ModifiedCentenePolicy CP.PHAR.634

Clinical Policy: Epcoritamab-bysp (Epkinly)

Policy governs medical necessity and prior authorization criteria for Epkinly (epcoritamab-bysp) for adult patients with certain relapsed/refractory B-cell lymphomas across Centene lines of business.

Policy Summary

PayerCentene

PolicyClinical Policy: Epcoritamab-bysp (Epkinly)

Policy CodePolicy CP.PHAR.634

Change TypeSubstantive coverage and criteria updatescoding and indication revisions

Effective DateSep 1, 2023

Next Review Date

Key ActionObtain prior authorization and submit documentation (office notes, labs, clinical information) showing the member meets all approval criteria; prescriber should be or consult with an oncologist/hematologist.

SourceLink

POLICY UPDATE CHANGES

Added NCCN Compendium supported off-label use for classic follicular lymphoma.

Updated FDA-approved indications to include follicular lymphoma per updated prescribing information.

Added use in second-line and subsequent therapy in combination with gemcitabine and oxaliplatin; removed specific criteria for histologic transformation of indolent lymphoma to DLBCL; added Appendix D to specify DLBCL subtypes per NCCN.

Updated with newly approved combination with lenalidomide and rituximab for relapsed or refractory FL and converted accelerated approval to traditional approval for FL.

Extended initial approval duration for Medicaid/HIM from 6 months to 12 months.

28-daycycle length

≥2lines required (some contexts)

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Coverage Criteria for Epcoritamab-bysp (Epkinly)

Initial Therapy — Covered when ALL of the following are met for B-cell lymphomas (Initial Approval).

Covered when ALL of the following are met for B-cell lymphomas (Initial Approval):

Initial B-cell lymphoma criteria: 1) Diagnosis: one of DLBCL (see Appendix D for subtypes), classic follicular lymphoma (grades 1-3A), histologic transformation of follicular or marginal zone lymphoma to DLBCL (off-label), HIV-related B-cell lymphomas (off-label), or post-transplant lymphoproliferative disorders (off-label); 2) Prescribed by or in consultation with an oncologist or hematologist; 3) Age ≥ 18 years; 4) Member has received ≥ 1 line of systemic therapy (see Appendix B) and meets one of the prior-therapy/regimen conditions specified below; 5) Dosing and administration requirements are met; 6) Prescribed regimen must be FDA-approved or recommended by NCCN.

See nested logic for prior therapy/regimen specifics and dosing constraints.

Criterion 4: prior therapy and regimen specifics: a) For any indication as monotherapy: member has partial response, no response, progressive, relapsed, or refractory disease following prior systemic therapy AND member has received ≥ 2 lines of systemic therapy; OR b) For DLBCL, HIV-related B-cell lymphomas, and post-transplant lymphoproliferative disorders: prescribed in combination with GemOx (gemcitabine and oxaliplatin) AND member has one of: relapsed or refractory disease; relapsed < 12 months after completion of first-line therapy or primary refractory disease in non-candidates for CAR T-cell therapy; relapsed > 12 months after completion of first-line therapy if there is no intention to proceed to transplant; OR c) For classic follicular lymphoma: prescribed in combination with lenalidomide and rituximab for relapsed or refractory disease (prior authorization may be required for lenalidomide and rituximab).

Prescriber must provide regimen details per Appendix B; prior authorization may be required for combination agents.

Dosing constraints: a) Cycle 1 step-up doses must not exceed: 0.16 mg on day 1; 0.8 mg on day 8; for FL only, 3 mg on day 15; and use of no more than three 4 mg/0.8 mL vials for step-up dosing; b) Maintenance/full dose: 48 mg per dose (one 48 mg vial) as per cycle-specific schedule; c) If prescribed with lenalidomide and rituximab for FL, total treatment does not exceed 12 cycles unless dose/regimen is supported by practice guidelines or peer-reviewed literature with prescriber submission of supporting evidence.48 mg per dose; step-up doses specified

Prescriber may submit evidence to support alternative dosing for off-label use; regimen must be FDA-approved or NCCN-recommended.

