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CurrentAetnaPolicy 0313

Trastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

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Medical necessity, coverage, dosing, and precertification requirements for trastuzumab products and Herceptin Hylecta for Aetna commercial medical plans; affects providers requesting coverage for these agents.

Policy Summary

PayerAetna

PolicyTrastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Policy CodePolicy 0313

Change TypeNo material change

Effective DateJan 11, 1999

Last ReviewFeb 15, 2024

Next Review DateFeb 22, 2024

Key ActionObtain prior authorization and submit documentation of HER2 positivity (IHC 2+/3+ or validated FISH) and relevant pathology when requesting trastuzumab or Herceptin Hylecta.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

12adjuvant duration (months)

600 mgHerceptin Hylecta dose q3w

Requiredprecertification

45.4% vs 40.7%pCR HannaH (Hylecta vs IV)

~111references

Coverage Criteria and Clinical Indications

Initial Therapy — Indications considered medically necessary

Covered when ANY one of the following disease-specific criteria is met

Breast cancer: Neoadjuvant, adjuvant, or treatment of recurrent, advanced, unresectable, or metastatic HER2-positive breast cancer (including brain metastases); intra‑CSF administration for leptomeningeal metastases is included.

Adjuvant and neoadjuvant approved for total of 12 months

Colorectal cancer: HER2‑amplified colorectal cancer (including appendiceal and anal adenocarcinoma) that is RAS and BRAF wild‑type when given in combination with pertuzumab or lapatinib for patients who are not appropriate for intensive therapy or as subsequent therapy for progression of advanced/metastatic disease.

Esophageal/gastric/GEJ cancer: HER2‑positive esophageal, gastric, or gastroesophageal junction adenocarcinoma for treatment or palliation in combination with chemotherapy.

Policy Summary

PayerAetna

PolicyTrastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Policy CodePolicy 0313

Change TypeNo material change

Effective DateJan 11, 1999

Last ReviewFeb 15, 2024

Next Review DateFeb 22, 2024

Key ActionObtain prior authorization and submit documentation of HER2 positivity (IHC 2+/3+ or validated FISH) and relevant pathology when requesting trastuzumab or Herceptin Hylecta.

SourceLink

On This Page

Hepatobiliary cancers: Subsequent treatment of unresectable or metastatic HER2‑positive hepatobiliary cancers (including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer) when used in combination with pertuzumab.

Salivary gland tumors: Treatment of HER2‑positive salivary gland tumors (eg, salivary duct carcinoma, carcinoma ex pleomorphic adenoma) when HER2 amplification/overexpression is documented.

Uterine serous carcinoma: Treatment of HER2‑positive advanced, recurrent, or metastatic uterine serous carcinoma in combination with carboplatin and paclitaxel.

Initial Therapy — Herceptin Hylecta

Covered when ANY of the following for Herceptin Hylecta

Breast cancer (Hylecta): Adjuvant, neoadjuvant, or treatment of recurrent, unresectable, advanced, or metastatic HER2‑positive breast cancer (including brain metastases).

Adjuvant and neoadjuvant approved for total of 12 months; metastatic use continued until disease progression

Continuation Therapy — Continuation of therapy

Continuation of therapy

Continuation of trastuzumab (including Herceptin Hylecta and biosimilars) is medically necessary when there is no unacceptable toxicity or disease progression on the current regimen.

Adjuvant and neoadjuvant treatment approved to complete a total of 12 months; metastatic therapy may continue until progression

Coverage Criteria

Covered when selection criteria and indications are met (FDA-approved or compendial uses):

FDA-approved indications: Use for HER2‑overexpressing breast cancer (adjuvant and metastatic) and HER2‑overexpressing metastatic gastric/gastroesophageal junction adenocarcinoma per FDA approvals.

See FDA labeling

Compendial/other uses: Compendial uses include neoadjuvant therapy, recurrent/advanced/unresectable disease, intra‑CSF (leptomeningeal) administration, HER2‑positive esophageal/EGJ cancer, uterine serous carcinoma, HER2‑amplified colorectal cancer in combination with pertuzumab or lapatinib, salivary gland tumors, and hepatobiliary cancers.

See compendial statements

Patient selection criteria: Documented tumor HER2 overexpression or amplification by an FDA‑approved companion diagnostic (IHC 2+ or 3+ or validated FISH) is required to select patients expected to benefit.

See diagnostic guidance

Duration of therapy (adjuvant): Adjuvant trastuzumab is generally provided for up to 1 year (approximately 52 weeks).1 year

Based on HERA and supporting trials

Monitoring and safety: Baseline and periodic cardiac function assessment (eg, LVEF) prior to and during therapy (eg, at 3, 6, and 9 months); discontinue for clinically significant decrease in left ventricular function or severe cardiotoxicity.

