CurrentViva HealthPolicy IC-0148

Yervoy (ipilimumab) — Intravenous; Coverage Criteria and Prior Authorization

Defines prior authorization, coverage criteria, dosing unit limits, and authorization duration for ipilimumab (Yervoy) across multiple oncology indications for Viva Health members.

Policy Summary

PayerViva Health

PolicyYervoy (ipilimumab) — Intravenous; Coverage Criteria and Prior Authorization

Policy CodePolicy IC-0148

Change TypeNo material change

Effective Date

Next Review DateMay 5, 2026

Key ActionPrior authorization is required; initial approvals are generally for 6 months (180 days) with indication-specific durations and documentation of diagnosis, prior therapies, and biomarker results.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

6 monthsstandard initial prior authorization validity

180 daysstandard renewal interval

350 BUcommon per-dose billable units

1150 BUper-dose BU for CNS/Uveal melanoma

MSI-H / TMB-Hfrequently required tumor biomarkers

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renewal requirement summary

Coverage Criteria by Indication

Prior Authorization

Prior Authorization: Provider Actions

Prior authorization is required. Provider must submit therapy-specific clinical proof demonstrating medical necessity, including indication-specific rationale and prior treatment history when applicable. Requests due to drug cost or high-cost therapies require prior authorization; include supporting documentation of financial coverage considerations if requested by the plan. Medicare members: providers must comply with Medicare Part B coverage rules (see Appendix 2) and be prepared to supply any additional documentation required by Medicare NCDs, LCDs, or LCAs.

Prior authorization: submit therapy-specific clinical proof (diagnosis, staging, prior therapies, biomarker test results, performance status, treatment intent).
Prior authorization due to cost: high-cost agents require prior auth; include justification if alternative therapies were considered or contraindicated.
Prior authorization — Medicare: Medicare Part B may impose additional requirements (NCD/LCD/LCA). Confirm applicability and submit supporting Medicare-required documentation.
Requests not meeting specified line-of-therapy or indication criteria will be denied; include line-of-therapy documentation (first-line, subsequent, adjuvant/neoadjuvant, re-induction).
NQTL and prior authorization consideration: utilization management rules and non-quantitative treatment limits (e.g., step therapy, site-of-care restrictions) may apply; document clinical contraindications to step therapy when requesting exceptions.

Documentation Required

Documentation Requirements

To support initial and renewal requests, the following documentation must be provided: primary diagnosis with ICD-10 code(s); pathology reports; tumor staging; ECOG performance status; comprehensive biomarker testing results relevant to the indication (e.g., MSI-H/dMMR, TMB with mut/Mb value, POLE/POLD1 status, PD-L1 CPS, actionable driver testing panel for NSCLC); prior systemic, surgical, and radiation therapies with dates and response; rationale for combination therapy (e.g., concomitant nivolumab); and any prior checkpoint inhibitor exposure.

Required diagnosis coding: include appropriate ICD-10 code(s) for the malignancy and site. (Medicare Part B: see Appendix 2 for covered diagnosis guidance.)
Documentation of biomarker testing results: provide test type, lab (FDA-approved or CLIA-compliant), assay name, date, and numeric results where applicable (e.g., TMB mut/Mb, PD-L1 CPS, MSI/dMMR status, POLE/POLD1 mutation status).
If prior checkpoint inhibitor therapy is relevant to indication, document agent(s), dosing regimen, dates, response, and reason for discontinuation (progression, intolerance, or contraindication).
For re-initiation/re-induction: document prior clinical benefit (complete/partial response or stable disease) and absence of residual toxicity; disease progression must be >3 months after treatment discontinuation for re-induction eligibility (where specified).
When prior exposure or specific prior therapies are required by the indication (e.g., prior sorafenib for HCC, prior chemotherapy for mesothelioma), provide treatment history and reasons for ineligibility for alternatives.

Prior Authorization

Renewal Requirements

Prior authorization validity and renewal rules: initial approvals follow indication-specific duration rules (see Length of Authorization). Renewals may be granted every 6 months (180 days) if renewal criteria are met. Renewal may be denied if duration limits for the indication have been exceeded, if there is unacceptable toxicity, or if there is lack of clinical response.

