Currentpremera-bluecrossPolicy 5.01.591

MEDICAL POLICY - 5.01.591 Immune Checkpoint Inhibitors

Policy governs medical necessity review for intravenous and injectable immune checkpoint inhibitor drugs, including site-of-service (SOS) criteria for age ≥13 and drug-specific indication coverage for multiple PD-1/PD-L1 and CTLA-4 agents. SOS criteria do not apply to Alaska fully-insured members. This extract is Part 1 of 4 and includes SOS rules and many drug-specific covered indications present in this part.

Policy Summary

Payerpremera-bluecross

PolicyMEDICAL POLICY - 5.01.591 Immune Checkpoint Inhibitors

Policy CodePolicy 5.01.591

Change TypeMultiple added/revised/clarified indications and SOS rules

Effective DateMar 1, 2026

Next Review DateN/A

Key ActionPrior medical necessity review required for IV and injectable immune checkpoint inhibitors; site-of-service review required for individuals aged ≥13 years (except Alaska fully-insured members).

SourceLink

POLICY UPDATE CHANGES

Added indication and coverage criteria for Loqtorzi (toripalimab-tpzi).

Added Tecentriq Hybreza (subcutaneous atezolizumab and hyaluronidase) and updated its age/weight criteria for ASPS to individuals ≥12 years and ≥40 kg.

Updated coverage criteria for multiple agents (Keytruda, Opdivo, Imfinzi, Jemperli, Tevimbra, Zynyz, penpulimab-kcqx, and others) reflecting new FDA indications through 2026.

Added coverage for Opdivo + Yervoy combination for first-line MSI-H/dMMR unresectable or metastatic colorectal cancer based on NEJM 2024 and NCCN support.

Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members per Alaska HB 226; exception added for CRS treatment.

Policy updated to indicate that Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members; only Medical Necessity criteria for the infusion drug applies pursuant to Alaska HB 226.

Multiple new drug indications, agents, and HCPCS codes were added across the policy history (examples include Keytruda Qlex, Tecentriq Hybreza, Opdivo Qvantig, Imjudo, Unloxcyt, Loqtorzi, Tevimbra).

Site of service review was added for Imfinzi, Jemperli, Opdivo Qvantig, Tecentriq, and Tecentriq Hybreza effective Oct 3, 2025 (90-day provider notification).

Clarified that the medications listed in this policy are subject to the product's FDA dosage and administration prescribing.

90-day provider notifications with future effective dates were used for certain coverage requirement changes (e.g., site-of-service additions effective Oct 3, 2025; other changes effective Feb 6, 2026).

Reformatted policy with no change to criteria except where noted (03/01/26).

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

20+Immune checkpoint inhibitor agents listed in Part 1

>=13Age threshold for SOS review

90 daysHospital outpatient medically necessary initial/re-initiation period

multipleAgents covered with specified indications in part

12 monthsTypical maximum approval duration (non-formulary exception)

90-dayProvider notification period used for some effective changes

Coverage Summary & Scope

Part 1 of 4 (extract): This policy governs medical necessity and site-of-service (SOS) criteria for intravenous (IV) and injectable immune checkpoint inhibitors (PD‑1, PD‑L1, CTLA‑4 agents). Payer/document header: MEDICAL POLICY - 5.01.591 Immune Checkpoint Inhibitors; Effective Date: 2026-03-01; Last review: 2026-02-10. Coverage stance: mixed — the policy lists numerous FDA‑approved indications with investigational/not covered uses noted for others. SOS criteria apply for individuals aged ≥13 years except that the Site of Service Medical Necessity criteria does NOT apply to Alaska fully‑insured members (refer to infusion/injection drug medical necessity only). This overview is an extract (Part 1 of 4) and does not repeat metrics shown elsewhere in the policy.

Site-of-Service (SOS) Medical Necessity Criteria

Prior Authorization

Provider Actions - SOS / Prior Authorization / Billing Rules

Medical necessity and site-of-service review required. Document clinical rationale and supporting medical record evidence for hospital-based outpatient use, including severity of CRS and planned escalation/transfer to inpatient care when applicable.