Cardiac monitoring advised due to cardiotoxicity risk

Breast cancer — adjuvant

Evidence-supported coverage contexts and key findings:

Adjuvant early-stage HER2-positive breast cancer: Covered when patient has early‑stage HER2‑positive breast cancer and is a candidate for adjuvant trastuzumab; standard duration supported is 12 months based on randomized trials (eg, HERA) showing DFS and OS benefit.duration = 12 months

One year remains standard of care; longer durations not superior

Gastric cancer — Advanced/metastatic gastric or gastroesophageal adenocarcinoma

Advanced/metastatic gastric or gastroesophageal adenocarcinoma:

Metastatic HER2-positive gastric cancer: Covered when tumor is HER2‑positive and trastuzumab is administered with chemotherapy as in the ToGA trial; trial demonstrated improved median overall survival (13.5 vs 11.1 months).HER2-positive by validated testing

Cardiac monitoring advised due to asymptomatic LVEF decreases observed

Leptomeningeal disease (IT) — Leptomeningeal carcinomatosis in HER2-positive breast cancer

Leptomeningeal carcinomatosis in HER2-positive breast cancer:

Intrathecal trastuzumab for leptomeningeal disease: Use is based on pooled case reports/series (17 patients) that suggest IT trastuzumab may be safe and produce clinical or CSF responses in some patients; evidence is limited and clinical trials are needed.case series evidence only

Consider investigational/limited evidence; not definitive for routine coverage without further evidence or trial context

Non-small cell lung cancer — Non-small cell lung cancer (NSCLC)

Non-small cell lung cancer (NSCLC):

Trastuzumab in NSCLC: Single‑agent trastuzumab and combinations tested in NSCLC showed minimal or inconsistent activity; routine use is investigational and not supported by phase II trials.no consistent benefit demonstrated

Evidence does not support routine coverage in NSCLC

Salivary gland cancer — Salivary gland cancers

Salivary gland cancers:

HER2-amplified salivary gland carcinoma: Case reports and small series report responses to trastuzumab (often combined with chemotherapy) in HER2‑amplified salivary duct carcinoma or carcinoma ex pleomorphic adenoma; testing for HER2 alterations is recommended and use may be considered in select patients.HER2 amplification or activating mutation documented

Evidence limited; consider in select patients or clinical trial

Urothelial (bladder) cancer — Urothelial/bladder cancer

Urothelial/bladder cancer:

Trastuzumab in HER2-positive urothelial carcinoma: Evidence is mixed: case reports show benefit in select patients but randomized phase II data did not demonstrate significant PFS/OS benefit overall when adding trastuzumab to gemcitabine+platinum; consider only in well‑selected HER2‑positive patients, preferably in trials.HER2 over-expression confirmed by IHC and FISH

Not standard therapy; consider clinical trial or select subsets

Penile cancer — Penile cancer

Penile cancer:

Trastuzumab in penile cancer: NCCN guideline for penile cancer does not mention trastuzumab as a therapeutic option; therefore trastuzumab is not recommended for this indication.no guideline support

Not recommended based on NCCN guidance

Consideration criteria (evidence-limited indications)

Evidence summaries indicate trastuzumab may be considered when specific HER2 biomarkers are present, but benefit is unproven or limited for many non‑breast indications.

Consideration criteria for non-breast tumors: All of the following: (1) Pathology‑documented HER2 over‑expression (IHC 2+ or 3+) or HER2 gene amplification by validated FISH; (2) Tumor type with biologic rationale or supportive case evidence (eg, HER2‑amplified colorectal, gallbladder, dermal adnexal carcinoma) and lack of effective standard therapies; (3) Multidisciplinary review and/or enrollment in a clinical trial preferred.

Evidence limited to case reports/series or small trials; use is conditional

FDA-approved and compendial uses for Herceptin Hylecta

FDA-approved and compendial uses described in document segments:

Herceptin Hylecta FDA-approved adjuvant and metastatic indications: Herceptin Hylecta is FDA‑approved for adjuvant treatment of adults with HER2‑overexpressing node positive or node negative (ER/PR negative or with one high‑risk feature) breast cancer as part of specified regimens, and for specified metastatic breast cancer settings including combination with paclitaxel for first‑line metastatic disease or as single agent after prior chemotherapy.

