ModifiedPremera BluecrossPolicy 5.01.514

HER2 Inhibitors

Coverage and medical necessity criteria for HER2-targeted drugs (oral and injectable), including indications, dosing limits, sequencing, and documentation requirements for Premera Blue Cross members.

Policy Summary

PayerPremera Bluecross

PolicyHER2 Inhibitors

Policy CodePolicy 5.01.514

Change TypeMaterial updates to indications, biosimilar preferences, and quantity limits

Effective DateJan 2, 2026

Next Review Date

Key ActionSubmit medical records documenting diagnosis, prior therapies, HER2 test results, and baseline LVEF to support prior authorization and reauthorization requests.

SourceLink

POLICY UPDATE CHANGES

Included ado-trastuzumab emtansine (Kadcyla) and current NCCN recommendations.

Added coverage for Enhertu for adults with unresectable or metastatic HER2-low breast cancer and unresectable or metastatic non-small cell lung cancer.

Added a new indication to Enhertu for treatment of adult individuals with HR-positive HER2-low or HER2-ultralow breast cancer progressed on one or more endocrine therapies in the metastatic setting.

Moved Trazimera to second-line (non-preferred) agent effective January 1, 2024 and added a quantity limit requirement for Tukysa (tucatinib) in colorectal cancer criteria.

Updated to include new data on expanded indications of trastuzumab and addition of criteria for pertuzumab.

1 yearrecommended duration of adjuvant trastuzumab

240 mgneratinib daily dose limit

600 mg/daytucatinib dose limit

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20-30%HER2+ breast cancer proportion

9.6 vs 6.4 moPFS (EMILIA)

72%Enhertu reported risk reduction (DESTINY-Breast03)

Coverage Criteria for HER2-Targeted Therapies

Other targeted agents (pertuzumab, pertuzumab/trastuzumab SC, ado-trastuzumab emtansine, trastuzumab deruxtecan, margetuximab)

Covered when ALL of the following are met:

ALL of the following

Pertuzumab (Perjeta) or pertuzumab-containing products (e.g., Phesgo) will be used in combination with trastuzumab (or trastuzumab-containing product) and chemotherapy as part of an approved regimen (adjuvant, neoadjuvant, or for metastatic disease).
For neoadjuvant use: intended for individuals with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer as part of a complete treatment regimen.
For adjuvant use: intended for individuals with HER2-positive early breast cancer in accordance with labeled indications and trial-based regimens.
For metastatic disease: intended for previously untreated or recurrent HER2-positive breast cancer when used in combination with trastuzumab and a taxane (e.g., docetaxel or paclitaxel) or other chemotherapy per label.
When prescribing Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) subcutaneous formulation: documentation of indication and combination chemotherapy regimen must be provided; can be used in the same settings as IV pertuzumab where clinically appropriate.

Ado-trastuzumab emtansine (Kadcyla)

Covered when ALL of the following are met:

ALL of the following

Ado-trastuzumab emtansine (Kadcyla) will be used as a single agent for individuals with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane (separately or in combination).
Ado-trastuzumab emtansine (Kadcyla) may be used as adjuvant therapy for HER2-positive early breast cancer when there is residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment, consistent with labeled indications.

Fam-trastuzumab deruxtecan (Enhertu)

Covered when ALL of the following are met:

ALL of the following

Fam-trastuzumab deruxtecan (Enhertu) for unresectable or metastatic HER2-positive breast cancer: individual is an adult who has received a prior anti-HER2–based regimen in the metastatic setting, or developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy.
Enhertu for HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) HR-positive breast cancer: disease progressed on one or more endocrine therapies in the metastatic setting and other criteria per labeled indication are met.
Enhertu for HER2-positive gastric/gastroesophageal junction adenocarcinoma or HER2-positive solid tumors: must be adult with locally advanced or metastatic disease and have received a prior trastuzumab-based regimen; for other solid tumors, no satisfactory alternative treatment options must be documented.
For Enhertu in NSCLC: activating HER2 (ERBB2) mutation and prior systemic therapy documented as required by labeling.

Margetuximab (Margenza)

Covered when ALL of the following are met:

ALL of the following

Margetuximab (Margenza) will be used for metastatic HER2-positive breast cancer in adults who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.
Margetuximab must be used in combination with chemotherapy per labeled indication.

