Epcoritamab-bysp (Epkinly)

Number: 1034

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses epcoritamab-bysp (Epkinly) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of epcoritamab-bysp (Epkinly) is required of all Aetna participating providers and members in applicable plan designs. For precertification of epcoritamab-bysp (Epkinly), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

  1. Criteria for Initial Approval

    Aetna considers epcoritamab-bysp (Epkinly) medically necessary for treatment of the following indications: 

    1. B-Cell Lymphomas

      For treatment of B-cell lymphoma when one of the following criteria is met:

      1. The requested medication will be used as subsequent therapy for follicular lymphoma in combination with lenalidomide and rituximab for up to 12 cycles total for no response, relapsed, or progressive disease; or
      2. The requested medication will be used as subsequent therapy in combination with GemOx (gemcitabine and oxaliplatin) for relapsed/refractory disease with any of the following subtypes:

        1. Diffuse large B-cell lymphoma (DLBCL); or
        2. High grade B-cell lymphoma; or
        3. HIV-related B-cell lymphoma including HIV-related DLBCL, primary effusion lymphoma, and HHV8-positive DLBCL, not otherwise specified, and HIV-related plasmablastic lymphoma; or
        4. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); or

      3. The requested medication will be used as a single agent after at least 2 prior lines of systemic therapy when the member has partial response, no response, progressive, relapsed or refractory disease with any of the following subtypes:

        1. Diffuse large B-cell lymphoma (DLBCL); or
        2. High grade B-cell lymphoma; or
        3. Histologic transformation of indolent lymphoma to DLBCL; or
        4. HIV-related B-cell lymphoma including HIV-related DLBCL, primary effusion lymphoma, and HHV8-positive DLBCL, not otherwise specified; or
        5. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); or
        6. Follicular lymphoma.

    2. Histologic (Richter) Transformation to DLBCL

      For treatment of histologic (Richter) transformation to DLBCL.

    Aetna considers all other indications as experimental, investigational, or unproven.

  2. Continuation of Therapy

    Aetna considers continuation of epcoritamab-bysp (Epkinly) therapy medically necessary in members requesting reauthorization for an indication listed in the Criteria for Initial Approval section when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. A maximum of 12 cycles total will be authorized for members using the requested medication in combination with lenalidomide and rituximab for follicular lymphoma.

Dosage and Administration

Epcoritamab-bysp is supplied as Epkinly in the following dosage forms and strengths:

  • Injection: 4 mg/0.8 mL in a single-dose vial. Dilute prior to use.
  • Injection: 48 mg/0.8 mL in a single-dose vial.

Epkinly is for subcutaneous injection only.

The recommended dosage schedule for Epkinly is noted in the table below. Administer Epkinly in 28-day cycles until disease progression or unacceptable toxicity.

Epkinly Dosage Schedule
DLBCL and High-grade B-cell Lymphoma
Cycle of TreatmentFootnote1*  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
Cycles 2 and 3  1, 8, 15, and 22 48 mg
Cycles 4 to 9  1 and 15 48 mg
Cycles 10 and beyond 1 48 mg
Epkinly as Monotherapy Follicular Lymphoma (FL)
Cycle of TreatmentFootnote1* 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 Step-up dose 3 3 mg
22 First full dose 48 mg
Cycles 2 and 3 1, 8, 15 and 22 48 mg
Cycles 4 to 9 1 and 15 48 mg
Cycles 10 and beyond 1 48 mg
Epkinly in Combination with Lenalidomide and Rituximab for FL
Cycle of TreatmentFootnote1* 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 Step-up dose 3 3 mg
  22 First full dose 48 mg
Cycles 2 and 3 1, 8, 15, and 22 48 mg
Cycles 4 to 12 1 48 mg

Footnote1*Cycle = 28 days

Refer to the full prescribing information for Epkinly for preparation and administration, dosage modifications, and management of adverse reactions.