Based on FDA labeling and HannaH/SafeHER trials

Evidence summaries influencing coverage decisions

Evidence for dual HER2-targeted therapy and other tumor types:

Dual HER2 therapy (pertuzumab + trastuzumab): Randomized trials in breast cancer demonstrate improved pCR in the neoadjuvant setting and improved outcomes in metastatic disease when pertuzumab is added to trastuzumab and chemotherapy; results vary by tumor type and gastric cancer trials did not show significant OS improvement with dual blockade.

References include Gianni, CLEOPATRA, JACOB and others

Use in non-breast cancers: Evidence for trastuzumab in other cancers (eg, gallbladder, ovarian, salivary duct carcinoma, osteosarcoma, ampullary, neuroendocrine tumors) is limited to case reports, small series, or trials with uncertain benefit; further study is needed.

Evidence limited

FDA-Approved Indications (Herceptin Hylecta)

Covered when indications match FDA-approved uses listed for Herceptin Hylecta and trastuzumab products

Herceptin Hylecta adjuvant indications: Adjuvant treatment of adults with HER2‑overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer as part of specified chemotherapy regimens or as single agent following multi‑modality anthracycline‑based therapy.

From FDA labeling

Herceptin Hylecta metastatic indications: In adults: in combination with paclitaxel for first‑line treatment of HER2‑overexpressing metastatic breast cancer; as a single agent for treatment of HER2‑overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

From FDA labeling

Compendial Uses

Compendial use guidance

Substitution: Herceptin Hylecta may be substituted for intravenous trastuzumab and used as a single agent or in combination with other systemic therapies for HER2‑positive breast cancer per compendia.

Based on compendial statement and trial evidence (HannaH, SafeHER)

Use of trastuzumab (including Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera) alone or in combination with chemotherapy is considered experimental and investigational for a list of tumor types for which efficacy has not been established. Examples include ampullary adenocarcinoma, bladder cancer, cancers of unknown primary, dermal adnexal cancer, hepatobiliary cancers (cholangiocarcinoma and gallbladder), intra-hepatic bile duct cancer, melanoma, neuroendocrine cervical cancer, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, and vulvar cancer.

Certain ICD-10 diagnoses are identified in the policy as not covered for the listed CPB indications. Notable examples called out include C07 (parotid gland), C25.0–C25.9 (pancreas), C40.00–C41.9 (osteosarcoma), and C43.0–C43.9 (melanoma), along with select gynecologic and genitourinary cancer codes; these diagnoses are listed as exclusions when trastuzumab is requested for the CPB indications.

The NCCN clinical practice guideline for penile cancer (Version 1.2023) does not mention trastuzumab as a therapeutic option; therefore trastuzumab is not supported for penile cancer outside of exceptional circumstances or clinical trial enrollment.

In a phase II trial of single‑agent trastuzumab for advanced or recurrent endometrial carcinoma that required tumor HER2 over‑expression or amplification for eligibility, no major tumor responses were observed and neither HER2 over‑expression nor amplification was associated with improved PFS or overall survival. For this reason, single‑agent trastuzumab is generally not considered effective as standard therapy for endometrial carcinoma absent new corroborating evidence.

Single‑agent trastuzumab demonstrated limited clinical value in recurrent ovarian cancer studies because of the low frequency of HER2 over‑expression in screened populations and low objective response rates among those with 2+/3+ HER2 expression; thus routine use of trastuzumab monotherapy for recurrent ovarian cancer is not supported.

No explicit exclusions beyond those listed elsewhere are stated in the cited document sections; however, multiple tumor types are described as having limited or uncertain benefit from trastuzumab, indicating that coverage is dependent on documented HER2 positivity and supporting evidence for the specific tumor type.

The excerpts provided in these chunks do not list additional explicit coverage exclusions. See the policy history and full policy text for any administrative or plan‑specific exclusion language that may apply.

Requests for Herceptin, Herceptin Hylecta, Kanjinti, Ontruzant, or Trazimera are limited by Aetna's brand‑selection policy: these products are considered medically necessary only when the member has a documented contraindication, intolerance, or ineffective response to lower‑cost equivalent anti‑HER2 monoclonal antibodies (for example, Herzuma or Ogivri).

Use of trastuzumab in tumors without documented HER2 over‑expression or gene amplification (for example, IHC 0–1 without confirmatory FISH amplification) is not expected to be beneficial. Patient selection should be based on an FDA‑approved companion diagnostic (e.g., HercepTest) demonstrating HER2 over‑expression (IHC 2+ or 3+) or HER2 gene amplification prior to initiating trastuzumab.

Phase II studies and other trial data do not support routine use of trastuzumab in non‑small cell lung cancer: single‑agent trastuzumab showed minimal activity even in tumors with IHC 2+/3+ HER2 expression, and combinations with chemotherapy have not demonstrated improved outcomes sufficient to support standard use.

