Author: [AUTHOR] Published on 6/16/2023 5:00:00 AM

FDA Approves EPKINLY (Epcoritamab-bysp) for Adult Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma

On May 19, 2023, the US Food and Drug Administration (FDA) approved EPKINLY (epcoritamab-bysp) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell 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).

EPKINLY is for subcutaneous injection only and should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The approved recommended dosage schedule for EPKINLY is provided in Table 1:

Table 1: EPKINLY dosage schedule

Cycle of treatment (Cycle = 28 days)	Day of treatment	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	First full dose	48 mg
	22	48 mg
Cycle 2 and 3	1, 8, 15 and 22	48 mg
Cycles 4 to 9	1 and 15	48 mg
Cycle 10 and beyond	1	48 mg

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving EPKINLY. Initiate treatment with the EPKINLY step-up dosing schedule to reduce the incidence and severity of CRS. Withhold EPKINLY until CRS resolves or permanently discontinue based on severity.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), including life-threatening and fatal reactions, can occur with EPKINLY. Monitor patients for neurological signs or symptoms of ICANS during treatment. Withhold EPKINLY until ICANS resolves or permanently discontinue based on severity.

Based on its mechanism of action, EPKINLY may cause fetal harm. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose.

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

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA: Epcoritamab-bysp is a bispecific CD20-directed CD3 T-cell engager.
General PK: PK parameters for epcoritamab-bysp were evaluated at the approved recommended dosage (48 mg) and are presented as geometric mean (CV%) unless otherwise specified. Epcoritamab-bysp area under the concentration-time curve (AUC) increased more than proportionally over a full dosage range from 1.5 to 60 mg (0.03125 to 1.25 times the approved recommended dosage). Epcoritamab-bysp maximum concentration (11.1 mcg/mL [41.5%]) is achieved after the first dose of the Q2W regimen (i.e., after the 11th dose of 48 mg at the first dose of Cycle 4). PK exposures are summarized for the recommended dosage of epcoritamab-bysp in Table 2.

Table 2: Exposure Parameters of Epcoritamab-bysp in Subjects with Relapsed or Refractory LBCL

		Cavg (mcg/mL)1	Cmax (mcg/mL)1	Ctrough (mcg/mL)1
First full 48 mg dose		1.6 (72.4)	2.2 (70.0)	1.7 (74.0)
End of weekly dosing (end of Cycle 3)		9.9 (45.1)	10.8 (41.7)	8.4 (53.3)
End of every 2-week dosing (end of Cycle 9)		5.9 (49.3)	7.5 (41.1)	4.1 (73.9)
Steady state2 with every 4-week dosing		2.7 (69.5)	4.8 (51.6)	1.2 (130)
1 Values are geometric mean with geometric CV% 2 Steady state values are approximated at Cycle 15 (Week 60)

Absorption: The median (range) Tmax of epcoritamab-bysp after the first full dose and end of the weekly dosing regimen (end of Cycle 3) treatment doses were 4 (0.3 to 7) days and 2.3 (0.3 to 3.2) days, respectively.

Distribution: The apparent total volume of distribution is 25.6 L (82%).

Elimination: The half-life of full dose epcoritamab-bysp (48 mg) was approximately 22 days (58%) at the end of Cycle 3, with apparent total clearance of approximately 0.53 L/day (40%) after the end of Cycle 3.

• Metabolism: Epcoritamab-bysp is expected to be metabolized into small peptides by catabolic pathways.

PD:

• Circulating B Cell Count: Circulating B cells decreased to undetectable levels (< 10 cells/microliter) after administration of the approved recommended dosage of EPKINLY in patients who had detectable B cells at treatment initiation by Cycle 1 Day 15 (after the first full dose of 48 mg), and the depletion was sustained while patients remained on treatment.
• Cytokine Concentrations: Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured. Transient elevation of circulating cytokines was observed at dose levels of 0.04 mg and above. After administration of the approved recommended dosage of EPKINLY, the cytokine levels increased within 24 hours after the first dose on Cycle 1 Day 1, reached maximum levels after the first 48 mg dose on Cycle 1 Day 15, and returned to baseline prior to the next 48 mg full dose on Cycle 1 Day 22.

Immunogenicity: Anti-epcoritamab-bysp antibodies developed in 2.6% of patients (4 of 156) treated with EPKINLY at the recommended dosage during treatment in the clinical efficacy trial (up to 10 cycles) using an electrochemiluminescence immunoassay (ECLIA). Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the PK, PD, safety, and effectiveness of epcoritamab-bysp is unknown.

Use in Specific Populations
No clinically significant differences in the PK of epcoritamab-bysp were observed based on age (20 to 89 years), sex, race (White or Asian), mild to moderate renal impairment (creatinine clearance [CLcr] 30 to < 90 mL/min as estimated by Cockcroft-Gault formula), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight.

Body Weight: In patients who received the recommended dosage of EPKINLY, Cycle 1 median average concentration was 13% lower in the higher body weight (BW) group (85 to 144 kg) and 37% higher in the lower BW group (39 to 65 kg) compared to patients with BWs of 65 to less than 85 kg.

Lactation: Because maternal IgG is present in human milk, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with EPKINLY and for 4 months after the last dose.

Drug Interactions
For certain CYP substrates, 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 EPKINLY. Epcoritamab-bysp 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 EPKINLY on Cycle 1 Day 1 and up to 14 days after the first 48 mg dose on Cycle 1 Day 15, and during and after CRS.

Efficacy and Safety
The efficacy of EPKINLY was demonstrated in an open-label, multi-cohort, multicenter, single-arm trial in 157 patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. Efficacy was established based on overall response rate (ORR) determined by Lugano 2014 criteria as assessed by an Independent Review Committee (IRC) and duration of response. Additional information regarding the efficacy trial(s) can be found in the full prescribing information linked below.

The most common (≥ 20%) adverse reactions are cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.

Visit the EPKINLY (epcoritamab-bysp) full prescribing information page to learn more about EPKINLY.

Visit Drugs@FDA at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at drug development and drug interactions - table of substrates, inhibitors and inducers webpage.

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 at http://www.fda.gov/medwatch/report.htm, 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.