Policy-level coverage and product preference

ALL of the following

All uses must follow the product's FDA-approved dosing, administration, and labeled indications unless specific off-label uses are explicitly listed as medically necessary elsewhere in this policy.
Biosimilar and interchangeable trastuzumab products (e.g., Kanjinti, Ogivri, Trazimera, Hercessi, Herzuma, Ontruzant) are preferred first-line IV products. Use of Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) or other SC formulations (e.g., Phesgo) may require documentation of inadequate response or intolerance to preferred IV biosimilars, except when clinically justified (for example, difficult venous access) and documented.
Switching between trastuzumab products (originator and biosimilars) is allowed when medically appropriate; prior authorization documentation should include rationale for product selection when non-preferred or brand formulations are requested.
All other uses of the medications listed in this policy that are not specifically enumerated as medically necessary are considered investigational and not covered.

Coding and Monitoring Requirements

HCPCS codes listedHCPCS

J3590	Unclassified biologics (use to report: Hercessi)
J9306	Injection, pertuzumab (Perjeta), mg
J9316	Injection, pertuzumab, trastuzumab, and hyaluronidase-zzxf; (Phesgo) per 10 mg
J9353	Injection, margetuximab-cmkb, (Margenza) 5 mg
J9354	Injection, ado-trastuzumab emtansine (Kadcyla), mg
J9355	Injection, trastuzumab, excludes biosimilar, (Herceptin) 10 mg
J9356	Injection; trastuzumab, (Herceptin Hylecta) and hyaluronidase-oysk 10 mg
J9358	Injection; fam-trastuzumab deruxtecan-nxki (Enhertu), mg
Q5112	Injection, trastuzumab-dttb, biosimilar; (Ontruzant), 10 mg
Q5113	Injection, trastuzumab-pkrk, biosimilar; (Herzuma) 10 mg

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1/2

HCPCS and coding updates referencedHCPCS

J9306	HCPCS code referenced in 2014 coding update
J9354	HCPCS code added effective 1/1/16
J9356	HCPCS code added 7/1/19
Q5112	HCPCS codes added 7/1/19
Q5113	HCPCS codes added 7/1/19
Q5114	HCPCS codes added 7/1/19
Q5116	HCPCS code added effective 10/1/19
Q5117	HCPCS code added effective 10/1/19
J3590	HCPCS code referenced/added in policy history
J9316	HCPCS code added/replaced in 2021

1–10 of 12

1/2

Left ventricular ejection fraction monitoring — baseline and periodic monitoring (eg, 3,6,12 months); discontinue if unacceptable decrease

Baseline LVEF measurementMeasure left ventricular ejection fraction (LVEF) before initiating trastuzumab therapy

Periodic monitoringRepeat LVEF assessments periodically (for example at approximately 3, 6, and 12 months) during therapy

Action for significant declineDiscontinue therapy if an unacceptable decrease in LVEF occurs (e.g., >15% absolute decrease from baseline)

Reference standardFollow FDA‑approved label recommendations for timing and interpretation of LVEF monitoring

Left ventricular ejection fraction (LVEF) requirement — measured before therapy; EMILIA trial required LVEF >= 50%; unacceptable decrease defined as >15% from baseline

Provider Actions, Authorization, and Safety Responsibilities

Prior Authorization

Prior authorization and exception duration

Non-formulary exception reviews for drugs in this policy may be approved up to 12 months. Most oral drug reviews may be approved up to 3 months for initial authorization; injectable drug reviews may be approved up to 12 months. Reauthorizations (including non-formulary exceptions) may be approved up to 12 months when drug-specific coverage criteria are met and documentation demonstrates continued clinical benefit.

Initial oral drug reviews (non-formulary exceptions): up to 12 months
Initial oral drug reviews (standard): up to 3 months
Injectable drug reviews: up to 12 months
Reauthorization (oral & injectable, incl. exceptions): up to 12 months when criteria and documentation met

Prior Authorization

Prior therapies and HER2 status for HER2-directed agents

Trastuzumab and other HER2-directed agents require documentation of HER2 positivity and prior therapies as used in supporting trials. For example, lapatinib and trials of trastuzumab required HER2 overexpression (IHC 3+ or IHC 2+ with FISH confirmation) and prior treatment with anthracyclines, taxanes, and trastuzumab for advanced/metastatic disease. Providers must submit medical records documenting prior systemic therapies and HER2 testing results to show medical necessity.