Evidence and guideline reviews for metastatic urothelial (bladder) cancer do not list trastuzumab as a therapeutic option, and clinical trials were limited by a low prevalence of HER2 over‑expression; thus trastuzumab is not supported as standard therapy for urothelial carcinoma outside of clinical trials or well‑defined HER2‑positive subsets.

The JACOB trial examined addition of pertuzumab to trastuzumab plus chemotherapy in first‑line HER2‑positive metastatic gastric or gastroesophageal junction cancer and did not show a statistically significant overall survival benefit (median OS 17.5 vs 14.2 months; HR 0.84; p = 0.057). Serious adverse events were more frequent in the pertuzumab arm. These results do not support routine use of dual HER2 blockade with pertuzumab and trastuzumab for first‑line metastatic gastric cancer based on that trial.

The provided excerpts do not contain explicit statements labeling particular uses as 'not medically necessary' beyond the experimental/investigational lists and brand‑selection constraints already described. Review the full policy for any additional 'not medically necessary' provisions.

This portion of the document does not list additional explicit 'not medically necessary' conditions. Refer to the full policy text for the complete set of not‑medically‑necessary statements and plan‑specific determinations.

Initial Therapy — Approval Criteria

Initial Therapy — Initial approval criteria

Initial approval criteria

Breast cancer (trastuzumab): Neoadjuvant, adjuvant, or treatment of recurrent, advanced, unresectable, or metastatic HER2‑positive breast cancer (including brain metastases); intra‑CSF for leptomeningeal metastases is included.

Adjuvant and neoadjuvant approved for total of 12 months

Initial therapy — Initial dosing and selection

Initial dosing and selection:

Dosing options: Recommended IV dosing: either 4 mg/kg IV loading dose then 2 mg/kg weekly OR 8 mg/kg IV loading dose then 6 mg/kg every 3 weeks.

See prescribing information

Selection requirement: Initiate trastuzumab only in patients with documented HER2 overexpression or amplification by an approved companion diagnostic (eg, IHC 2+/3+ or validated FISH).

See diagnostic guidance

Adjuvant initial therapy — Adjuvant breast cancer initial therapy

Adjuvant breast cancer initial therapy

Initial adjuvant regimen: Standard administration historically uses IV trastuzumab with an initial loading dose (eg, 8 mg/kg then 6 mg/kg q3w for IV formulations); recommended total duration is approximately 12 months.duration = 12 months

6‑month regimens failed non‑inferiority vs 12 months

Reported trial eligibility and dosing (example)

Reported trial eligibility and dosing (example): Example: endometrial carcinoma trial required HER2 overexpression (IHC 2+/3+) or FISH amplification; single‑agent trastuzumab dosing reported as 4 mg/kg IV loading then 2 mg/kg weekly.

Trial reported no major tumor responses

Neoadjuvant pertuzumab + trastuzumab

Neoadjuvant approval context for pertuzumab:

Neoadjuvant pertuzumab indication: Pertuzumab received accelerated FDA approval for neoadjuvant use in combination with trastuzumab and chemotherapy for certain high‑risk HER2‑positive early breast cancers; patients should continue trastuzumab after surgery to complete 1 year of therapy.

Based on FDA accelerated approval and trial evidence

Trial evidence supporting subcutaneous trastuzumab

Clinical trial dosing and evidence supporting Herceptin Hylecta

HannaH trial: HannaH randomized 596 patients and demonstrated comparable pCR between Herceptin Hylecta and IV trastuzumab (pCR 45.4% vs 40.7%), supporting subcutaneous formulation as an alternative.

SafeHER trial: SafeHER evaluated 600 mg fixed‑dose Herceptin Hylecta q3w in 1,864 patients demonstrating safety/tolerability with common AEs including fatigue, arthralgia, diarrhea, and injection site reactions.

Continuation of Therapy — Conditions to Continue

Continuation of Therapy — Continuation rules for ongoing therapy

Continuation rules for ongoing therapy

Continuation: Continue trastuzumab (including Herceptin Hylecta and biosimilars) when there is no unacceptable toxicity or disease progression on current regimen; adjuvant/neoadjuvant limited to 12 months total.