Confirm continued eligibility against the universal and indication-specific criteria (including concomitant therapy requirements, performance status).
Provide objective evidence of disease response or stability (imaging reports, tumor measurements, clinician assessment).
Report absence of unacceptable toxicity (document adverse events and their management).
Some indications: prior authorization validity may NOT be renewed (see Length of Authorization list). Exceptions: Cutaneous melanoma first-line/subsequent/adjuvant requests may be renewed only where re-induction provisions apply. Maximum cumulative therapy limits apply for certain indications (refer to Section I).

Note

Sequencing, Prior Exposure, and Re-initiation

Sequencing and prior exposure considerations: many indications require prior exposure to specific therapies or exclusion of prior checkpoint inhibitor use. Check indication-specific criteria for required prior therapies, contraindications to prior agents, and allowances for combination or monotherapy use. Providers must document prior therapy lines and rationale for current choice.

Some indications require prior exposure to specified agents (e.g., sorafenib for HCC) — provide dates and outcomes of prior therapies.
For indications that prohibit prior checkpoint inhibitor therapy as a condition for first-line use, document absence of prior PD-1/PD-L1/CTLA-4 therapy.
Where an indication permits subsequent use only if no prior checkpoint inhibitor was given, nivolumab + ipilimumab may be considered if prior checkpoint inhibitor monotherapy was previously received (see appendiceal criteria).
Re-initiation conditions: for re-induction eligibility, document prior benefit and relapse >3 months after discontinuation and no residual toxicity.

Denial Risk

Denial Risks / Noncoverage Triggers

Denial risks and operational notes: prior authorization may be denied for requests that do not meet the exact lineage-, biomarker-, or prior-therapy-specified scenarios; for lack of required documentation; for exceeded maximum duration; for unacceptable toxicity; or for requests for indications listed as non-renewable. Medicare requirements or local coverage policies may additionally restrict coverage.

Missing or incomplete biomarker reports (e.g., no TMB mut/Mb value, no assay name/lab).
Lack of documentation of prior therapies or incorrect line-of-therapy designation.
Requests for uses outside the specified lineage-, biomarker-, or prior-therapy-specified scenarios.
Renewal requests when indication-specific non-renewal rules apply (see Section I).
Failure to comply with Medicare NCD/LCD/LCA requirements when applicable.

Coding, Biomarkers and Thresholds

Covered ICD-10 CodesICD-10Covered

C15.8	Malignant neoplasm of overlapping sites of esophagus
C15.9	Malignant neoplasm of esophagus, unspecified
C16.2	Malignant neoplasm of body of stomach
C16.3	Malignant neoplasm of pyloric antrum
C16.4	Malignant neoplasm of pylorus
C16.5	Malignant neoplasm of lesser curvature of stomach, unspecified
C16.6	Malignant neoplasm of greater curvature of stomach, unspecified
C16.8	Malignant neoplasm of overlapping sites of stomach
C16.9	Malignant neoplasm of stomach, unspecified
C17.0	Malignant neoplasm of duodenum

1–10 of 254

1/26

HCPCS / Drug CodesHCPCS

J9228

Injection, ipilimumab, 1 mg; 1 billable unit = 1 mg

NDCsNDC

00003-2327-xx	Yervoy 50 mg/10 mL injection single-dose vial
00003-2328-xx	Yervoy 200 mg/40 mL injection single-dose vial

Coding, Biomarkers and Thresholds — Key Thresholds

TMB threshold>= 10 mut/Mb

Tumor mutational burden (TMB-H)>= 10 mutations/megabase (mut/Mb)

None specifiedplaceholder

Prior Authorization & Provider Requirements

Prior Authorization

Request prior authorization before treatment; initial approvals are generally for 6 months (180 days)

Obtain prior authorization before initiating therapy; initial approvals are generally granted for 6 months (180 days) unless an indication‑specific initial validity period is specified in the policy.