Medical necessity and site-of-service review required for listed IV and SC formulations (Keytruda, Imfinzi, Jemperli, Opdivo, Opdivo Qvantig, Tecentriq, Tecentriq Hybreza, Imjudo, Yervoy) except when given concurrently with other infusion/injection cancer medications.
Document the clinical justification for hospital-based outpatient use: history, physical exam findings, relevant labs, supportive imaging, reason why alternative sites (office, infusion center, home) are not appropriate.
Document CRS severity and plan: include temperature, blood pressure and vasopressor requirement, oxygen requirements and modality, and explicit plan for inpatient admission and escalation of care.
Medical record documentation required: indication, FDA-approved diagnosis or rationale for off-label use, prior therapies and response, dates of prior infusions, evidence of discontinuation interval if re-initiation claimed, and notes from infusion/home-infusion vendor if unavailable.
Site-of-service review applicability: applies to members aged ≥13 for site-of-service review; Alaska fully-insured members are exempt from SOS criteria (refer to infusion/injection drug criteria).
Adhere to FDA dosing and prescribing information for each agent; document dosing, schedule, and intent (initial vs continuation).
Site of Service Review Requirement (selected agents): SOS review applies to listed agents and formulations (including SC formulations Opdivo Qvantig and Tecentriq Hybreza).
Trial exclusion-like documentation considerations: when clinical trial participation or investigational use is asserted, include trial identifier, protocol synopsis, and documentation that the use matches protocol-specified administration site and monitoring.
Tecentriq Hybreza administration difference: document hyaluronidase-containing SC formulation as distinct from IV Tecentriq; include administration route and use appropriate coding.
Follow FDA dosing and administration for transition between IV and SC formulations; document rationale and equivalence if switching formulation.
Use of unlisted codes for new SC formulations: when no specific HCPCS exists for a new subcutaneous formulation, use appropriate unlisted drug or CPT/HCPCS codes and provide supporting documentation including NDC, formulation, and administration details.

Drug-specific Medical Necessity Criteria

Drug-specific Medical Necessity Criteria (selected agents in Part 1)

Each drug below is subject to medical necessity review and, unless otherwise noted, site-of-service review (except when used concurrently with other infusion/injection cancer medications). Criteria reflect age and indication-specific requirements as listed.

Drug-specific Medical Necessity Criteria

Imjudo (tremelimumab-actl): Individual is aged 18 years or older AND meets one of: unresectable hepatocellular carcinoma (uHCC) when used in combination with Imfinzi (durvalumab); metastatic NSCLC with no sensitizing EGFR mutations or ALK aberrations when used in combination with Imfinzi (durvalumab).age >=18
Yervoy (ipilimumab) IV: May be considered medically necessary for listed indications including melanoma (age >=12 for some melanoma uses), RCC in combination with Opdivo, MSI-H/dMMR colorectal cancer in combination with Opdivo, HCC in combination with Opdivo, NSCLC and mesothelioma per specified combos; follow agent-specific age and combination requirements.

Administration, Site-of-Service Exceptions & Practical Billing Notes

Actionable SOS callouts

Coding (HCPCS / J-codes)

Drugs/agents listed (no billing codes present in Part 1)mixed

No codes listed

HCPCS / J-codes listed for agents in policyHCPCS

C9399	Unclassified drugs or biologicals (use to report: Keytruda Qlex and penpulimab-kcqx)
J3263	Injection, toripalimab-tpzi (Loqtorzi), 1 mg
J3590	Unclassified biologics (use to report; Keytruda Qlex)
J9022	Injection, atezolizumab (Tecentriq), 10 mg
J9023	Injection, avelumab (Bavencio), 10 mg
J9024	Injection, atezolizumab, 5 mg and hyaluronidase-tqjs (Tecentriq Hybreza) (new code effective 04/01/25)
J9119	Injection, cemiplimab-rwlc (Libtayo), 1 mg
J9173	Injection, durvalumab (Imfinzi), 10 mg
J9228	Injection, ipilimumab (Yervoy), 1 mg
J9271	Injection, pembrolizumab (Keytruda), 1 mg

