ModifiedHealth NetPolicy CP.PHAR.228

Trastuzumab (and biosimilars) and trastuzumab-hyaluronidase coverage

Defines medical necessity, prior authorization and step-therapy requirements for trastuzumab products (Herceptin and listed biosimilars) and trastuzumab-hyaluronidase (Herceptin Hylecta) for oncology indications across commercial, HIM/ICHRA, and Medicaid lines of business.

Policy Summary

PayerHealth Net

PolicyTrastuzumab (and biosimilars) and trastuzumab-hyaluronidase coverage

Policy CodePolicy CP.PHAR.228

Change TypeAnnual review with material additions and coding updates

Effective DateJun 1, 2016

Next Review Date

Key ActionSubmit documentation demonstrating the member meets all listed approval criteria, including diagnosis, oncologist involvement, dosing limits, and any applicable step therapy.

SourceLink

POLICY UPDATE CHANGES

2Q 2026 annual review: for gastric, esophageal and esophagogastric junction cancer, added option for use in members who are not surgical candidates per NCCN; for endometrial carcinoma, added option for carcinosarcoma histology; added off-label indication for brain metastasis due to breast cancer; appendiceal neoplasms and small bowel adenocarcinoma per NCCN; for all indications for Medicaid and HIM, extended initial approval duration from 6 to 12 months; references reviewed and updated.

RT4: added Hercessi to policy as non-preferred biosimilar and added new multi-dose vial formulation for Hercessi with HCPCS code Q5146; removed codes J3590 and C9399.

Added member has received ≤ 52 weeks of therapy per prescribing information and multiple NCCN-based off-label indications (gallbladder, cholangiocarcinoma, etc.) with associated regimen/combination updates (tucatinib, maintenance options).

Updated Appendix E language and state-specific step therapy exceptions (e.g., Tennessee exception, Illinois bypass for IL HB 5395); Appendix F residual tumor classification added.

J9355, J9356, Q5112–Q5117, Q5146HCPCS codes cited

Applies

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12 moApproval duration (Medicaid/HIM)

6 moApproval duration (Commercial)

≤52 weeksAdjuvant max duration

600 mg/10k UHylecta SC dose q3w

Coverage Criteria for Trastuzumab and Biosimilars

Continued Approval

Continued approval — covered when ALL of the following are met

Continued therapy general criteria: 1. Member is currently receiving medication via Centene benefit, or documentation supports current receipt of the agent for a covered indication with at least 30 days of therapy; 2. Member is responding positively to therapy; 3. For adjuvant breast cancer therapy, total therapy received ≤ 52 weeks; 4. If request is for Herceptin, Hercessi, Herzuma, or Ontruzant, member meets biosimilar sequencing unless exceptions; 5. Dose increases must not exceed FDA limits for respective indications or be supported by guidelines/literature with evidence submission.

Dose ceilings specified (e.g., 8 mg/kg IV adjuvant; 4 mg/kg IV metastatic; Herceptin Hylecta SC 600 mg/10,000 units q3w).

Other diagnoses/indications

Other diagnoses/indications — covered when ALL of the following are met

Other oncology indications: 1. One of the following applies: a) Request is for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E); b) If request is for Herceptin, member must trial Kanjinti, Ogivri, and Trazimera (and if failed these, may trial Ontruzant, Hercessi, and Herzuma) unless clinically significant adverse effects or contraindications; c) If request is for Herzuma, Hercessi, or Ontruzant, member must trial Kanjinti, Ogivri, and Trazimera unless clinically significant adverse effects or contraindications; 2. If drug label changed recently or requested use is not listed under section III, refer to formulary/no-coverage or non-formulary policies or the off-label use policy as applicable (see referenced policies).

Prior authorization may be required; see CP.CPA.190, HIM.PA.33, CP.PMN.255, HIM.PA.103, CP.PMN.16 and off-label policies for guidance.

