Epkinly

Epkinly is used to treat relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) in adults. It is given as an injection under the skin (subcutaneously) every 1 to 4 weeks.

Epkinly is a bispecific CD20-directed CD3 T-cell engager approved to treat adults with relapsed or refractory (R/R):

• 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. Approved under accelerated approval; continued approval may depend on confirmatory trial results demonstrating clinical benefit.
• Follicular lymphoma (FL), in combination with lenalidomide and rituximab.
• FL after two or more lines of systemic therapy, as monotherapy.

Clinical Trial Results

Epkinly (epcoritamab) first gained FDA approval on May 19, 2023, under the accelerated approval designation. Full approval was granted for R/R FL on November 18, 2025, based on the results of the Phase 3 EPCORE FL-1 clinical trial (NCT05409066), which demonstrated:

• Epkinly, in combination with rituximab and lenalidomide (Epkinly + R2), reduced the risk of disease progression or death by 79% compared to rituximab and lenalidomide alone (hazard ratio 0.21, 95% CI: 0.13-0.33, p<0.0001).
• For the overall response rate, 89% of patients receiving Epkinly with rituximab and lenalidomide responded to treatment (216 out of 243 patients, 95% CI: 84-93%; p<0.0001), versus 74% response rate with rituximab and lenalidomide alone (181 out of 245 patients, 95% CI: 68-79%).

Previous results from the EPCORE NHL-1 (NCT03625037) clinical trial reported:

• 61% of patients with R/R DLBCL responded to treatment (overall response rate) and responses lasted a median of 15.6 months.
• 82% of patients with R/R FL responded to treatment and >50% were still responding at 14.8 months.

Epkinly (epcoritamab) has a bispecific mechanism of action and works by binding to two different immune system targets: the CD20 protein on B cells and the CD3 protein on T cells. This brings T cells into proximity to B cells, making them more effective at killing cancerous B cells.

Epkinly belongs to the drug class called Bispecific T-cell engagers (BiTE).

Epkinly will be given as an injection under your skin (subcutaneous injection) by your healthcare provider.

• It is usually given in the lower part of your stomach area (abdomen) or upper, outer, thigh.
• Your treatment schedule is divided into cycles that are usually 28 days (4 weeks) long.
• Epkinly is usually given 1 time a week during Cycles 1 to 4, every 2 weeks from Cycle 4 to 9, and every 4 weeks starting with Cycle 10.
• Your healthcare provider will decide how many treatment cycles you will receive.

Your healthcare provider may hospitalize you for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg.

Before administering Epkinly, you may receive premedications to decrease the risk of CRS.

• These premedications may include a steroid such as prednisolone or dexamethasone or equivalent, an antihistamine such as diphenhydramine or equivalent, and acetaminophen.
• Premedications for the remaining cycles include prednisolone or dexamethasone or equivalent.

Before you receive treatment, tell your healthcare provider about all of your medical conditions, including if you:

• have an infection
• are pregnant or intend to become pregnant
• are breastfeeding.

Pregnancy

This medicine may cause harm to your unborn baby. Females who can become pregnant:

• Your healthcare provider should do a pregnancy test before you start treatment
• You should use effective birth control (contraception) during treatment, and for 4 months after your last dose
• Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment.

Breastfeeding

Do not breastfeed during treatment and for 4 months after your last dose.

The most common side effects of Epkinly are:

• Tiredness
• Muscle and bone pain
• Injection site reactions
• Fever
• Stomach-area (abdominal) pain
• Nausea
• Diarrhea.

Serious side effects and warnings

Epkinly carries a Boxed Warning for cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

Cytokine Release Syndrome (CRS) happens when your immune system responds to immunotherapy drugs more aggressively than it should. It is common during treatment and can also be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop any signs or symptoms of CRS, including:

• fever of 100.4°F (38°C) or higher
• dizziness or light-headedness
• trouble breathing
• chills
• fast heartbeat
• feeling anxious
• headache
• confusion
• shaking (tremors)
• problems with balance and movement, such as trouble walking

Due to the risk of CRS, you will receive treatment on a "step-up dosing schedule".