Continuation Therapy — Covered when ALL of the following are met for continuation/renewal.

Covered when ALL of the following are met for continuation/renewal:

Continuation criteria: 1) Member is currently receiving Epkinly via the Centene benefit, or documentation supports that the member has received Epkinly for a covered indication for at least 30 days; 2) Member is responding positively to therapy; 3) If used in combination with lenalidomide and rituximab for FL, treatment does not exceed a total of 12 cycles; 4) If the request is for a dose increase, the new dose does not exceed 48 mg per dose (one 48 mg vial) OR the new dose is supported by practice guidelines or peer-reviewed literature with prescriber submission of supporting evidence; 5) Prescribed regimen must be FDA-approved or recommended by NCCN.

Documentation (office notes, labs, or other clinical information) should be provided to support continuation.

Not Medically Necessary / Not Authorized — 1 top-level node describing exclusions/denials.

Not authorized: Non–FDA approved indications that are not addressed in this policy are not authorized unless sufficient documentation of efficacy and safety is provided in accordance with the referenced off‑label use policies (CP.CPA.09 for commercial, HIM.PA.154 for Health Insurance Marketplace, and CP.PMN.53 for Medicaid) or evidence of coverage documents.

Refer to off‑label use policies for required documentation.

Covered indications and dosing — FDA- and NCCN-recognized indications with regimen-specific dosing schedules; coverage expansions noted.

Policy covers epcoritamab-bysp for FDA- and NCCN-recognized indications with regimen-specific dosing schedules; coverage was expanded over time per compendium and label updates.

Dosing/Administration: Administer in 28‑day cycles until disease progression or unacceptable toxicity using step‑up dosing in cycle 1 as specified for DLBCL and FL. DLBCL: Cycle 1 step‑up doses 0.16 mg (Day 1), 0.8 mg (Day 8), first full dose 48 mg (Day 15) and 48 mg (Day 22); Cycles 2–3 weekly 48 mg; Cycles 4–9 every 2 weeks 48 mg; Cycle 10+ every 4 weeks 48 mg. FL: Cycle 1 step‑up doses 0.16 mg (Day 1), 0.8 mg (Day 8), 3 mg (Day 15), 48 mg (Day 22); Cycles 2–3 weekly 48 mg; as monotherapy cycles 4–9 q2w 48 mg and cycle 10+ q4w 48 mg; in combination with lenalidomide and rituximab cycles 4–12 day 1 48 mg (maximum 12 cycles when combined).

Cycle length 28 days; see Appendix B and dosing tables for full schedule and vial strengths.

Indications include diffuse large B‑cell lymphoma (DLBCL) — including NCCN‑specified subtypes — and follicular lymphoma (grades 1–3A) per updated FDA approval and NCCN compendium. Policy additions include use in second‑line and subsequent therapy in combination with gemcitabine and oxaliplatin per the 3Q 2025 update. Refer to Appendix D for DLBCL subtype listing.

Coverage expansions and label updates summarized in policy history.

Non–FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider supplies sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policies: CP.CPA.09 (Commercial), HIM.PA.154 (Health Insurance Marketplace), or CP.PMN.53 (Medicaid) or other evidence of coverage documents.

This policy does not list any absolute contraindications for epcoritamab‑bysp; however, the product carries boxed warnings for cytokine release syndrome (CRS) and immune effector cell‑associated neurotoxicity syndrome (ICANS), which should be considered when assessing patient safety and monitoring requirements.

Codes shown in this clinical policy are provided for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage; providers should consult current professional coding guidance and plan‑specific rules prior to claim submission, and note that not‑medically‑necessary (NMN) or other coverage determinations are governed by the policy criteria rather than the presence of a code alone.