General medical necessity criteria

Covered when dosing and indication align with product labeling or NCCN-supported indications and prior authorization requirements are met.

General coverage requirements: 1. Member has a diagnosis supported by the product prescribing information or NCCN where cited; 2. Dosing matches labeled regimen (IV or subcutaneous as applicable) and member has not exceeded label-recommended durations (e.g., adjuvant total ≤ 52 weeks where specified); 3. Prior authorization obtained and required documentation submitted; 4. For certain products, biosimilar sequencing/step therapy requirements apply unless exceptions; 5. Off-label uses must be supported by NCCN or submitted evidence per off-label policies.see individual product dosing

Policy includes expanded NCCN off-label indications and state-specific provisions; prior authorization may be required.

Herceptin Hylecta (trastuzumab-hyaluronidase) is a subcutaneous formulation distinct from IV trastuzumab products; in the FDA indication table in this policy Hylecta is shown as not indicated for gastric or EGJ adenocarcinoma (Hylecta = -), while IV trastuzumab and listed biosimilars are indicated for HER2‑overexpressing metastatic gastric/EGJ disease. Providers seeking coverage for Hylecta for gastric/EGJ cancer should note this difference when documenting indication and product selection.

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized for coverage unless the prescriber submits sufficient documentation of efficacy and safety per the applicable off‑label use policy for the line of business (see CP.CPA.09 for commercial, HIM.PA.154 for HIM/ICHRA, and CP.PMN.53 for Medicaid). Inclusion or exclusion of billing codes in this policy is informational and does not by itself establish coverage for off‑label uses.

The HCPCS codes listed in this policy are provided for informational purposes only. Inclusion of a code does not guarantee coverage and omission of a code does not imply noncoverage. Providers must ensure submitted codes match the product administered (for example, J9355/J9356 for originator trastuzumab and the Q‑codes for biosimilars) and follow current professional coding guidance.

Coding information in this clinical policy is intended as an administrative guide only. It is not a substitute for claim‑level coding verification — providers should reference the latest coding resources and ensure HCPCS codes billed correspond to the exact drug product, formulation, and vial size used because coding mismatches may lead to processing issues or denials.

Coding, Dosing and Approval Durations

HCPCS codes citedHCPCS

J9355	Injection, trastuzumab, excludes biosimilar, 10 mg
J9356	Injection, trastuzumab, 10 mg and hyaluronidase-oysk
Q5112	Injection, trastuzumab-dttb, biosimilar, (Ontruzant), 10 mg
Q5113	Injection, trastuzumab-pkrb, biosimilar, (Herzuma), 10 mg
Q5114	Injection, trastuzumab-dkst, biosimilar, (Ogivri), 10 mg
Q5116	Injection, trastuzumab-qyyp, biosimilar, (Trazimera), 10 mg
Q5117	Injection, trastuzumab-anns, biosimilar, (Kanjinti), 10 mg
Q5146	Injection, trastuzumab-strf (hercessi), biosimilar, 10 mg

Adjuvant breast cancer therapy duration — ≤ 52 weeks

Adjuvant durationMaximum total adjuvant trastuzumab therapy per PI and policy: ≤ 52 weeks (total course administered according to dosing schedules for a total of 52 weeks)

Continued approval conditionFor continued approval, member must be currently receiving medication via Centene benefit or have documentation supporting at least 30 days of therapy

Dose rounding referenceSee Appendix D for dose rounding and vial quantity recommendations when calculating doses within the 52-week course

Herceptin Hylecta subcutaneous dose — 600 mg trastuzumab + 10,000 units hyaluronidase every 3 weeks

Hylecta SC dosingHerceptin Hylecta subcutaneous formulation: 600 mg trastuzumab plus 10,000 units hyaluronidase administered once every 3 weeks (maximum dose = 600 mg/10,000 units q3w)

Provider Requirements, Prior Authorization and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization may be required. Provider must demonstrate the member meets all listed approval criteria; lack of submitted documentation supporting approval criteria may trigger denial.