Standard initial prior authorization validity: 6 months (180 days)
Refer to Section I for indication‑specific shorter/longer initial validity periods (e.g., 6 weeks, 12 weeks, 16 weeks)

Prior Authorization

Provide therapy‑specific clinical proof: diagnosis, line of therapy, and prior systemic treatments

When requesting authorization, provide indication‑specific clinical proof: documentation of the diagnosis, the line of therapy, and prior systemic treatments (e.g., prior sorafenib for HCC or prior anti‑PD‑1/PD‑L1 exposure for MCC) as required by the indication.

State whether request is first‑line, subsequent, neoadjuvant, adjuvant, or re‑induction
List prior systemic therapies with dates (e.g., sorafenib for HCC)
Provide biomarker results when required by the indication

Initial Therapy Authorization and Dosing

inv-75: Initial therapy authorization

Initial authorization durations and per-dose unit limits vary by indication

Initial Authorization Durations: Initial prior authorization validity generally 6 months (180 days) unless otherwise specified; shorter initial validity applies for certain neoadjuvant/neoadjuvant regimens (examples: cutaneous melanoma neoadjuvant 6 weeks/2 doses; some GI neoadjuvant 12 weeks or 16 weeks); some indications have specified initial maxima (see Length of Authorization)varies by indication

See 'Length of Authorization' section for indication-specific values

inv-76: First-line therapy

Initial (first-line) therapy rules where specified

First-line use: Multiple tumor types allow ipilimumab (often with nivolumab) as first-line therapy when specified (e.g., HCC, RCC poor/intermediate risk, PM, cutaneous melanoma age >=12); documentation of no prior checkpoint inhibitor or no progression while on prior checkpoint inhibitor is required where specified

Renewal, Continuation and Maintenance

inv-78: Renewal rules

Renewal provisions vary by indication; some allow renewals every 6 months, others are not renewable

General Renewal: Prior authorization validity may be renewed every 6 months (180 days) unless otherwise specified; some indications are not renewable (see list) and some indications allow renewals up to a maximum duration (eg, up to 2 years/18 doses for certain indications)180 days

See indication-specific renewal restrictions and maximums

inv-79: Continuation maintenance

Continuation maintenance

NSCLC continuation maintenance: Used as continuation maintenance in combination with nivolumab when member achieved response or stable disease following first-line therapy with nivolumab and ipilimumab with or without chemotherapy

See maintenance dosing guidance

Step-Therapy and Sequencing Requirements

Requirement	Policy details
Coverage label	For appendiceal neoplasms and cancers: member must have MSI‑H/dMMR OR POLE/POLD1 ultra‑hypermutated phenotype (e.g., TMB >50 mut/Mb) as determined by an FDA‑approved or CLIA‑compliant test; ipilimumab must be used in combination with nivolumab if the member has not previously received a checkpoint inhibitor. Nivolumab + ipilimumab may be considered as subsequent therapy if prior checkpoint inhibitor monotherapy was received; therapy is for recurrent, progressive, metastatic peritoneal‑only or extraperitoneal disease.

Requirement

Policy details

Coverage label

For appendiceal neoplasms and cancers: member must have MSI‑H/dMMR OR POLE/POLD1 ultra‑hypermutated phenotype (e.g., TMB >50 mut/Mb) as determined by an FDA‑approved or CLIA‑compliant test; ipilimumab must be used in combination with nivolumab if the member has not previously received a checkpoint inhibitor. Nivolumab + ipilimumab may be considered as subsequent therapy if prior checkpoint inhibitor monotherapy was received; therapy is for recurrent, progressive, metastatic peritoneal‑only or extraperitoneal disease.

Requirement	Policy details
Coverage label	Where specified by indication, prior treatment or documented contraindication to listed therapies is required. Examples: HCC — subsequent therapy pathway requires prior treatment with sorafenib; MCC — single‑agent ipilimumab requires prior progression on or contraindication to anti‑PD‑1/PD‑L1 therapy. Requests lacking required prior therapy or documented contraindication may be considered not medically necessary.