Covered Regimens and Dosing Schedules

Regimen	Indication / Line	Coverage status
Epcoritamab in combination with GemOx (gemcitabine + oxaliplatin)
DLBCL, HIV-related B-cell lymphomas, and post-transplant lymphoproliferative disorders for relapsed/refractory disease or specified relapse timing (see criteria: relapsed/refractory; relapsed <12 months after first-line; relapsed >12 months if not proceeding to transplant)
Covered

Regimen	Indication / Line	Coverage status
Epcoritamab in combination with lenalidomide and rituximab
Relapsed or refractory follicular lymphoma (FL) — combination regimen; when used in combination, treatment limited to a maximum of 12 cycles
Covered

Dose timing	Dose (SC)	Notes / Duration
Cycle 1 - Day 1 (step-up dose 1)
0.16 mg
Part of Cycle 1 step-up schedule; administer in 28-day cycles until progression or unacceptable toxicity

Dose timing	Dose (SC)	Notes / Maximum cycles (when combined)
Cycle 1 - Day 8 (step-up dose 2)
0.8 mg
Part of Cycle 1 step-up schedule; for FL the Cycle 1 Day 15 step-up differs (see next row)
Cycle 1 - Day 15 (FL step-up dose 3)
3 mg (FL only)
Step-up dose specific to FL regimen
Cycle 1 - Day 22 (first full dose)
48 mg
Full dose administered starting Day 22 of Cycle 1; maintenance 48 mg per dosing schedule
Cycles 2–3 (DLBCL and FL)
48 mg on days 1, 8, 15, 22
Weekly dosing during cycles 2–3
Cycles 4–9 (DLBCL)
48 mg on days 1 and 15 (q2w)
For DLBCL maintenance schedule; continue until progression or unacceptable toxicity
Cycles 4–9 (FL as monotherapy)
48 mg on days 1 and 15 (q2w)
FL monotherapy maintenance schedule
Cycle 10 and beyond (DLBCL and FL monotherapy)
48 mg on day 1 (q4w)
Long-term maintenance dosing until progression or unacceptable toxicity
Cycles 4–12 (FL in combination with lenalidomide + rituximab)
48 mg on day 1 of each cycle
When given with lenalidomide and rituximab, treatment is limited to a maximum of 12 cycles

Coding and Billing References

HCPCS Codes referencedHCPCS

J9321

Injection, epcoritamab-bysp, 0.16 mg

Cycle length

Cycle length28-day cycles until disease progression or unacceptable toxicity

Cycle structureCycle 1 includes step-up doses per regimen (see dosing); subsequent cycles vary by weeks as specified for DLBCL vs FL

Maintenance schedulingDLBCL: Cycles 4-9 q2w (days 1 & 15), Cycle 10+ q4w (day 1); FL monotherapy: same schedule; FL combination: up to 12 cycles

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior Authorization Required

Prior Authorization Required — Prescriber must be or consult with an oncologist/hematologist and submit supporting documentation. Prior authorization is required for Epkinly (epcoritamab) requests. The prescriber must be or consult with an oncologist or hematologist when requesting therapy.

Prescriber requirement: prescribed by or in consultation with an oncologist or hematologist.
Prior authorization is required for initial and continuation requests per plan prior authorization procedures.

Billing Rule

HCPCS Code and Prior Authorization

HCPCS code referenced in this policy for billing and prior authorization purposes. Inclusion or exclusion of codes does not guarantee coverage; providers should reference current professional coding guidance prior to claim submission.

Line of Therapy Requirements

second-line — criteria node for second-line use (top-level node).

Line of therapy rules (second-line): Member must have received ≥ 1 line of systemic therapy generally; for monotherapy and certain accelerated‑approval contexts member must have received ≥ 2 lines of systemic therapy. Policy was updated to add use in second‑line and subsequent therapy in combination with gemcitabine and oxaliplatin per 3Q 2025 review.