Initial Therapy and Sequencing Criteria

Initial therapy sequencing

Sequencing requirements

Tykerb after generic lapatinib: For coverage of Tykerb (branded lapatinib), an adequate trial and inadequate response or intolerance to generic lapatinib is required unless an exception is documented

Step‑therapy/sequencing requirement for some oral agents

Initiation

Initiation and sequencing

Initiation timing: Optimal timing (concurrent vs sequential) of trastuzumab relative to chemotherapy is unresolved; some trial data (NCCTG N9831) favor concurrent administration with paclitaxel for improved DFStiming unresolved

Clinical judgment and trial contexts should guide initiation timing

Continuation and Reauthorization Criteria

Reauthorization

Reauthorization conditions

Reauthorizations may be approved up to 12 months if drug‑specific coverage criteria are met and documentation (chart notes) demonstrates continued positive clinical response to therapy

Non‑formulary exception and prior authorization duration guidance

Duration of therapy

Continuation/Duration

Continuation of trastuzumab: Continuation beyond 1 year is not supported by HERA (2 years not superior and associated with more adverse events); recommended duration supported by trials and meta‑analysis is 1 yearduration <= 1 year

PHARE trial and Cochrane meta‑analysis support 1‑year duration

Continuation in gastric cancer

Step Therapy and Preferred Product Trials

Step	Requirement	Failure criteria / exception
1	Trial and inadequate response or intolerance to specified trastuzumab biosimilars (Kanjinti, Ogivri, Trazimera) is required prior to coverage of certain other trastuzumab formulations (eg, Herceptin Hylecta)	Coverage may be granted without biosimilar trial if documentation of difficult venous access is provided

Observation	Policy note	Supporting trial evidence
No formal step-therapy algorithm provided	Policy does not mandate a specific sequencing algorithm; timing of trastuzumab (concurrent vs sequential) is unresolved	NCCTG N9831 interim results showed longer DFS with concurrent trastuzumab (with paclitaxel) vs sequential administration

Trial context	Relevance to sequencing	Policy implication
Many pivotal trials enrolled patients after progression on trastuzumab and other agents (eg, lapatinib+capecitabine trial)	Prior exposure to anthracyclines, taxanes, and trastuzumab was common in trial populations, making sequencing clinically relevant	Policy requires documentation of prior therapies where applicable to align coverage with trial contexts (eg, prior trastuzumab/taxane before ado-trastuzumab emtansine)

Coverage label	Requirement	Notes
Preferred products required first	Preferred trastuzumab agents must be tried prior to coverage of specified non-preferred trastuzumab products; non-preferred products were updated to require trial with all preferred trastuzumab products	Provider notification given prior to status changes; see history for effective dates and specific preferred products (eg, Kanjinti, Trazimera)

Step	Required trial	Effective / history notes
1	Trial of preferred trastuzumab agents (examples: Kanjinti or Trazimera) required prior to coverage of certain non-preferred trastuzumab products	History entries document movement of products between preferred/non-preferred lists and requirement for trials with preferred products (provider notification periods and effective dates in history)

Quantity Limits and Dose Constraints

neratinib — 240 mg

Quantity limit (daily dose)Neratinib: 240 mg per day (six tablets)

Use casesApplies to extended adjuvant neratinib and metastatic-use criteria per policy

Policy coding/historyDose limit noted in policy history and coding updates

tucatinib — 600 mg

Total daily doseTucatinib (Tukysa) dose limit: 600 mg per day (300 mg twice daily)

Combination useDose limit applies when used in combination with trastuzumab and capecitabine for HER2-positive breast cancer

Site of Care and Administration

Note

Infusion administration and formulation‑specific notes

Trastuzumab and many biosimilar products are administered by IV infusion; certain formulations (Herceptin Hylecta, Phesgo) have specific subcutaneous administration notes—schedule administration and monitoring accordingly.

Plan for IV infusion administration of trastuzumab products unless using an indicated subcutaneous formulation.
Ensure infusion center or appropriate setting is arranged and monitoring for infusion‑related events and cardiac/LFT safety is planned.