Prior Authorization

Prior Authorization Time Limits

Approvals are time‑limited: Medicaid/HIM/ICHRA — 12 months; Commercial — 6 months or to the member's renewal date, whichever is longer. Initial approval durations and allowed indications are defined in the policy.

Prior Authorization

Prior Authorization for Trastuzumab Products

Initial and continued therapy requests for trastuzumab (Herceptin) and specified biosimilars require prior authorization. For trastuzumab products, initial approval durations differ by line of business and program — refer to the policy approval duration definitions.

Covered Regimens and Dosing Schedules

Regimen	Indication / Notes	Coverage Status
Trastuzumab or listed biosimilars (Herceptin, Hercessi, Herzuma, Ogivri, Ontruzant, Trazimera, Kanjinti) in combination with doxorubicin + cyclophosphamide followed by paclitaxel or docetaxel
Adjuvant HER2‑overexpressing breast cancer as part of the specified anthracycline‑ and taxane‑containing regimens per FDA indication; total therapy administered according to PI (examples shown in dosing section) for a total of 52 weeks

Regimen	Indication / Notes	Coverage Status
Trastuzumab (Herceptin) or listed biosimilars in combination with cisplatin plus capecitabine or cisplatin plus 5‑fluorouracil
First‑line treatment of HER2‑overexpressing metastatic gastric or gastroesophageal junction (EGJ) adenocarcinoma in patients not previously treated for metastatic disease; Herceptin Hylecta (trastuzumab‑hyaluronidase) is not indicated for this use (Hylecta = '-')

Product / Combination	Indication / Guidance	Coverage Status
Trastuzumab (Herceptin) and listed biosimilars (Ogivri, Herzuma, Ontruzant, Trazimera, Kanjinti, Hercessi)
Used as monotherapy or in combination with other agents (e.g., pertuzumab, tucatinib, lapatinib where indicated) per FDA labeling or NCCN recommendations; dosing must be within FDA maximums or supported by guidelines/literature

Route / Example dosing	Setting / Duration	Coverage Status
IV example: initial 4 mg/kg IV infusion over 90 minutes then 2 mg/kg IV weekly during chemotherapy (paclitaxel/docetaxel or docetaxel/carboplatin), then 6 mg/kg IV every 3 weeks following weekly dosing
Adjuvant breast cancer — dosing schedules administered for a total of 52 weeks per prescribing information (examples shown)

Route / Example dosing	Setting / Notes	Coverage Status
Metastatic IV example: initial 4 mg/kg IV as 90‑minute infusion followed by 2 mg/kg IV weekly until progression; alternative regimen: 8 mg/kg loading IV then 6 mg/kg IV every 3 weeks as applicable per PI
Metastatic breast cancer — dosing continued until disease progression; IV dose maximums: 4 mg/kg (weekly dosing context) or per PI alternatives as noted; dose increases must not exceed FDA limits

IV Regimen / Dosing	Indication / Notes	Coverage Status
Initial 8 mg/kg IV as a 90‑minute infusion followed by subsequent doses of 6 mg/kg IV every 3 weeks (subsequent doses 6 mg/kg IV over 30–90 minutes every 3 weeks)
Metastatic gastric cancer — administer initial 8 mg/kg IV then maintenance per PI; biosimilars follow equivalent IV dosing and maximums (up to 8 mg/kg where specified)

Line of Therapy and Treatment Setting

not specified

Not specified: Prescribed in combination with one of the following as applicable: pertuzumab; lapatinib (Tykerb) if colorectal disease; tucatinib (Tukysa).

Prior authorization may be required.

first-line | continuation depending on indication

First-line or continuation depending on indication: Adjuvant: dosing schedules totaling 52 weeks per PI (examples: IV loading and maintenance or Herceptin Hylecta 600 mg + 10,000 units SC q3w); Metastatic: IV initial and maintenance dosing per PI (e.g., 4 mg/kg loading then 2 mg/kg weekly or 8 mg/kg loading then 6 mg/kg q3w) until progression; specific regimens per labeling and NCCN.