Requirement

Policy details

Coverage label

Where specified by indication, prior treatment or documented contraindication to listed therapies is required. Examples: HCC — subsequent therapy pathway requires prior treatment with sorafenib; MCC — single‑agent ipilimumab requires prior progression on or contraindication to anti‑PD‑1/PD‑L1 therapy. Requests lacking required prior therapy or documented contraindication may be considered not medically necessary.

Requirement	Policy details
Coverage label	Re‑initiation of checkpoint inhibitor therapy is permitted when members relapse ≥6 months after discontinuation for duration (e.g., after completing 24 months of PD‑directed therapy) or progress ≥6 months after completing adjuvant therapy. Re‑initiation may also be considered case‑by‑case if re‑biopsy shows a change in actionable tumor mutations (for example, MSS converting to MSI‑H).

Requirement

Policy details

Coverage label

Re‑initiation of checkpoint inhibitor therapy is permitted when members relapse ≥6 months after discontinuation for duration (e.g., after completing 24 months of PD‑directed therapy) or progress ≥6 months after completing adjuvant therapy. Re‑initiation may also be considered case‑by‑case if re‑biopsy shows a change in actionable tumor mutations (for example, MSS converting to MSI‑H).

Quantity Limits and Dose Units

ipilimumab (Yervoy) — per-dose billable units

Per-dose billable units vary by indicationExamples include 150 BU, 350 BU, and 1150 BU depending on tumor type and setting

Example: RCC / SBA / Ampullary / CRC / Appendiceal150 BU per dose (per unit time: 21 days x 4 doses for some indications)

Example: Hepatocellular carcinoma350 BU per dose (21 days x 4 doses) for HCC

Ipilimumab (Yervoy) — Maximum 4 doses

Maximum doses for 4‑dose coursesA maximum of 4 doses must be administered within 16 weeks of the first dose

ApplicabilityApplies to regimens where ipilimumab is given as a 4‑dose induction course (many combination regimens)

Administration Site Considerations

Billing Rule

Administer ipilimumab as IV infusion in an oncology outpatient/infusion setting

Administer intravenous infusions in an outpatient infusion setting; the policy describes IV administration commonly given in combination with nivolumab on the same day and does not specify alternative sites of care.

Ipilimumab is given intravenously, often on the same day as nivolumab per dosing instructions
No additional site‑of‑care restrictions are specified in the excerpt

Note

No explicit site‑of‑care restrictions—use standard infusion center procedures

There are no explicit site‑of‑care restrictions in the policy excerpt; follow standard infusion center practices and the regimen‑specific dosing schedules when combining with nivolumab.

Coordinate scheduling when ipilimumab is given on the same day as nivolumab

Background and Definitions

Ipilimumab (Yervoy) is a monoclonal antibody that functions as an anti‑CTLA‑4 immune checkpoint inhibitor. It is used as single‑agent therapy or, commonly, in combination with the anti‑PD‑1 agent nivolumab across multiple tumor types to enhance anti‑tumor immune responses. The combination of nivolumab plus ipilimumab is referenced throughout the policy as a dual immune‑checkpoint inhibitor regimen for indications where combination therapy is specified.

MSI‑H / dMMR — Definition and test requirements

DefinitionMSI-H/dMMR = microsatellite instability‑high or mismatch repair deficient status as determined by an FDA‑approved or CLIA‑compliant test

Test requirementAn FDA‑approved or CLIA‑compliant assay is required to document MSI‑H/dMMR for indicated tumor types

Indication examplesRequired for ampullary adenocarcinoma, colorectal cancer, gastric and certain esophageal/EGJ pathways as specified

TMB‑H — Definition and test requirements

Policy Summary

PayerViva Health

PolicyYervoy (ipilimumab) — Intravenous; Coverage Criteria and Prior Authorization

Policy CodePolicy IC-0148

Change TypeNo material change

Effective Date

Next Review DateMay 5, 2026

SourceLink

On This Page

Documentation Required

Renewal requires documentation of continued eligibility, no unacceptable toxicity, and disease response

For renewals, submit documentation showing the member continues to meet universal and indication‑specific criteria, that authorization duration has not been exceeded, there is absence of unacceptable toxicity, and there is evidence of disease response (stabilization or decrease in tumor burden).