Note

No explicit site restriction; safety monitoring required

No site‑of‑care restriction is specified in the policy excerpt; safety monitoring requirements (eg, LFTs, cardiac function) apply regardless of administration setting.

Document monitoring plans irrespective of whether therapy is given in infusion center, office, outpatient hospital, or home.

Biosimilars and Product Preference

Billing Rule

Biosimilar preference and required trials

Trastuzumab biosimilars may be used per the policy; some trastuzumab products (including certain formulations) require prior inadequate response or intolerance to preferred biosimilars before coverage.

If requesting a non‑preferred trastuzumab formulation, include documentation of prior inadequate response or intolerance to preferred biosimilars where required.

Note

Confirm current preferred trastuzumab product status

Specific trastuzumab products have been moved between preferred and non‑preferred status in policy updates; confirm current preferred product requirements when submitting a PA.

Note policy history: some biosimilars (eg, Ogivri) were updated from non‑preferred to preferred; other products were moved to second‑line non‑preferred—provide trial/failure evidence as required.

Background and Definitions

HER2 (human epidermal growth factor receptor 2, ERBB2) encodes a transmembrane receptor tyrosine kinase implicated in oncogenesis and is amplified or overexpressed in approximately 20–30% of breast cancers. HER2 inhibitors include monoclonal antibodies (eg, trastuzumab and pertuzumab), antibody–drug conjugates (eg, ado‑trastuzumab emtansine, fam‑trastuzumab deruxtecan), and small‑molecule tyrosine kinase inhibitors (eg, lapatinib, neratinib, tucatinib) that target the HER2 pathway to inhibit tumor growth. Selection for trastuzumab‑based therapy requires demonstration of HER2 overexpression or gene amplification using validated assays (IHC or FISH) as performed in trial populations.

HER2 overexpression — Detection methods (IHC, FISH) and clinical relevance

Detection methodsHER2 overexpression should be assessed using validated immunohistochemistry (IHC) assays or fluorescence in situ hybridization (FISH) assays (eg, PathVysion, HER2 FISH pharmDx) by facilities with demonstrated proficiency

Assay reliabilityTesting must be performed by competent laboratories because improper assay performance can yield unreliable results

PurposeAssay results are used to select appropriate candidates for trastuzumab and other HER2-directed therapies

Policy Revision History and Material Changes

08/09/2005history entry

Policy replaced prior policy BC.5.01.12 and began to consider off-label uses of trastuzumab medically necessary for breast cancer; trastuzumab remained investigational for other malignancies.

07/08/2013history entry

Added ado-trastuzumab emtansine (Kadcyla) and clinical guidance; updated coding and policy statements related to ado-trastuzumab emtansine.

10/01/2019history entry

Added HCPCS updates and clarified trastuzumab and biosimilar coding and use for indications beyond HER2-positive breast cancer.

Policy Summary

PayerPremera Bluecross

PolicyHER2 Inhibitors

Policy CodePolicy 5.01.514

Change TypeMaterial updates to indications, biosimilar preferences, and quantity limits

Effective DateJan 2, 2026

Next Review Date

Key ActionSubmit medical records documenting diagnosis, prior therapies, HER2 test results, and baseline LVEF to support prior authorization and reauthorization requests.

SourceLink

On This Page

Pre-therapy requirementLVEF must be measured before initiating HER2-directed therapy and be within the treating institution's normal range

EMILIA trial enrollment thresholdEMILIA required a baseline LVEF of at least 50%

Unacceptable decrease definitionAn unacceptable decrease is defined as greater than a 15% absolute drop from baseline LVEF

DocumentationRecord baseline LVEF and subsequent monitoring results in the medical record per policy guidance

neratinib dose limit — 240 mg

Daily dose limitNeratinib dose limited to 240 mg per day (six tablets)

Indication context240 mg/day limit applies for extended adjuvant neratinib and as specified in coverage criteria

Policy history referenceDose limit added/clarified in policy updates and coding/history notes

lapatinib dose limit — 1,500 mg per day

Maximum daily doseLapatinib dose limit: up to 1,500 mg per day

Typical regimen contextLapatinib is used in combination with capecitabine for previously treated HER2-positive metastatic breast cancer

Trial/population noteDose and use described in pivotal trials and prescribing information summarized in policy references