Continuation therapy — Continuation beyond initial authorization

Continuation beyond initial authorization:

Adjuvant continuation: Continue trastuzumab to complete approximately 1 year of therapy if started for adjuvant treatment and patient tolerates therapy without clinically significant cardiotoxicity.1 year

See HERA and other trials

Metastatic continuation: In the metastatic setting, continue trastuzumab until disease progression unless significant toxicity (eg, cardiomyopathy) necessitates discontinuation.until progression

IT continuation — Intrathecal trastuzumab continuation in leptomeningeal disease

Intrathecal trastuzumab continuation in leptomeningeal disease:

Continuation after CNS progression: Pooled case reports note IT trastuzumab was sometimes given beyond CNS progression with responses observed in a subset; continuation may be considered in select patients with clinical benefit documented.clinical benefit observed

Based on small pooled case series

Continuation after neoadjuvant therapy — Post-neoadjuvant continuation guidance

Post-neoadjuvant continuation guidance from FDA approval context:

Post-neoadjuvant trastuzumab continuation: Following neoadjuvant therapy that included pertuzumab plus trastuzumab and chemotherapy, patients should continue trastuzumab after surgery to complete 1 year of treatment as per FDA labeling for pertuzumab/neoadjuvant regimens.

Based on Perjeta FDA‑approved indication and trial design

Billing Codes and Coding Guidance

HCPCS codes covered if selection criteria are metHCPCSCovered

J9355	Trastuzumab, 10 mg
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, 10 mg (Kanjinti)

Related CPT/HCPCS codesmixed

96365	Intravenous infusion, for therapy; initial, up to 1 hour
96366	Each additional hour
96372	Therapeutic injection; subcutaneous or intramuscular
96401-96450	Chemotherapy administration
G0461	Immunohistochemistry per specimen; first antibody stain
G0462	Each additional antibody stain

Related drugs (coded)HCPCS

J9306

Injection, pertuzumab, 1 mg

ICD-10 codes covered if selection criteria are metICD-10Covered

C50.011-C50.929	Malignant neoplasm of breast [HER2 positive]
C16.0-C16.9	Malignant neoplasm of stomach [HER2 positive]
C15.3-C15.9	Malignant neoplasm of esophagus [HER2 positive]
C18.0-C18.9	Malignant neoplasm of colon [unresectable, advanced, or metastatic]
C20	Malignant neoplasm of rectum
C21.0-C21.8	Malignant neoplasm of anus and anal canal
C22.0-C22.9	Malignant neoplasm of liver and intrahepatic bile ducts

ICD-10 codes noted as not covered for indications listedICD-10Not Covered

C07	Malignant neoplasm of parotid gland
C25.0-C25.9	Malignant neoplasm of pancreas
C40.00-C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]

Related HCPCS/J-codesHCPCS

Q5113	Injection, trastuzumab-dttb, biosimilar, (Ontruzant), 10 mg
Q5114	Injection, trastuzumab-pkrb, biosimilar, (Herzuma), 10 mg
Q5116	Injection, trastuzumab-dkst, biosimilar, (Ogivri), 10 mg
Q5117	Injection, trastuzumab-qyyp, biosimilar, (Trazimera), 10 mg
J9306	Injection, pertuzumab, 1 mg
J9264	Injection, paclitaxel protein-bound particles, 1 mg
J9265	Paclitaxel, 30 mg
J9258	Carboplatin, 50 mg
J9259	Injection, paclitaxel protein-bound particles (teva) not therapeutically equivalent to j9264, 1 mg
J9045	Tucatinib, lapatinib – no specific code listed

Herceptin Hylecta HCPCSHCPCSCovered

J9356

Injection, trastuzumab, 10 mg and Hyaluronidase-oysk (Herceptin Hylecta)

Covered ICD-10 codes (when selection criteria met)ICD-10Covered

C50.011-C50.929	Malignant neoplasm of breast [HER2 positive]
C16.0-C16.9	Malignant neoplasm of stomach [HER2 positive]
C15.3-C15.9	Malignant neoplasm of esophagus [HER2 positive]
C18.0-C18.9	Malignant neoplasm of colon [unresectable, advanced, or metastatic]
C20	Malignant neoplasm of rectum
C21.0-C21.8	Malignant neoplasm of anus and anal canal
C22.0-C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C23	Malignant neoplasm of gallbladder
C24.0-C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C34.00-C34.92	Malignant neoplasm of bronchus and lung [non-small cell lung cancer]

ICD-10 codes listed as not covered for CPB indications (partial list)ICD-10Not Covered

C07	Malignant neoplasm of parotid gland (listed as not covered for CPB indications)
C25.0-C25.9	Malignant neoplasm of pancreas
C40.00-C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C43.0-C43.9	Malignant melanoma of skin
C51.0-C51.9	Malignant neoplasm of vulva
C53.0-C53.9	Malignant neoplasm of cervix uteri
C54.1-C54.9	Malignant neoplasm of corpus uteri, except isthmus
C56.1-C56.9	Malignant neoplasm of ovary
C60.0-C60.9	Malignant neoplasm of penis
C61	Malignant neoplasm of prostate