Current performance status and concomitant therapy status
Evidence of disease response or stability (imaging, clinical notes)
Documentation of any adverse events and assessment of unacceptable toxicity

Note

Expect prior authorization as a cost‑driven utilization management measure (NQTL)

Be aware prior authorization is used as a utilization management NQTL in this policy; the NQTL Factor Checklist identifies drug cost as a factor considered when applying prior authorization.

Cost of drug listed as a reason to consider prior authorization in Appendix A (NQTL Checklist)

Prior Authorization

Check Medicare NCDs/LCDs/LCAs for additional prior authorization requirements

For Medicare beneficiaries, verify and comply with any applicable CMS National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), or Local Coverage Articles (LCAs); the policy notes Medicare guidance may impose additional requirements.

Medicare Part B coverage rules and any NCD/LCD/LCA must be followed where applicable
Use the CMS coverage database to search for relevant NCD/LCD/LCA documents

Step Therapy

Adhere to checkpoint‑inhibitor sequencing: combine with nivolumab if no prior checkpoint inhibitor

Follow the policy sequencing rules for checkpoint inhibitors: for appendiceal neoplasms, use ipilimumab in combination with nivolumab if the member has had no prior checkpoint inhibitor; if prior checkpoint inhibitor monotherapy was given, combination may be considered as subsequent therapy.

Appendiceal neoplasms: combination with nivolumab required if no prior checkpoint inhibitor
Combination may be considered later if prior checkpoint inhibitor monotherapy was previously received

Prior Authorization

Confirm and document any required prior therapies or failures before approval

Ensure prior‑therapy requirements are met for indications that specify them; some indications require prior exposure or failure of specified agents (for example, prior sorafenib is required for one HCC pathway; MCC single‑agent use requires prior progression on or contraindication to anti‑PD‑1/PD‑L1).

HCC subsequent pathway: documentation of prior sorafenib treatment when applicable
MCC single‑agent use: evidence of progression on or contraindication to anti‑PD‑1/PD‑L1 therapy

Step Therapy

Re‑initiation allowed for relapse or progression ≥6 months after discontinuation—document timing

Members who relapse ≥6 months after treatment discontinuation for duration, or who progress ≥6 months after completing adjuvant therapy, may be eligible to re‑initiate checkpoint inhibitor therapy; document timing of prior therapy and relapse/progression for re‑initiation requests.

Document prior therapy end date and relapse/progression date
If re‑biopsy shows a new actionable mutation, note that re‑initiation may be evaluated case‑by‑case

Documentation Required

For prior‑authorization requests, include documentation supporting diagnosis, biomarkers, prior therapies, and treatment intent

Submit the same required clinical documentation described for initial requests: diagnosis, biomarker test results, prior therapies, treatment intent, and evidence that the member continues to meet universal and indication‑specific criteria when requesting renewal.

Current disease status and imaging reports
Confirmation that authorization duration limit has not been exceeded

Documentation Required

Attach the specific biomarker test reports required by the indication (NSCLC panel; SBA MSI‑H/POLE; TMB results)

Include explicit biomarker documentation as required by the indication: a comprehensive molecular panel for NSCLC, MSI‑H/dMMR or POLE/POLD1 mutation status for SBA, and TMB numeric results where the policy requires TMB‑H.

NSCLC: provide complete molecular testing report per chunk 29
SBA: include MSI‑H/dMMR or POLE/POLD1 ultra‑hypermutated result (e.g., TMB>50) per chunk 30
Where TMB‑H is required, include the numeric TMB and assay used (TMB‑H ≥10 mut/Mb per chunk 33)

Documentation Required

Renewal submissions must document continued compliance with universal and indication‑specific criteria

For renewals, provide documentation that the member continues to meet universal and indication‑specific criteria (including concomitant therapy status and performance status), that the authorization duration has not been exceeded, and that there is disease response or stability.