Source: Genmab US, 2026

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:
96401 Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic

HCPCS codes covered if selection criteria are met:
J9321 Injection, epcoritamab-bysp, 0.16 mg

Other HCPCS codes related to the CPB:
Lenalidomide –no specific code
J9184 Injection, gemcitabine hydrochloride (avyxa), 200 mg
J9196 Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9198 Injection, gemcitabine hydrochloride, (infugem), 100 mg
J9201 Injection, gemcitabine hydrochloride, not otherwise specified, 200 mg
J9263 Injection, oxaliplatin, 0.5 mg
J9312 Injection, rituximab, 10 mg

ICD-10 codes covered if selection criteria are met:
C82.00 – C82.99 Follicular lymphoma
C83.00 - C83.09 Small cell B-cell lymphoma
C83.30 - C83.3A Diffuse large B-cell lymphoma
C83.50 – C83.59 Lymphoblastic (diffuse) lymphoma
C83.80 - C83.89 Other non-follicular lymphoma
C85.10 – C85.19 Unspecified B-cell lymphoma
C85.20 – C85.29 Mediastinal (thymic) large B-cell lymphoma
C88.40 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, not having achieved remission [MALT-lymphoma]
C88.41 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, in remission [MALT-lymphoma]
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)

Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

  • Epkinly is indicated 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 (HGBL), after two or more lines of systemic therapy.
  • Epkinly is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) in combination with lenalidomide and rituximab.
  • Epkinly is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) as monotherapy after two or more lines of systemic therapy.

Compendial Uses

  • Diffuse large B-cell lymphomas
  • High grade B-cell lymphomas
  • Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
  • Human immunodeficiency virus (HIV)-related B-cell lymphomas
  • Monomorphic post-transplant lymphoproliferative disorders
  • Follicular lymphoma
  • Histologic (Richter) transformation

Epcoritamab-bysp is available as Epkinly (Genmab US, Inc.) and is bispecific antibody that activates T-cells by binding to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells. In vitro, this activation of T-cells resulted in the release of proinflammatory cytokines and death of CD20 B-cells (Genmab US, 2026).

Per the prescribing information, boxed warnings for Epkinly, include:

  • Cytokine release syndrome (CRS), including serious or life-threatening reactions: 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: Monitor patients for neurological signs or symptoms of ICANS during treatment. Withhold Epkinly until ICANS resolves or permanently discontinue based on severity.

According to the prescribing information, Epkinly carries the following warnings and precautions:

  • Infections: Can cause serious or fatal infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately.
  • Cytopenias: Monitor complete blood cell counts during treatment.
  • Embryo-fetal toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.

Per the prescribing information for Epkinly, 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.

On May 19, 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Epkinly (epcoritamab-bysp) for the treatment of 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. The FDA approval was based on supporting data from the EPCORE NHL-1 study (FDA, 2023).

In the EPCORE NHL-1 study, an open-label, multi-cohort, multicenter, single-arm trial, Thieblemont et al. (2023) evaluated the efficacy of Epkinly (epcoritamab-bysp) in 157 patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. Epkinly monotherapy was administered via subcutaneous injection according to the following 28-day cycle schedule: 1) cycle 1: Epkinly 0.16 mg on day 1, 0.8 mg on day 8, 48 mg on days 15 and 22, 2) cycles 2-3: Epkinly 48 mg on days 1, 8, 15, and 22, 3) cycles 4-9: Epkinly 48 mg on days 1 and 15, and 4) cycles 10 and beyond: Epkinly 48 mg on day 1. Epkinly treatment continued until disease progression or unacceptable toxicity. The efficacy population was made up of 148 patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy, including at least one anti-CD20 monoclonal antibody-containing therapy. The primary efficacy end point was overall response rate (ORR) determined by Lugano 2014 criteria, as assessed by an independent review committee. The ORR was 61% (95% confidence interval [CI]: 53, 69) with 38% of patients achieving complete responses. The median follow-up was 9.8 months among responders with an estimated median duration of response (DOR) of 15.6 months (95% CI: 9.7, not reached).

On June 26, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval to epcoritamab-bysp (Epkinly), a bispecific CD20-directed CD3 T-cell engager, for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. The FDA approval was based on supporting data from the EPCORE NHL-1 study (FDA, 2024).

References

The above policy is based on the following references:

  1. Genmab US, Inc. Epkinly (epcoritamab-bysp) injection, for subcutaneous use. Prescribing Information. Plainsboro, NJ: Genmab US; revised March 2026.
  2. National Comprehensive Cancer Network (NCCN). Epcoritamab-bysp. NCCN Drugs and Biologics Compendium. Plymouth Meeting, PA: NCCN; April 2026.
  3. U.S. Food and Drug Administration (FDA). FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. Drugs. Sliver Spring, MD: FDA; May 19, 2023.
  4. U.S Food and Drug Administration (FDA). FDA approves epcoritamab-bysp for follicular lymphoma indications. Drugs. Silver Spring, MD: FDA; November 18, 2025.
  5. U.S. Food and Drug Administration (FDA). FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. Drugs. Silver Spring, MD: FDA; June 26, 2024.
  6. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II trial. J Clin Oncol. 2023;41(12):2238-2247.