Adjuvant/neoadjuvant therapy duration — 52 weeks (12 months)

Standard adjuvant/neoadjuvant duration52 weeks (12 months)

Treatment stop conditionUntil disease recurrence (adjuvant) or until progression (metastatic)

Evidence basisHERA and related trials supporting 12-month adjuvant duration

Recommended loading dose (IV) — 4 mg/kg loading then 2 mg/kg weekly OR 8 mg/kg loading then 6 mg/kg every 3 weeks

Recommended IV loading/maintenance (weekly)4 mg/kg loading dose then 2 mg/kg weekly

Recommended IV loading/maintenance (q3w)8 mg/kg loading dose then 6 mg/kg every 3 weeks

Clinical sourceFDA labeling and Herceptin dosing guidance (Genentech; HERA trial)

Authorization, Documentation, and Operational Requirements

Prior Authorization

Precertification / Prior Authorization Required

Precertification / Prior Authorization Required — Prior authorization (precertification) is required for trastuzumab products and Herceptin Hylecta for Aetna commercial medical plans. For precertification, call (866) 752-7021 or fax (888) 267-3277. Submit Statement of Medical Necessity (SMN) forms as applicable.

Precertification contact: (866) 752-7021; Fax: (888) 267-3277
Submit SMN forms via Specialty Pharmacy Precertification portal

Documentation Required

HER2 testing and pathology documentation required

HER2 diagnostic documentation required — Therapy selection should be based on an FDA‑approved companion diagnostic. Prior authorization requires documentation of tumor HER2 status using validated methods (IHC 2+ or 3+ or FISH amplification) with supporting pathology reports.

Acceptable tests: FDA‑approved IHC (eg, HercepTest) showing IHC 2+ or 3+; or validated FISH with HER2/CEP17 ratio > 2.0
Provide pathology report showing the specimen tested and results (IHC and/or FISH)

Documentation Required

HER2 testing and prior therapy documentation required

Require documented HER2 testing and prior therapy documentation — Prior authorization should include documentation of HER2 positivity and relevant prior therapies (eg, prior chemotherapy regimens, neoadjuvant/adjuvant treatments) to support the requested use and line of therapy.

Document prior chemotherapy (agents, dates, response) when requesting trastuzumab for metastatic or recurrent disease
Provide HER2 test date, method, and results (IHC and/or FISH)

Step Therapy

Combination therapy expectation; step therapy / substitution

Combination therapy expectation and step/substitution guidance — Clinical evidence and indications commonly pair trastuzumab with standard chemotherapy regimens (eg, cisplatin + fluoropyrimidine in gastric cancer; carboplatin/paclitaxel or anthracycline‑based regimens in breast cancer). Aetna generally expects use of recommended chemotherapy backbones unless product label or compendia support single‑agent use or substitution (eg, Herceptin Hylecta as subcutaneous alternative to IV trastuzumab). Brand‑step requirements apply: lower‑cost anti‑HER2 biosimilars (Herzuma, Ogivri) should be used prior to higher‑cost products unless contraindicated or ineffective.

Expect trastuzumab to be used in combination with guideline‑recommended chemotherapy for non‑breast indications (eg, ToGA regimen in gastric cancer)
Herceptin Hylecta may substitute for IV trastuzumab for indicated breast cancer uses
Brand step: prefer Herzuma (trastuzumab‑pkrb) or Ogivri (trastuzumab‑dkst) before higher‑cost products unless contraindication/intolerance documented

Documentation Required

Require standard chemotherapy before investigational targeted therapy

Require standard chemotherapy before investigational targeted therapy in select rare tumors — For uncommon sites (eg, cervical neuroendocrine tumors), follow NCCN guidance recommending standard small‑cell lung cancer chemotherapy regimens (eg, cisplatin or carboplatin plus etoposide) prior to investigational targeted therapy unless clinical rationale and evidence justify earlier targeted use.

Document rationale if requesting trastuzumab instead of guideline‑recommended chemotherapy for neuroendocrine or rare tumors

Denial Risk

Lack of demonstrated efficacy in endometrial cancer

Lack of demonstrated efficacy in endometrial cancer — Single‑agent trastuzumab failed to show major tumor responses in trials of HER2‑positive endometrial carcinoma; evidence does not support routine single‑agent use in endometrial cancer.

Fleming et al (2010): no major tumor responses observed in enrolled endometrial cancer patients despite some HER2 amplification

Documentation Required

Baseline cardiac and performance status required for trial‑level eligibility

Baseline cardiac and performance status requirements in trials — Key trials required baseline left ventricular ejection fraction (LVEF) ≥55% and ECOG performance status 0–1. Absence of baseline cardiac assessment or poor performance status may affect appropriateness of trastuzumab therapy and prior authorization.