• The step-up dosing schedule is when you receive smaller "step-up" doses on Day 1 and Day 8 of your first cycle of treatment (Cycle 1).
• You will receive your first full dose on Day 15 of Cycle 1.
• If your dose is delayed for any reason, you may need to repeat the "step-up dosing schedule".
• Before each dose in Cycle 1, you will receive medicines to help reduce your risk of CRS. Your healthcare provider will decide if you need to receive medicine to help reduce your risk of CRS with future cycles.
• See How will I receive Epkinly? for more information about how you will receive this medicine.

Neurologic Problems (Immune Effector Cell-Associated Neurotoxicity Syndrome or ICANS). Epkinly can cause serious neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive this medicine. Your healthcare provider may refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems, including:

• trouble speaking or writing
• confusion and disorientation
• drowsiness
• tiredness or lack of energy
• muscle weakness
• shaking (tremors)
• seizures
• memory loss.

Hospital Monitoring. Due to the risk of CRS and neurologic problems, you should be hospitalized for 24 hours after receiving your first full dose on Day 15 of Cycle 1. Your healthcare provider will monitor you for signs and symptoms of CRS and neurologic problems during treatment, as well as other side effects and treat you if needed. Your healthcare provider may temporarily stop or completely stop your treatment if you develop CRS, neurologic problems, or any other severe side effects.

Other serious side effects of Epkinly include:

Infections. Epkinly can cause serious infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment with Epkinly. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment, including:

• fever of 100.4°F (38°C) or higher
• cough
• chest pain
• tiredness
• shortness of breath
• painful rash
• sore throat
• pain during urination
• feeling weak or generally unwell.

Low blood cell counts. Low blood cell counts are common during treatment, and can also be serious or severe. Your healthcare provider will check your blood cell counts during treatment.Epkinly may cause the following low blood cell counts:

• low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection
• low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath
• low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems.

Your healthcare provider may temporarily stop or completely stop treatment if you develop certain side effects.

It is not known if Epkinly is safe and effective in children.

These are not all the possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Adult Dose for Diffuse Large B-cell Lymphoma (DLBCL) or High-grade B-cell Lymphoma

The dose of Epkinly for DLBCL or high-grade B-cell lymphoma depends on the Cycle and day of treatment. Your healthcare provider will calculate the dosage.

Adult Dose for Follicular Lymphoma (FL)

The dose of Epkinly for FL depends on the Cycle and day of treatment. Your healthcare provider will calculate the dosage.

Epkinly may cause dizziness, confusion, tremors, sleepiness, or other symptoms that may impair your ability to drive or operate heavy machinery, and you should not do these tasks if you are impaired.

• These may be symptoms of CRS or neurologic problems, and you should tell your healthcare provider right away.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Epkinly may cause small changes in the concentration of other medications that are metabolized by the CYP hepatic enzyme system. Monitor for any increase in side effects.

Epkinly causes the release of cytokines that may suppress the activity of CYP enzymes, and enhance the concentration of CYP substrates. This is more likely to occur after the first dose of Epkinly and up to 14 days after the 48 mg dose.

Active ingredient: epcoritamab-byspInactive ingredients: acetic acid, polysorbate 80, sodium acetate, sorbitol, and Water for Injection.

Epkinly is manufactured by Genmab, a Danish biotechnology company headquartered in Copenhagen, Denmark, in collaboration with AbbVie, an American biopharmaceutical company based in North Chicago, Illinois. Other notable drugs by these companies include:

• Genmab: Darzalex - for multiple myeloma Kesimpta - for multiple sclerosis Tivdak - for cervical cancer.
• AbbVie: Humira - for various autoimmune conditions Rinvoq - for rheumatoid arthritis Skyrizi - for psoriasis Venclexta - for certain leukemias Vraylar - for schizophrenia and bipolar disorder.