Document HER2 test results (IHC/FISH) consistent with trial eligibility
Document prior chemotherapy regimens and prior trastuzumab where required (eg, anthracycline + taxane + trastuzumab)
For indications supported by specific trials (eg, EMILIA, Van Cutsem), include trial-consistent prior therapy information

Documentation Required

Safety requirements for ado-trastuzumab emtansine

Ado‑trastuzumab emtansine (T‑DM1) has specific safety requirements. Do not use in pregnancy; counsel about gestational risks and require effective contraception during treatment and for at least 6 months after the last dose. Monitor liver function tests and follow recommended dose modifications for hepatotoxicity. Include baseline LVEF (trial eligibility often ≥50%) and ongoing cardiac monitoring; be aware of infusion reactions, pulmonary toxicity, GI adverse effects, and fatigue.

Pregnancy avoidance counseling and effective contraception during therapy and for ≥6 months after last dose
Baseline LFTs and periodic monitoring; follow dose modification guidance for elevated liver enzymes
Baseline LVEF documented (EMILIA inclusion ≥50%) and periodic LVEF monitoring; report and document actions for clinically significant declines
Document counseling and safety monitoring in the chart

Documentation Required

Cardiac monitoring and LVEF thresholds

Follow FDA‑label and policy cardiac monitoring expectations for trastuzumab and related agents. Obtain and document a baseline left ventricular ejection fraction (LVEF) within the treating institution's normal range before initiating therapy. Perform periodic LVEF assessments (for example at ~3, 6, and 12 months) and document results and any management decisions. An unacceptable decrease (eg, >15% from baseline) should prompt re-evaluation and may lead to treatment modification or denial if not addressed.

Baseline LVEF documented in medical record prior to initiation
Periodic LVEF monitoring (examples: 3, 6, 12 months) with documentation of values and actions taken
Unacceptable decrease (eg, >15% from baseline) should be documented and justified if therapy is continued

Step Therapy

Trastuzumab preferred product trial requirement

Preferred trastuzumab products must be tried prior to coverage of certain non-preferred trastuzumab products per the policy updates. The policy requires an adequate trial and failure (or intolerance) of preferred trastuzumab agents (eg, Ogivri and other designated preferred products) before approving non-preferred trastuzumab biosimilars moved to second-line status.

Document trial and inadequate response or intolerance to all preferred trastuzumab products before requesting coverage for specified non-preferred products
Verify product preference status at time of request; coverage may change based on formulary updates communicated to providers

Step Therapy

Step therapy / sequencing

Step‑therapy or sequencing requirements may apply for some oral HER2‑directed agents. Coverage can require an adequate trial and documented inadequate response or intolerance to specified prior agents (for example, trial of generic lapatinib before Tykerb). Sequencing and concurrent versus sequential timing may be relevant for adjuvant trastuzumab decisions; document prior regimens and timing relative to trastuzumab per trial contexts.

Document trials of required prior oral agents and outcomes (response, intolerance) when step-therapy is specified
For adjuvant decisions, document timing of prior chemotherapy and trastuzumab (concurrent vs sequential) consistent with trial evidence when applicable

Documentation Required

Required documentation and benefit verification

Clinical documentation must support medical necessity for all coverage requests. Submit office visit notes with diagnosis, relevant history, physical exam, medication history, HER2 test results, prior therapy records, baseline and follow-up cardiac testing (LVEF), liver function tests, and counseling/consent notes (eg, pregnancy avoidance for ado‑trastuzumab emtansine). Insufficient documentation (missing visits, med list, test results) may lead to denial.

Office visit notes showing diagnosis, history, exam, and medication history
HER2 testing reports (IHC/FISH) and prior therapy records
Baseline and periodic LVEF reports and management notes
LFTs and documentation of dose modifications where applicable
Counseling/consent notes for pregnancy avoidance when using T‑DM1

Note

Benefit documentation, formulary changes, and benefit verification

Coverage is subject to member benefits and plan limits. Formulary preference changes (including movement of a trastuzumab product to preferred or non-preferred status) may alter benefit coverage following provider notification. Always consult the member benefit booklet or contact customer service to confirm applicable benefit limitations and prior authorization requirements.