1–10 of 19

1/2

Referenced HCPCS/J-codes (historical additions noted)HCPCS

J9173	HCPCS code added for Tecentriq (not further specified in this part)
J9023	HCPCS code added (referenced in history; exact agent mapping not provided in this part)
J9119	HCPCS code added (referenced in history; exact agent mapping not provided in this part)
J3490	Removed from policy (historical)
J3590	HCPCS code added (referenced in history)

Added HCPCS / J-codes (history entries)HCPCS

J3590	Unlisted biologics/drug code — added and removed in multiple history entries; used to report certain products (e.g., Imjudo, Keytruda Qlex) at times.
C9082	HCPCS code (termed later) — referenced in historical coverage changes for Tecentriq.
J9272	HCPCS code added (historical) then termed.
C9147	Added April 2023 then termed later; coding update.
J9298	HCPCS code added (historical entry).
J9258	HCPCS code added (historical entry).
J3263	HCPCS code added effective 7/1/2024.
J9329	HCPCS code added effective 10/1/2024 for Tevimbra.
J9024	HCPCS code added for Opdivo Qvantig (nivolumab and hyaluronidase-nvhy).
J9275	HCPCS added for Unloxcyt (effective 8/1/25 coding updates).

1–10 of 18

1/2

Unlisted / miscellaneous HCPCSHCPCS

C9399	Unlisted code for Tecentriq Hybreza (historical addition).
J9999	Unlisted code for Tecentriq Hybreza (historical addition).
C9147	Termed code referenced in history.

Efficacy, Indication Summaries & Safety Considerations

This document includes agent‑specific trial evidence summaries, efficacy endpoints, and safety considerations for immune checkpoint inhibitors; selected agents and evidence summaries are presented here as an extract (Part 1). Provider and coding implications (site‑of‑service applicability, documentation, and HCPCS/J‑code updates) are included for listed agents.

Selected agent evidence and key efficacy results (brief): Loqtorzi (toripalimab‑tpzi) — POLARIS‑02: ORR 20.5%, DCR 40.0%, median OS 17.4 months for recurrent/metastatic nasopharyngeal carcinoma. Opdivo (nivolumab) — CheckMate subset (advanced melanoma interim): reported ORR 32% (efficacy subset) with immune‑mediated adverse events described (pneumonitis, colitis, hepatitis, endocrine events; 9% discontinued for adverse reactions; serious AEs ~41%). Tevimbra (tislelizumab‑jsgr) — RATIONALE‑302: median OS 8.6 vs 6.3 months (HR=0.70) vs chemotherapy; common ≥20% adverse reactions noted. Unloxcyt (cosibelimab‑ipdl) — CK‑301‑101: ORR 50% (mCSCC) and 55% (laCSCC); median DOR not reached. Tecentriq (atezolizumab) ASPS cohort: ORR 24% (12/49); 67% of responders had DOR ≥6 months. (These summaries reflect the brief.evidence labels/values provided in the policy extract.)

Trial exclusion / common safety criteria (from evidence and trial designs): Common exclusions across trials included active or suspected autoimmune disease, recent allogeneic transplant within specified timeframes, prior anti‑PD‑1/PD‑L1 or other immune checkpoint inhibitor therapy for some cohorts, uncontrolled or significant cardiovascular disease, ECOG performance status ≥2, active infection with HIV/HBV/HCV, active or corticosteroid‑dependent brain metastases, recent live vaccine, and recent systemic immunostimulatory or immunosuppressive medications. Immune‑related adverse events (irAEs) are a class effect and may require corticosteroids, drug withholding or discontinuation; endocrine irAEs can require long‑term hormone replacement.