Biomarker and Test Requirements

RAS (KRAS and NRAS) — wild-type (mutation-negative)

RequirementRAS (KRAS and NRAS) must be wild-type (mutation‑negative)

Applicable settingsRequired for colorectal cancer, appendiceal neoplasm/cancer, and small bowel adenocarcinoma per NCCN‑recommended uses

Test specificationDetermination must be by an FDA‑approved test when required by the criteria

BRAF — wild-type (mutation-negative)

RequirementBRAF must be wild-type (mutation‑negative)

Applicable settingsRequired for colorectal cancer, appendiceal neoplasm/cancer, and small bowel adenocarcinoma per NCCN‑recommended uses

Definitions and Key Terms

Trastuzumab-hyaluronidase — Herceptin Hylecta definition

Generic nameTrastuzumab‑hyaluronidase‑oysk (Herceptin Hylecta) — combination of trastuzumab and hyaluronidase

FormulationSubcutaneous formulation combining trastuzumab with hyaluronidase to enable SC administration

Primary indicationsIndicated in adjuvant and certain metastatic breast cancer regimens per product labeling (SC dose: 600 mg/10,000 units q3w)

Trastuzumab biosimilars — listed biosimilars (Ogivri, Herzuma, Ontruzant, etc.)

Listed biosimilarsTrastuzumab-dkst (Ogivri), trastuzumab-pkrb (Herzuma), trastuzumab-dttb (Ontruzant), trastuzumab-qyyp (Trazimera), trastuzumab-anns (Kanjinti), trastuzumab-strf (Hercessi)

Therapeutic equivalenceThese products are listed as trastuzumab biosimilars to Herceptin in the policy and are subject to biosimilar sequencing/step therapy requirements

Background

Trastuzumab is a monoclonal antibody directed against the HER2 receptor and is used to treat HER2‑overexpressing malignancies including breast and certain gastric/EGJ cancers. Multiple IV trastuzumab products and biosimilars are listed in the policy; trastuzumab‑hyaluronidase (Herceptin Hylecta) is a subcutaneous combination of trastuzumab with hyaluronidase and is a distinct formulation with specific labeled uses. As with all trastuzumab products, accurate documentation of diagnosis, HER2 status, product selection, and dosing is required for prior authorization and claims submission.

Revision History and Policy Changes

2026-04-24annual_reviewLatest

2Q 2026 annual review: added option for gastric/EGJ use in members who are not surgical candidates per NCCN; added carcinosarcoma histology for endometrial carcinoma; added off-label indication for brain metastasis from breast cancer; added appendiceal neoplasms and small bowel adenocarcinoma per NCCN; extended initial approval duration from 6 to 12 months for Medicaid and HIM; references reviewed and updated; Appendix E updated to include Indiana and ICHRA line added.

2026-03-05administrative_change

Added step therapy bypass for Illinois HIM per IL HB 5395 (step therapy exception updated).

Policy Summary

PayerHealth Net

PolicyTrastuzumab (and biosimilars) and trastuzumab-hyaluronidase coverage

Policy CodePolicy CP.PHAR.228

Change TypeAnnual review with material additions and coding updates

Effective DateJun 1, 2016

Next Review Date

Key ActionSubmit documentation demonstrating the member meets all listed approval criteria, including diagnosis, oncologist involvement, dosing limits, and any applicable step therapy.