Obtain baseline LVEF and document value (many pivotal trials required ≥55%)
Document ECOG performance status (0–1 in most trials)

Note

Refer to prescribing information and pivotal trials when documenting medical necessity

Prescribing information and trial evidence referenced — Coverage determinations are informed by product prescribing information, pivotal trials (eg, ToGA, HannaH, JACOB), and compendial guidance (NCCN). Providers should refer to prescribing information and cited trials when supplying supporting documentation for authorization.

Refer to Herceptin/Herceptin Hylecta prescribing information and cited randomized trials (HannaH, ToGA, JACOB)
NCCN Drugs & Biologics Compendium referenced for compendial uses

Note

Operational PA rules and denial triggers not fully specified here

No explicit authorization criteria or denial triggers stated in this excerpt — While the policy outlines clinical expectations and documentation needs, specific operational PA code lists, denial code triggers, and complete exclusion ICD‑10 lists are not presented here; use the CPT/HCPCS/ICD‑10 code tables and full policy for operational PA rules.

See CPT/HCPCS/ICD‑10 tables elsewhere in the policy for covered codes and ICD‑10 inclusion/exclusion lists
Operational prior authorization codes and denial triggers are maintained in the payer’s precertification workflow

Step Therapy and Sequencing Considerations

Step	Requirement
1	Brand step requirement: Use preferred lower‑cost trastuzumab biosimilars (e.g., Herzuma [trastuzumab‑pkrb], Ogivri [trastuzumab‑dkst]) prior to higher‑cost trastuzumab products (Herceptin, Herceptin Hylecta, Kanjinti, Ontruzant, Trazimera) unless a documented contraindication, intolerance, or ineffective response to the biosimilars is provided.

Step	Requirement
1	Expect trastuzumab to be administered in combination with specified chemotherapy regimens per FDA‑approved indications when applicable (examples: in adjuvant regimens that include doxorubicin/cyclophosphamide followed by paclitaxel or docetaxel; as combination with docetaxel and carboplatin; and with paclitaxel for first‑line metastatic breast cancer).

Step	Requirement
1	Use trastuzumab with evidence‑based chemotherapy regimens where trial benefit was demonstrated (e.g., ToGA regimen — trastuzumab plus cisplatin and capecitabine or 5‑fluorouracil for HER2‑positive metastatic gastric/GEJ cancer; and in bladder trials, trastuzumab was studied added to gemcitabine + platinum backbones).

Step	Requirement
1	Consider trastuzumab only after standard‑of‑care cytotoxic therapy has been used for the tumor type or in the setting of HER2‑amplified refractory disease or enrollment in a clinical trial; for rare neuroendocrine/extra‑pulmonary small cell histologies follow guideline chemotherapy (e.g., cisplatin/carboplatin + etoposide) before investigational targeted use.

Step	Requirement
1	Comparative effectiveness note: Evidence discusses alternative or additive HER2‑directed strategies (lapatinib, pertuzumab, and combinations with trastuzumab) showing varying benefit versus trastuzumab monotherapy; the policy does not mandate a specific sequencing but allows consideration of dual HER2‑targeted therapy where supported by evidence and indication (e.g., pertuzumab + trastuzumab + chemotherapy in appropriate settings).

Step

Requirement

Comparative effectiveness note: Evidence discusses alternative or additive HER2‑directed strategies (lapatinib, pertuzumab, and combinations with trastuzumab) showing varying benefit versus trastuzumab monotherapy; the policy does not mandate a specific sequencing but allows consideration of dual HER2‑targeted therapy where supported by evidence and indication (e.g., pertuzumab + trastuzumab + chemotherapy in appropriate settings).

Step	Requirement
1	Compendial substitution: Herceptin Hylecta (subcutaneous trastuzumab + hyaluronidase) may be substituted for intravenous trastuzumab for indicated HER2‑positive breast cancer uses; these chunks do not specify a formal step therapy sequence for Hylecta versus IV trastuzumab.

Quantity and Dosing Constraints

Herceptin (trastuzumab) IV vials — per dosing as clinically indicated; vial size referenced 440 mg per vial

Vial presentationHerceptin IV powder for solution: 440 mg per vial

Dose-based useUse per dosing as clinically indicated (IV regimens: 4 mg/kg then 2 mg/kg weekly or 8 mg/kg then 6 mg/kg q3w)

Reconstitution detailReconstitution yields ~21 mg/mL (440 mg vial with diluent as specified)

Administration Setting and Site-of-Care Guidance

Note

Biosimilars, Substitution, and Brand Preference

Note

Definitions and Dosing Summary

Dosing summary — Adjuvant/neoadjuvant trastuzumab: typical IV dosing includes 4 mg/kg loading then 2 mg/kg weekly or an 8 mg/kg loading then 6 mg/kg every...