Definitions & Abbreviations

Term	Definition
Site of Service (SOS)
Location where the drug is administered (hospital-based outpatient, infusion center, physician's office, home). SOS Medical Necessity criteria apply to medical benefit reviews and, for individuals aged 13 and older, the site of service is reviewed unless the member is an Alaska fully-insured member (SOS criteria do not apply to Alaska fully-insured members).
CRS (Cytokine Release Syndrome)
An inflammatory state graded; grade 3–4 CRS is defined by ALL of: temperature ≥38 °C; hypotension requiring one or more vasopressors; and hypoxia requiring high-flow nasal cannula, face mask, non-rebreather, Venturi mask OR positive pressure (CPAP, BiPAP, intubation, or mechanical ventilation). Hospital-based outpatient or inpatient admission is required when these criteria are met.
TMB-H
Tumor mutational burden-high defined as ≥10 mutations per megabase (mut/Mb).
PD-1
Programmed cell death protein 1, an immune checkpoint protein on T-cells that down-regulates T-cell inflammatory activity and promotes self-tolerance. PD-1 blockade releases inhibition of the antitumor immune response.
PD-L1
Programmed death-ligand 1, a protein that binds PD-1 and suppresses immune responses; PD-L1 expression on tumor cells or tumor-infiltrating immune cells may guide therapy decisions (PD-L1 assay thresholds vary by indication).
ORR
Objective Response Rate — proportion of individuals with tumor size reduction of a predefined amount and for a minimum time period as reported in trials and labels.
DCR
Disease Control Rate — proportion of individuals achieving response or stable disease per trial definitions.
DOR
Duration of Response — time from initial response until progression or death as reported in clinical studies.
ASPS
Alveolar Soft Part Sarcoma — a rare soft tissue sarcoma; Tecentriq is approved for unresectable or metastatic ASPS (approval includes pediatric ages per specific criteria).
MSI-H/dMMR
Microsatellite Instability-High / mismatch repair deficient — biomarker category; MSI-H/dMMR tumors may be eligible for certain PD-1/CTLA-4 therapies per policy indications.
Site of Service Medical Necessity
A review to determine the most appropriate, safe, and cost-effective administration location for infusion/injectable therapy (preferred medically necessary sites include physician's office, infusion center, and home infusion). Hospital-based outpatient setting is medically necessary for the initial course or re-initiation after ≥6 months (first 90 days) or when clinical risk factors or lack of local services apply. Exceptions and applicability (e.g., Alaska fully-insured members, CRS) are documented in the policy history and criteria sections.

Policy Revision History (selected changes)

2024added

Added indication and coverage criteria for Loqtorzi (toripalimab-tpzi).

2025-04-01added

Added Tecentriq Hybreza (subcutaneous atezolizumab and hyaluronidase) and noted administration time difference (~7 minutes vs IV 30–60 minutes).

2026-03-01revised

Updated Tecentriq Hybreza age/weight criteria to individuals ≥12 years and ≥40 kg.

Policy Summary

Payerpremera-bluecross

PolicyMEDICAL POLICY - 5.01.591 Immune Checkpoint Inhibitors

Policy CodePolicy 5.01.591

Change TypeMultiple added/revised/clarified indications and SOS rules

Effective DateMar 1, 2026

Next Review DateN/A

SourceLink

On This Page

age >=12 for certain melanoma and pediatric MSI-H uses

Jemperli (dostarlimab-gxly) IV: Individual aged >=18 AND specific endometrial cancer or dMMR solid tumor indications per criteria (combination with carboplatin+paclitaxel for primary advanced/recurrent endometrial cancer; dMMR progressed after platinum and not candidate for curative surgery/radiation; recurrent/advanced dMMR solid tumors progressed after prior treatment with no satisfactory alternatives).age >=18

Subject to SOS review except when used concurrently with other infusion/injection cancer meds.