Latest imaging and clinical assessment demonstrating stabilization or tumor reduction
Report of adverse events to confirm absence of unacceptable toxicity

Billing Rule

Submit ICD‑10 diagnosis codes from the policy's covered diagnosis list with the request

When requesting coverage, include ICD‑10 diagnosis codes from the policy's covered diagnosis code list (Appendix 1) that correspond to the requested indication.

Select and submit the appropriate covered ICD‑10 code(s) from Appendix 1
Ensure codes reflect the current clinical diagnosis and site (e.g., C18.x for colon, C34.x for lung)

Note

For Medicare claims, verify applicable CMS NCD/LCD/LCA guidance (Medicare Benefit Manual §50)

For Medicare patients, consult the Medicare Benefit Policy Manual Chapter 15 §50 and search the CMS coverage database for any NCDs, LCDs, or LCAs that apply; the policy notes Medicare determinations may impose additional requirements.

Use the CMS coverage database search link provided in Appendix 2
Follow any applicable NCD/LCD/LCA for Medicare Part B claims

Denial Risk

Be aware: prior authorization may NOT be renewed for many listed indications — verify before requesting renewal

Do not expect renewal for indications specifically listed as non‑renewable; prior authorization validity may NOT be renewed for indications such as ampullary adenocarcinoma, appendiceal neoplasms, colorectal cancer, gastric cancer, HCC, CNS cancer (with nivolumab), and others listed in Section I.

Review Section I, 'Prior authorization validity may NOT be renewed' list before submitting a renewal
Cutaneous melanoma first‑line/subsequent/neoadjuvant/adjuvant in combination with nivolumab is non‑renewable per the list (with limited re‑induction provisions)

Denial Risk

Risk of denial if line‑of‑therapy or prior‑treatment prerequisites are not met

Requests that do not meet the policy's specified line‑of‑therapy or prior‑treatment requirements (for example, using HCC pathways without required prior sorafenib or using MCC single‑agent without prior PD‑1/PD‑L1 progression/contraindication) may be denied.

Confirm the member's prior therapy history matches the indication‑specific prerequisites
Document contraindications if prior therapy was not given

Denial Risk

Renewal may be denied for exceeded duration, unacceptable toxicity, or lack of response

Renewal requests may be denied if the original authorization duration has been exceeded, if the member has unacceptable toxicity from the drug, or if there is lack of disease response (no stabilization or decrease in tumor burden).

Provide evidence that authorization duration limits (Section I) have not been exceeded
Document absence of severe immune‑mediated adverse events or other unacceptable toxicity

Note

Prior authorization applied as an NQTL; cost was considered in the PA decision

The policy's use of prior authorization was informed by an NQTL evaluation; prior authorization may be applied because the checklist identified drug cost as a factor considered in utilizing PA for this therapy.

Expect consistent application of PA as a utilization management NQTL across drug classes per Appendix A

Note

Medicare determinations (NCD/LCD/LCA) can affect coverage—comply where applicable

Medicare coverage determinations (NCDs/LCDs/LCAs) may exist and must be followed for Medicare beneficiaries; the policy indicates compliance with applicable CMS policies is required where they apply.

Medicare Part B covered diagnosis codes are noted as N/A in this policy excerpt; check applicable NCD/LCD/LCA documents for Medicare coverage rules

See tumor-specific nodes for details

inv-77: Initial dosing examples

Initial dosing varies by tumor type and regimen (weight-based and combination examples below)

RCC/SBA/Ampullary Adenocarcinoma: Administer 1 mg/kg IV every 3 weeks for 4 doses (given in combination with nivolumab on the same day), then follow with nivolumab monotherapy4 doses

Weight-based dosing; see dosing section for exceptions

Biliary Tract Cancers (subsequent): Administer 1 mg/kg IV every 6 weeks (given in combination with nivolumab every 2 weeks) until progression or unacceptable toxicity