Verify member benefits and any formulary restrictions or quantity limits (eg, Tukysa quantity limit) before prescribing
Formulary changes communicated to providers may affect coverage; confirm current product status at time of request
Contact customer service or review member benefit booklet for plan-specific limits

Trial-based initial therapy contexts

Initial therapy contexts from clinical trials

Lapatinib+capecitabine context: Lapatinib was studied in combination with capecitabine in patients with HER2‑positive breast cancer who progressed after anthracyclines, taxanes, and trastuzumab; trial demonstrated improved time to progression and response ratesprior therapy with anthracyclines, taxanes, and trastuzumab per trial

Phase III trial context

Ado‑trastuzumab emtansine (EMILIA): Ado‑trastuzumab emtansine was studied in patients with unresectable, locally advanced or metastatic HER2‑positive breast cancer previously treated with trastuzumab and a taxane, showing improved PFS (9.6 vs 6.4 months) and OS (30.9 vs 25.1 months) versus lapatinib+capecitabineprior trastuzumab and taxane exposure per trial

EMILIA trial results summarized

Continuation of trastuzumab in gastric cancer trials:

Trastuzumab continuation: In the Phase III gastric trial, trastuzumab was given every 3 weeks for 6 cycles and continued until disease progression in the study protocoltreatment until progression or unacceptable toxicity

Van Cutsem Phase III described median OS benefit and continuation until progression

Colorectal indication

Same 600 mg/day limit applied for use in unresectable/metastatic RAS wild-type, HER2-positive colorectal cancer in combination with trastuzumab

Tukysa (tucatinib) — quantity limit requirement added

Quantity-limit additionA quantity limit requirement for Tukysa (tucatinib) was added to the colorectal cancer coverage criteria

ContextChange recorded in the 2024 policy update to reflect a quantity limit for the colorectal indication

Authorization implicationRequests for Tukysa in the colorectal criteria should meet the quantity-limit policy when processed

neratinib — 240 mg (duplicate dose limit reference)

Daily dose limitNeratinib: 240 mg per day (six tablets)

Policy placementDose limit specified in the neratinib coverage criteria and reiterated in coding/history entries

Duration noteExtended adjuvant use limited to a maximum duration of 1 year when used as specified

Ado‑trastuzumab emtansine: IV every 3 weeks per trial

Ado‑trastuzumab emtansine (Kadcyla) is administered by IV infusion every 3 weeks per trial protocol; ensure authorization reflects the correct dosing interval and monitoring.

Schedule infusions every 3 weeks and include LVEF and LFT monitoring in the treatment plan.

Billing Rule

Site‑of‑care coverage subject to member benefit limits

Coverage for infusion at a given site is subject to member benefit plan limits; confirm site‑specific coverage prior to scheduling.

Verify member benefits for infusion center, office, hospital outpatient, or home infusion coverage.

HER2 definition — HER2 (ERBB2) amplified/overexpressed in 20-30% of breast cancers

DefinitionHER2 (ERBB2) is a transmembrane receptor tyrosine kinase encoded by ERBB2 that is amplified and overexpressed in approximately 20–30% of breast cancers

Clinical significanceHER2 amplification/overexpression is associated with more aggressive disease and higher relapse and mortality rates

Other tumorsHER2 may also be overexpressed in other epithelial cancers (eg, ovarian, lung, salivary gland, stomach, colon, prostate), making it a therapeutic target in select settings

Ado-trastuzumab emtansine (Kadcyla) — definition and mechanism as ADC

Definition and compositionAdo-trastuzumab emtansine (Kadcyla) is an antibody–drug conjugate combining trastuzumab with the cytotoxic agent emtansine (DM1) to deliver a cytotoxic payload to HER2-expressing cells

MechanismKadcyla binds HER2, is internalized, and releases the cytotoxic metabolite (MCC‑emtansine) intracellularly after proteolytic degradation of the linker

Safety considerationsAssociated safety concerns include decreases in LVEF and hepatic enzyme elevations; EMILIA trial required baseline LVEF ≥50%

Lapatinib (Tykerb) — definition as small molecule TKI and indication context

Drug classLapatinib (Tykerb) is a small-molecule tyrosine kinase inhibitor targeting the intracellular kinase domains of EGFR and HER2

Indication contextIndicated in combination with capecitabine for advanced or metastatic HER2-positive breast cancer in patients previously treated with an anthracycline, a taxane, and trastuzumab