Keytruda (pembrolizumab) IV: Subject to site-of-service review except when used concurrently with other infusion/injection cancer meds. May be considered medically necessary for multiple indications including melanoma (adults and pediatrics >=12 for some uses), NSCLC with PD-L1 requirements and no EGFR/ALK/ROS1 aberrations, HNSCC, urothelial cancer with PD-L1/CPS thresholds, MSI-H/dMMR and TMB-H cancers, gastric/GEJ with PD-L1 CPS thresholds, HCC and many others as specified in policy.PD-L1, CPS, TMB-H, MSI-H thresholds as per indication

Keytruda Qlex (pembrolizumab + berahyaluronidase alfa): May be considered medically necessary for indications essentially identical to Keytruda in adults; FDA-approved testing for PD-L1/EGFR/ALK/ROS1 or TMB-H required before coverage determination for Keytruda Qlex; not FDA-approved for cHL or PMBCL.testing required prior to coverage for Keytruda Qlex

Libtayo (cemiplimab) IV: May be considered medically necessary for listed indications including CSCC (metastatic or locally advanced and specified adjuvant high-risk features), locally advanced/metastatic BCC after hedgehog inhibitor, NSCLC indications with PD-L1/TPS thresholds, and others per policy.age and tumor PD-L1 thresholds as specified

Loqtorzi (toripalimab-tpzi) IV: May be considered medically necessary for adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma in combination with cisplatin+gemcitabine, and adults with recurrent unresectable or metastatic NPC progressed after platinum chemotherapy.adults

Added agent; criteria per indications

Opdivo (nivolumab) IV: Subject to site-of-service review except when used concurrently with other infusion/injection cancer meds. May be considered medically necessary for multiple indications including melanoma (adjuvant and unresectable/metastatic), neoadjuvant/adjuvant and metastatic NSCLC (resectable tumors >=4 cm or node positive for neoadjuvant), urothelial carcinoma, RCC, classical Hodgkin lymphoma, MSI-H/dMMR colorectal cancer (in combination with Yervoy), HCC in combination with Yervoy, and others per policy. Note: Opdivo + Yervoy combination not subject to site-of-service review.age thresholds and biomarker requirements per indication

Opdivo+Yervoy not subject to SOS review

Opdivo Qvantig (nivolumab + hyaluronidase-nvhy) SC: Subject to site-of-service review except when used concurrently with other infusion/injection cancer meds. May be considered medically necessary for indications similar to IV Opdivo including melanoma (>=12 for some uses), neoadjuvant/adjuvant NSCLC (resectable tumors >=4 cm or node positive), metastatic NSCLC with progression after platinum chemo (EGFR/ALK/ROS1 patients must have progressed on targeted therapy), advanced RCC including prior anti-angiogenic therapy, cHL relapsed after HSCT/brentuximab or >=3 lines, and HCC first-line following IV Opdivo+Yervoy per policy updates.age and prior therapy requirements per indication

Added SC formulation criteria

Imfinzi (durvalumab) IV and Imjudo combinations: Imfinzi is subject to site-of-service review except when used concurrently with other infusion/injection cancer meds. May be considered medically necessary for listed NSCLC indications (neoadjuvant/adjuvant, unresectable stage III after cCRT, metastatic combinations), limited- and extensive-stage SCLC, biliary tract cancer with gemcitabine+cisplatin, uHCC in combination with Imjudo, dMMR endometrial cancer combinations, MIBC neoadjuvant/adjuvant, resectable GC/GEJC with FLOT per MATTERHORN, and others as specified.age >=18 for many Imfinzi uses; indication-specific prior therapy requirements

Tecentriq (atezolizumab) IV and Tecentriq Hybreza (SC): Subject to site-of-service review except when used concurrently with other infusion/injection cancer meds. Tecentriq and Tecentriq Hybreza may be considered medically necessary for ES-SCLC first-line with carboplatin+etoposide and maintenance with Zepzelca, unresectable/metastatic HCC with bevacizumab, BRAF V600 melanoma combinations, ASPS (age >=2 for IV; Hybreza age >=12 and >=40 kg per update), NSCLC indications including Hybreza SC with PD-L1 high TC>=50% or IC>=10%, adjuvant Stage II/IIIA NSCLC with PD-L1 >=1%, and other specified uses. Note Hybreza SC administration ~7 minutes vs IV 30-60 minutes.age and weight for Hybreza (>=12 years and >=40 kg for ASPS), PD-L1 thresholds as indicated