Multiple tumor types (examples): Examples include single-agent 10 mg/kg IV every 3 weeks for 4 doses with maintenance 10 mg/kg q12w for select indications; combination schedules commonly 1 mg/kg or 3 mg/kg IV every 3 weeks for up to 4 doses; some neoadjuvant regimens specify 1 mg/kg q3w x2 doses

See dosing section for tumor-specific regimens

inv-80: Continuation therapy

Continuation therapy — transition to maintenance or nivolumab monotherapy where applicable

General continuation: When given in combination with nivolumab, follow induction ipilimumab dosing (varies by tumor type) then continue nivolumab monotherapy per disease-specific protocols until progression or unacceptable toxicity; many regimens limit ipilimumab to a maximum of 4 doses administered within 16 weeksMax 4 doses within 16 weeks for many regimens

Some indications allow longer combination dosing intervals or maintenance schedules noted in dosing section

Renewal/continuation implicationAfter induction, continuation typically transitions to nivolumab monotherapy per disease‑specific protocols

Follow institution's infusion center protocols for administration and monitoring

Billing Rule

Give IV infusions per regimen (often same‑day with nivolumab) and bill using J9228 units

Schedule dosing per the policy's IV regimen examples (many combinations are given on the same day as nivolumab); ensure billing reflects intravenous administration and the appropriate J9228 units per mg administered.

Administer ipilimumab IV per the indication‑specific schedule (e.g., 1 mg/kg every 3 weeks for 4 doses when combined with nivolumab for several indications)
Use HCPCS code J9228 (1 mg = 1 billable unit) for billing

TMB‑H = tumor mutational burden‑high defined as ≥ 10 mutations/megabase (mut/Mb)

Test requirementTMB must be measured by an FDA‑approved or CLIA‑compliant test to meet eligibility criteria

Clinical useUsed as an eligibility biomarker for multiple indications including biliary tract cancers, bone cancers, STS subtypes, and uterine endometrial carcinoma

PD‑L1 CPS ≥1 — Definition

DefinitionPD‑L1 CPS ≥1 = tumor expresses PD‑L1 with Combined Positive Score ≥1 as determined by an FDA‑approved or CLIA‑compliant test

Use caseUsed to define eligibility in some esophageal and esophagogastric junction indications (may be alternative path independent of MSI‑H)

Testing requirementPD‑L1 CPS must be reported from an FDA‑approved or CLIA‑compliant assay per policy criteria

Actionable biomarkers — required for NSCLC

Required biomarkers for NSCLCComplete molecular testing including EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, NRG1 and ERBB2 (HER2)

Testing modalityMolecular assessment via tumor biopsy and/or plasma testing per guideline recommendations

Treatment implicationIf a clinically actionable marker is found, treatment should be guided by the identified marker rather than default checkpoint inhibitor pathways

TMB‑H — threshold reiterated

Restated thresholdTMB‑H defined as ≥ 10 mutations/megabase (mut/Mb)

Test requirementDetermination must be by an FDA‑approved or CLIA‑compliant test

RelevanceApplied across STS, uterine, and other tumor‑specific criteria where TMB‑H is required

TMB‑H — threshold reiterated

Restated thresholdTumor mutational burden‑high (TMB‑H) = ≥ 10 mutations/megabase (mut/Mb)

ContextSpecified as an eligibility requirement for endometrial carcinoma and uterine sarcoma when used as subsequent therapy in combination with nivolumab

Test standardMust be measured by an FDA‑approved or CLIA‑compliant assay

Dual checkpoint therapy — Nivolumab + ipilimumab

Definition of dual checkpoint therapyDual immune checkpoint inhibitor therapy = combination of an anti‑PD‑1 agent (nivolumab) plus an anti‑CTLA‑4 agent (ipilimumab)

Clinical contextMany indications specify ipilimumab is used in combination with nivolumab; combination sequencing and prior checkpoint exposure rules are described in indication‑specific sections

Dosing implicationCombination regimens commonly limit ipilimumab to a maximum of 4 induction doses within 16 weeks before transitioning to nivolumab maintenance