SourceLink

On This Page

Administered subcutaneously over approximately 2–5 minutes

Indication contextsUsed as part of specified adjuvant regimens (with doxorubicin/cyclophosphamide then paclitaxel/docetaxel or docetaxel+carboplatin) or as single-agent following anthracycline-based therapy per labeling

Step Therapy

Step Therapy Required for Herceptin Requests

Requests for Herceptin (reference and certain biosimilars) are subject to step therapy requiring trial of specified biosimilars first. For Herceptin requests, the member must use ALL of the following in sequence unless clinically significant adverse effects occur or agents are contraindicated: Kanjinti, Ogivri, Trazimera; if the member has failed Kanjinti, Ogivri, and Trazimera, then the member must use Ontruzant, Hercessi, and Herzuma. For requests for Herzuma, Hercessi, or Ontruzant, the member must use ALL of Kanjinti, Ogivri, and Trazimera first unless clinically significant adverse effects or contraindications exist. State-specific exceptions (for example Illinois HIM per IL HB 5395) and oncology setting restrictions in Appendix E may modify these requirements.

Kanjinti, Ogivri, Trazimera required first for Herceptin requests
If failed above, require Ontruzant, Hercessi, Herzuma
For Herzuma/Hercessi/Ontruzant requests, require Kanjinti, Ogivri, Trazimera first
State-specific exceptions apply (see Appendix E)

Documentation Required

Supporting Documentation Required

Provider must submit supporting documentation (e.g., office chart notes, pathology and laboratory results, prior treatment history) that demonstrates the member meets all approval criteria, including diagnosis, staging, prior therapies tried and failed, and current regimen. Documentation should also support indication (FDA-approved or NCCN-supported off-label) and clinical response for continuation requests.

Office chart notes
Relevant lab/pathology results
Documentation of prior therapies and reasons for discontinuation
Clinical response/progress notes

Documentation Required

Off‑Label or Out‑of‑Range Dosing Documentation

If the requested dose or product is outside FDA limits or is for an off‑label dosing regimen, the prescriber must submit supporting evidence (peer‑reviewed literature or practice guideline recommendations such as NCCN) that justifies the dose or product. Off‑label requests not addressed in this policy require sufficient documentation of efficacy and safety per applicable off‑label use policies.

Prescriber-submitted literature or guideline evidence for off‑label dosing
Dose must be within FDA maximum limits or supported by evidence
Refer to CP.CPA.09, HIM.PA.154, or CP.PMN.53 for off‑label authorization pathways

Prior Authorization

State‑Specific Step Therapy Rules and Exceptions

Providers must follow state-specific step therapy rules and document any applicable state exceptions. Failure to follow required biosimilar sequencing or to document an allowed medical exception may result in denial.

State-specific restrictions and exceptions listed in Appendix E (e.g., IL HIM bypass per IL HB 5395)
Document clinical rationale for exceptions

Billing Rule

Coding and Coverage — Provider Actions

Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date professional coding guidance prior to claim submission. Submit documentation that supports the diagnosis, indication, dosing regimen, vial size used and HCPCS/J‑code (e.g., J9355, J9356, Q5112–Q5117, Q5146) to reduce claim processing issues.

Inclusion/exclusion of codes does not guarantee coverage
Reference current coding guidance before claim submission
Support claims with documentation of diagnosis, regimen, dosing, and vial size
Relevant HCPCS: J9355, J9356, Q5112, Q5113, Q5114, Q5116, Q5117, Q5146

BRAF mutation‑negative status as determined by an FDA‑approved test when applicable

HER2 — HER2-positive / overexpressing

DefinitionHER2 — disease must be HER2‑positive / overexpressing to meet labeled or NCCN‑recommended indications

ScopeRequired across breast, gastric/EGJ, endometrial (serous/carcinosarcoma), salivary gland, gallbladder/cholangiocarcinoma, and NCCN off‑label uses listed in policy

VerificationHER2 positivity should be established per standard diagnostic testing consistent with FDA labeling and NCCN guidance

KRAS/NRAS — wild-type (KRAS and NRAS mutation‑negative) as determined by FDA‑approved test

RequirementKRAS and NRAS must be wild‑type (mutation‑negative) as determined by an FDA‑approved test

IndicationsRequired for colorectal cancer, appendiceal neoplasm/cancer, and small bowel adenocarcinoma for NCCN‑recommended uses