Clinical trial contextLapatinib was evaluated in randomized trials (eg, in combination with capecitabine) for patients progressing after standard therapies

trastuzumab — definition as humanized monoclonal antibody and approvals

Agent class and targetTrastuzumab is a humanized monoclonal antibody against the extracellular domain of HER2/ERBB2

ApprovalsFDA‑approved for HER2‑positive breast cancer in adjuvant and metastatic settings (initial metastatic approval 1998; adjuvant approvals followed in 2006–2008)

FormulationsAvailable as IV formulations and in subcutaneous combinations (eg, Herceptin Hylecta, Phesgo) and with multiple biosimilars referenced in the policy

Enhertu (trastuzumab deruxtecan) — ADC approved/expanded for metastatic HER2-low and certain NSCLC indications

Agent classEnhertu (fam‑trastuzumab deruxtecan‑nxki) is an antibody‑drug conjugate (trastuzumab deruxtecan)

Indication expansionsApproved and covered for unresectable or metastatic HER2‑low breast cancer, expanded earlier‑line use in HER2‑positive disease, and for certain NSCLC indications with activating HER2 mutations per DESTINY trials and subsequent updates

Policy updatesCoverage criteria were updated to reflect DESTINY trial results and expanded labeled indications; policy history documents these changes

HER2 inhibitors — class definition (monoclonal antibodies and TKIs)

Class definitionHER2 inhibitors include monoclonal antibodies (eg, trastuzumab, pertuzumab), antibody–drug conjugates (eg, ado‑trastuzumab emtansine, trastuzumab deruxtecan), and small‑molecule tyrosine kinase inhibitors (eg, lapatinib, tucatinib)

Therapeutic intentThese agents target HER2/ERBB2 signaling to inhibit tumor growth in HER2‑overexpressing or HER2‑mutant cancers

ExamplesExamples listed in policy include trastuzumab, pertuzumab, lapatinib (Tykerb), ado‑trastuzumab emtansine (Kadcyla), trastuzumab deruxtecan (Enhertu), neratinib (Nerlynx), tucatinib (Tukysa), and margetuximab (Margenza)

10/01/2022history entry

Added coverage for Enhertu (fam-trastuzumab deruxtecan-nxki) for unresectable or metastatic HER2-low breast cancer and certain NSCLC indications.

01/01/2024policy change

Moved Trazimera to second-line (non-preferred) trastuzumab agent effective January 1, 2024 after a 90-day provider notification.

01/01/2025coding update

New HCPCS code Q5146 (Hercessi) added effective January 1, 2025.

04/01/2025policy addition

Added an Enhertu indication for HR-positive HER2-low or HER2-ultralow metastatic breast cancer and clarified non-formulary exception authorization durations up to 12 months (annual review approved March 11, 2025).

01/02/2026product-preference updateLatest

Ogivri (trastuzumab-dkst) updated from non-preferred to preferred and related preferred/non-preferred trastuzumab product requirements effective January 2, 2026 following provider notification.

06/14/2022annual review

Annual review approved June 14, 2022; moved Ogivri to preferred trastuzumab product and updated coverage criteria for certain non-preferred products to require trial and failure with preferred agents.

10/01/2022coverage expansion

Interim review approved September 13, 2022 and on October 1, 2022 added coverage for Enhertu for unresectable or metastatic HER2-low breast cancer and unresectable or metastatic non-small cell lung cancer.

01/01/2024formulary change

Effective January 1, 2024 (after 90-day provider notification), Trazimera moved to second-line (non-preferred) agent, affecting product-preference sequencing.

10/01/2024preferred status change

Effective January 3, 2025 (90-day provider notification), Kanjinti and Trazimera were changed to preferred trastuzumab products while several others were moved to non-preferred status.

01/01/2025coding update

Added HCPCS code Q5146 effective January 1, 2025 to report Hercessi (trastuzumab-strf).

04/01/2025indication expansion and administrative clarification

Annual review approved March 11, 2025 added Enhertu indication for HR-positive HER2-low/ultralow metastatic breast cancer and clarified that non-formulary exception authorizations may be approved up to 12 months.

01/02/2026product-preference updateLatest

Effective January 2, 2026 (after 90-day provider notification) Ogivri (trastuzumab-dkst) was updated from non-preferred to preferred and policy updated required trials of preferred products before coverage of certain non-preferred trastuzumab products.