See policy criteria for indication‑specific line‑of‑therapy requirements (e.g., GemOx combination criteria for DLBCL and related indications).

second-line — additional/alternative second-line criteria node (top-level node).

Second-line update: Per 3Q 2025 annual review (NCCN Compendium), policy added use in second‑line and subsequent therapy in combination with gemcitabine and oxaliplatin; policy history also documents removal of specific histologic transformation requirements and addition of Appendix D for DLBCL subtypes.

Refer to policy history for approval dates and detailed changes.

Background and Drug Information

Epcoritamab‑bysp (Epkinly) is a bispecific CD20‑directed CD3 T‑cell engager indicated for certain relapsed or refractory B‑cell lymphomas. The agent is administered subcutaneously with a cycle structure that uses step‑up dosing in the first cycle and continued 48 mg maintenance dosing in subsequent cycles according to indication‑specific schedules. The product carries boxed warnings for cytokine release syndrome and immune effector cell‑associated neurotoxicity syndrome and may be used as monotherapy or in specified combination regimens (for example, with lenalidomide and rituximab in follicular lymphoma or with gemcitabine/oxaliplatin in selected diffuse large B‑cell lymphoma scenarios) as described in the policy and supporting compendia.

Definitions and Safety Information

Epkinly (epcoritamab-bysp)

AgentEpkinly (epcoritamab-bysp)

Mechanism of actionBispecific CD20-directed CD3 T-cell engager

FDA indications (selected)Relapsed/refractory DLBCL after ≥2 lines; relapsed/refractory FL as monotherapy after ≥2 lines; in combination with lenalidomide and rituximab for relapsed/refractory FL

DLBCL subtypes (per NCCN, Appendix D)

DLBCL, NOSIncluded per NCCN (Appendix D)

DLBCL arising from follicular or marginal zone lymphomaIncluded per NCCN (Appendix D)

Revision History and Policy Changes

2024-07-03annual_review

3Q 2024 annual review added NCCN Compendium–supported off‑label use for classic follicular lymphoma and updated references.

2025-04-17annual_review

3Q 2025 annual review added use in second‑line and subsequent therapy in combination with gemcitabine and oxaliplatin, removed specific criteria for histologic transformation to DLBCL, and added Appendix D specifying DLBCL subtypes per NCCN.

2025-12-11regulatory_and_operational_updateLatest

Policy Summary

PayerCentene

PolicyClinical Policy: Epcoritamab-bysp (Epkinly)

Policy CodePolicy CP.PHAR.634

Change TypeSubstantive coverage and criteria updatescoding and indication revisions

Effective DateSep 1, 2023

Next Review Date

SourceLink

On This Page

Documentation Required

Documentation Required to Support Approval

Provider must submit documentation (such as office chart notes, relevant laboratory results, imaging, pathology reports, prior therapy records, and other clinical information) supporting that the member meets all approval criteria. Lack of required documentation may result in denial or deferral of the prior authorization request.

Examples of acceptable documentation: office/clinic notes, infusion records, chemotherapy administration records, pathology reports, radiology reports, relevant lab results, documentation of prior lines of systemic therapy and response.
If requesting an off‑label regimen or a dose outside standard step‑up dosing, submit supporting peer‑reviewed literature or guideline references.

Step Therapy

Regimen Sequencing Note

Regimen sequencing and combination therapy notes that may affect prior authorization decisions. Ensure documentation supports prior lines of therapy and the specific combination regimen being requested.

Member must have received prior systemic therapy as specified in the policy (≥1 line for some indications; ≥2 lines for monotherapy use per criteria).
Combination regimens: requests for Epkinly in combination with gemcitabine + oxaliplatin (GemOx) or lenalidomide + rituximab must meet the policy’s indication-specific sequencing criteria (e.g., relapsed/refractory status, timing relative to first‑line therapy, and intent regarding transplant or CAR T‑cell therapy).
If regimen sequencing deviates from FDA‑approved or NCCN‑recommended pathways, submit literature or guideline support with the prior authorization request.