Administration time difference noted

Unloxcyt (cosibelimab-ipdl): May be considered medically necessary for metastatic or locally advanced CSCC when ALL are met: individual aged >=18, not candidate for curative surgery or radiation, no prior anti-PD-1/PD-L1 therapy, and prescribed as monotherapy.age >=18; all listed conditions must be met

Zynyz (retifanlimab-dlwr): May be considered medically necessary for metastatic or recurrent locally advanced Merkel cell carcinoma (no prior systemic therapy required) and for certain anal canal SCAC indications per policy.adults

Penpulimab-kcqx: May be considered medically necessary for first-line treatment of adults with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma in combination with cisplatin or carboplatin + gemcitabine.adults

Investigational / Not covered uses: All other uses of the listed agents (Bavencio, Imfinzi, Imjudo, Jemperli, Keytruda, Keytruda Qlex, Libtayo, Loqtorzi, Opdivo, Opdivo Qvantig, Opdualag, Tecentriq, Tecentriq Hybreza, Tevimbra, Unloxcyt, Yervoy, and Zynyz) not listed in this policy are considered investigational.

Note

Drug-specific Prior Authorization, Documentation, and Approval Length

Prior medical necessity review required for all listed IV and injectable agents. FDA-approved tumor biomarker testing must be documented when specified by agent (example: PD-L1, EGFR, ALK/ROS1, TMB-H testing required before coverage determination for Keytruda Qlex; PD-L1, MSI-H/dMMR, TMB-H testing referenced for other agents where indicated). Non-formulary exception and initial/re-authorization approvals may be granted up to 12 months when drug-specific criteria are met and chart notes show continued positive clinical response. Office visit notes and medical records must document diagnosis, relevant history, physical exam, medication history, and any testing supporting agent-specific eligibility.

Prior medical necessity review required for IV/injectable immune checkpoint inhibitors.
Tumor biomarker testing requirements: FDA-approved testing confirming PD-L1, EGFR, ALK/ROS1, or TMB-H is required before coverage determination for Keytruda Qlex; other agents reference PD-L1, MSI-H/dMMR, or TMB-H testing as indicated by their specific criteria.
Documentation required: office visit notes documenting diagnosis, relevant history, physical exam, medication history, and testing to demonstrate medical necessity.
Length of approval/authorization: non-formulary exception reviews and other initial/re-authorization reviews may be approved up to 12 months if criteria met and clinical response documented.

2024-2026revised

Updated coverage criteria for multiple agents (Keytruda, Opdivo, Imfinzi, Jemperli, Tevimbra, Zynyz, penpulimab-kcqx, and others) reflecting new FDA indications through 2026.

2024 (NEJM 2024)added

Added coverage for Opdivo + Yervoy combination for first-line MSI-H/dMMR unresectable or metastatic colorectal cancer based on NEJM 2024 and NCCN support.

2025-10-03revised

Site of service review was added for Imfinzi, Jemperli, Opdivo Qvantig, Tecentriq, and Tecentriq Hybreza (90-day provider notification; effective Oct 3, 2025).

2025added

Multiple new drug indications, agents, and HCPCS codes were added across the policy history (examples include Keytruda Qlex, Tecentriq Hybreza, Opdivo Qvantig, Imjudo, Unloxcyt, Loqtorzi, Tevimbra).

2026-03-01effectiveLatest

Policy effective date: Mar. 1, 2026; last review: Feb. 10, 2026.

2025-01-03clarified

Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members per Alaska HB 226; exception added for CRS treatment.

2026-03-01reformattedLatest

Policy reformatted with no change to criteria except where noted (03/01/26).

Provider notification: 90‑day provider notification periods were used for some future effective changes noted in the revision history. Effective date for this policy extract is 2026-03-01 with last review on 2026-02-10.