IV dosing options4 mg/kg loading then 2 mg/kg weekly OR 8 mg/kg loading then 6 mg/kg every 3 weeks

SC dosing (Hylecta)600 mg subcutaneously every 3 weeks (SafeHER/HannaH trial dosing)

Adjuvant durationAdjuvant/neoadjuvant therapy typically given for 52 weeks (12 months)

HER2 over-expression/amplification — Presence of increased HER2 protein on tumor cells (IHC 2+ or 3+) or gene amplification by validated FISH assay; used to select candidates...

DefinitionPresence of increased HER2 protein on tumor cells (IHC 2+ or 3+) or gene amplification by validated FISH assay

PurposeUsed to select candidates for trastuzumab therapy

Approved diagnosticsHercepTest (IHC) and validated FISH assays (e.g., PathVysion) per FDA/ASCO guidance

Biosimilar — A biological product highly similar to an FDA-approved reference product with no clinically meaningful differences in safety, purity, or ...

DefinitionA biological product highly similar to an FDA-approved reference product with no clinically meaningful differences in safety, purity, or potency

ExamplesOgivri, Herzuma, Ontruzant, Trazimera, Kanjinti listed as trastuzumab biosimilars

Regulatory noteBiosimilars approved for the same indications as reference Herceptin

Intrathecal (IT) trastuzumab — Administration of trastuzumab directly into cerebrospinal fluid for leptomeningeal carcinomatosis; pooled reports suggest possible safety...

DefinitionAdministration of trastuzumab directly into cerebrospinal fluid for leptomeningeal carcinomatosis

EvidencePooled reports (13 articles, 17 patients) suggest possible safety and clinical/CSF responses but remain limited

Coverage stanceConsidered investigational/limited evidence; clinical trials preferred for routine adoption

Adjuvant trastuzumab — Systemic trastuzumab given following surgery/chemotherapy to reduce recurrence in early HER2-positive breast cancer; standard duration is...

DefinitionSystemic trastuzumab given following surgery/chemotherapy to reduce recurrence in early HER2-positive breast cancer

Standard durationStandard duration is 12 months (52 weeks) based on HERA and other trials

Safety considerationsAssociated with increased cardiac events; monitor LVEF during treatment

HER2 positivity / amplification — HER2 over-expression by IHC (2+ or 3+) or HER2 gene amplification by FISH (HER2/CEP17 ratio > 2.0) as used in cited studies to identify p...

DefinitionHER2 over-expression by IHC (2+ or 3+) or HER2 gene amplification by FISH (HER2/CEP17 ratio > 2.0)

Trial requirementMany trials required documented HER2 over-expression/amplification for eligibility

Clinical implicationPatients with IHC 0-1 without amplification are unlikely to benefit

HER2 over-expression — Tumor cell overexpression/amplification of the human epidermal growth factor receptor 2 (HER2/neu), commonly assessed by IHC (2+/3+) or o...

DefinitionTumor cell overexpression/amplification of HER2/neu assessed by IHC (2+/3+) or FISH; predicts responsiveness to trastuzumab

Prevalence in breast cancerOccurs in approximately 15–25% of breast cancers

Testing guidanceUse FDA-approved companion diagnostics for selection (IHC or FISH)

Herceptin Hylecta — Herceptin Hylecta: Combination of trastuzumab and hyaluronidase-oysk for subcutaneous administration to treat HER2-overexpressing breast ...

Product descriptionHerceptin Hylecta is trastuzumab combined with hyaluronidase-oysk for subcutaneous administration

SC dosing600 mg subcutaneous every 3 weeks (used in trials like SafeHER and HannaH)

Substitution noteCompendial guidance indicates Herceptin Hylecta may substitute for IV trastuzumab in HER2-positive breast cancer

Policy History and References

References and prescribing information for trastuzumab products and for Herceptin Hylecta are cited in the policy. Providers should refer to the individual product prescribing information and the cited NCCN/clinical references for detailed dosing, administration, safety, and monitoring information when requesting authorization.

Prescribing information and randomized trial evidence are cited for Herceptin Hylecta and IV trastuzumab; these references imply that documentation of tumor HER2 over‑expression/amplification (e.g., IHC 2+/3+ or validated FISH) consistent with FDA‑approved indications is required to support use in indicated settings.