DocumentationPrescriber must provide test results showing wild‑type KRAS/NRAS when required by the criteria

BRAF — wild-type (BRAF mutation‑negative)

RequirementBRAF must be wild‑type (BRAF mutation‑negative)

Applicable indicationsApplied to colorectal, appendiceal, and small bowel adenocarcinoma per NCCN‑recommended uses

EvidenceProvide FDA‑approved test results demonstrating wild‑type BRAF when requested

HER2 — disease is HER2 positive

RequirementDisease is HER2 positive (HER2‑overexpressing) — required for listed indications

Coverage implicationHER2 positivity is a core eligibility criterion for FDA‑labeled and NCCN‑recommended uses in this policy

TestingHER2 status should be documented per standard diagnostic methods consistent with product labeling and NCCN guidance

HER2 — (additional HER2 note from document)

Clinical noteHerceptin Hylecta is the subcutaneous formulation of trastuzumab combined with hyaluronidase; used in indicated adjuvant and certain metastatic regimens

CompositionCombination of trastuzumab and hyaluronidase (an endoglycosidase)

Administration routeAdministered subcutaneously (600 mg trastuzumab + 10,000 units hyaluronidase q3w for Hylecta)

Use considerationsBiosimilar sequencing requirements apply for certain products unless clinically significant adverse effects, contraindication, or state rules prohibit redirection

HER2 — human epidermal growth factor receptor 2 (Appendix D)

DefinitionHER2 = human epidermal growth factor receptor 2

Reference locationHER2 is listed and defined in Appendix D of the policy materials

Clinical roleHER2 overexpression is the biomarker target for trastuzumab and biosimilar therapy per labeling and NCCN guidance

Boxed warnings — cardiomyopathy, embryo‑fetal toxicity, pulmonary toxicity, infusion reactions

Boxed warnings listCardiomyopathy; embryo‑fetal toxicity; pulmonary toxicity

Infusion reactionsInfusion reactions are noted for Herceptin and listed biosimilars (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, Kanjinti, Hercessi)

ContraindicationsNo contraindications reported in Appendix C, but boxed warnings require monitoring per labeling

R0 — Resected, negative margin; no residual tumor

R0 definitionResected, negative margin; no residual tumor (R0)

ContextUsed in surgical/residual tumor classification referenced in Appendix F

ImplicationR0 denotes no residual tumor following resection

R1 — Resected, microscopic residual tumor (positive margin)

R1 definitionResected, microscopic residual tumor (positive margin) (R1)

ContextResidual Tumor (R) classification used to define resection status in policy

ImplicationR1 indicates microscopic residual disease after resection

R2 — Resected, macroscopic residual disease (gross residual)

R2 definitionResected, macroscopic residual disease (gross residual) (R2)

ContextUsed in criteria for gallbladder/cholangiocarcinoma where R2 (gross residual) is an allowed disease state

ImplicationR2 denotes macroscopic residual tumor following resection

2024-11-19coding_update

RT4: added new multi-dose vial formulation for Hercessi and added HCPCS code Q5146; removed codes J3590 and C9399.

2024-06-05formulary_update

RT4: added Hercessi to policy as a non-preferred biosimilar; Appendix E updated to include Mississippi.

2024-01-18policy_revision

Added ≤52 weeks maximum therapy language per PI; revised gastric/EGJ criteria to include unresectable disease and systemic chemotherapy options; added single-agent maintenance option for endometrial carcinoma; removed prior HER2-inhibitor restriction for colorectal cancer and added tucatinib combination option; added R2 resected gross residual option for gallbladder/cholangiocarcinoma; Appendix F residual tumor classification added; references updated.

2023-01-20annual_review

2Q 2023 annual review: added gallbladder cancer and cholangiocarcinoma as NCCN-supported off-label indications; references reviewed and updated.

2022-10-10template_update

Template changes applied to other diagnoses/indications and clarified intent for biosimilar steerage; references reviewed and updated.