle 1 Day 1, and in 88.2% of patients by Cycle 1 Day 10 after the first glofitamab-gxbm dose of 2.5 mg on Cycle 1 Day 8.
• Cytokine Concentrations: Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured and transient elevation of cytokines was observed at doses of 0.045 mg and above. After administration of the recommended dosage of COLUMVI, the highest elevation of cytokines was generally observed within 6 hours after the first glofitamab-gxbm dose of 2.5 mg on Cycle 1 Day 8. The elevated cytokine levels generally returned to baseline within 48 hours after the first 30 mg dose on Cycle 2 Day 1.

Immunogenicity: During treatment in the clinical efficacy trial (up to 9 months), using an enzyme-linked immunosorbent assay (ELISA), the incidence of anti-glofitamab antibody formation was 1.1% (5/448) in patients treated with COLUMVI. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the PK, PD, safety, and/or effectiveness of glofitamab-gxbm is unknown.

Use in Specific Populations
No clinically significant changes in the PK of glofitamab-gxbm were observed based on age (21 to 90 years), body weight (31 to 148 kg), sex, mild to moderate renal impairment (CLcr 30 to < 90 mL/min as estimated by Cockcroft-Gault formula) and mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 x ULN or AST > ULN).

The effects of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST), and race/ethnicity on the PK of glofitamab-gxbm are unknown.

Lactation: Because human IgG is present in human milk, and there is potential for glofitamab-gxbm absorption leading to B-cell depletion, advise women not to breastfeed during treatment with COLUMVI and for 1 month after the last dose of COLUMVI.

Drug Interactions
For certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions, monitor for toxicity or drug concentrations of such CYP substrates when co-administered with COLUMVI. Glofitamab-gxbm causes release of cytokines that may suppress 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.

Efficacy and Safety
Efficacy of COLUMVI was demonstrated in an open-label, multicenter, multicohort, single-arm clinical trial that included patients with relapsed or refractory LBCL after two or more lines of systemic therapy. Efficacy was based on objective response rate (ORR) and duration of response (DOR), as determined by an Independent Review Committee (IRC) using the 2014 Lugano criteria. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

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.

Visit the COLUMVI (glofitamab-gxbm) prescribing information to learn more about COLUMVI.

Visit the Drugs@FDA Database for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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