Medical necessity and site-of-service review criteria for immune checkpoint inhibitor drugs (IV and SC formulations) and related administration locations; applies to Premera members and providers for medical benefit reviews, with an Alaska exception for fully insured members.
Policy Summary
PayerPremera Bluecross
PolicyImmune Checkpoint Inhibitors
Policy CodePolicy N/A
Change TypeMultiple additions, removals, and updates to indications and site-of-service reviews
Effective DateMar. 1, 2026
Next Review DateN/A
Key ActionSubmit prior authorization and site-of-service documentation for IV or injectable immune checkpoint inhibitors for individuals aged 13 and older; follow required biomarker and clinical documentation per indication.
Added a new indication to Opdivo (nivolumab) for resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting combined with platinum-doublet chemotherapy, followed by adjuvant nivolumab.
Added a new product Tecentriq Hybreza (atezolizumab and hyaluronidase-tqjs), a subcutaneous form of atezolizumab, to the policy for multiple cancer types.
Updated coverage criteria across multiple years (2019–2025) adding and removing FDA indications for several agents including Keytruda, Tecentriq, Opdivo, Imfinzi, and others.
Removed coverage for several withdrawn indications (e.g., Keytruda for small cell lung cancer; Tecentriq and Imfinzi withdrawn urothelial indications; Opdivo melanoma indications removed).
Added coverage criteria for multiple new agents and indications (e.g., Zynyz for Merkel cell carcinoma; Tevimbra; Loqtorzi; penpulimab; Jemperli expansions).
Added coverage criteria for Imfinzi (durvalumab) in combination with Imjudo (tremelimumab-actl) for certain metastatic NSCLC and for uHCC.
Updated coverage to include Imfinzi for limited-stage SCLC and muscle invasive bladder cancer and perioperative durvalumab in gastric/GEJC.
Added site of service review for Imfinzi, Jemperli, Opdivo Qvantig, Tecentriq, and Tecentriq Hybreza effective October 3, 2025.
Updated Yervoy criteria for ESCC to require tumors express PD-L1 (>=1) effective February 6, 2026.
Updated Opdivo and Opdivo Qvantig gastric/GEJ/esophageal adenocarcinoma criteria to require tumor PD-L1 >=1 effective February 6, 2026.
Added numerous new indications and HCPCS codes for agents including Opdivo Qvantig, Tecentriq Hybreza, Unloxcyt, Tevimbra, Loqtorzi, Keytruda Qlex and others across 2022-2026 history entries.
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20+distinct drugs/formulations listed
2018-2026history years documented
90 dayshospital outpatient initial period
50 milesdistance threshold
>=1%PD-L1 threshold referenced
12 monthsmax authorization length
Coverage Criteria and Clinical Indications
Site of Service Medical Necessity
Site of Service (SOS) Medical Necessity criteria applies for medical benefit reviews and for members aged 13 and older (Alaska fully‑insured exception).
SOS applicability: SOS criteria applies to IV and injectable drugs for medical benefit reviews; does not apply to Alaska fully-insured members (refer to infusion and injection drug Medical Necessity criteria).
For ages 13 and older site-of-service review performed; contact Customer Service for details.
Medically necessary sites: Physician's office, infusion center, or home infusion are preferred medically necessary sites. A hospital-based outpatient setting is considered medically necessary for the first 90 days for the initial course of infusion/injection or for re-initiation after ≥6 months, or when no outpatient infusion center is within 50 miles and no contracted home infusion agency will travel, or when clinical conditions increase risk of complications.90 days; 50 miles
Clinical conditions include symptomatic cardiac or significant pulmonary disease, unstable renal function, difficult/unstable vascular access, acute cognitive impairment, or prior severe anaphylaxis.
CRS criteria for hospital site: Hospital-based outpatient setting is medically necessary when the individual has grade 3 or 4 cytokine release syndrome (CRS) (temperature ≥38°C AND hypotension requiring ≥1 vasopressors AND hypoxia requiring high-flow oxygen or positive pressure) AND the individual will be admitted to an inpatient setting as soon as possible.CRS grade 3 or 4
Admission to inpatient setting must be expected; meets criteria for hospital-based outpatient site.
Drug-specific Medical Necessity Indications
Each listed immune checkpoint inhibitor is described with specific indications and combination/regimen requirements; medical necessity is determined per listed indication.
Imjudo (tremelimumab-actl): May be considered medically necessary for adults (≥18) when used in combination with Imfinzi for unresectable HCC or for metastatic NSCLC without sensitizing EGFR or ALK aberrations in combination with Imfinzi.
See drug-specific combination requirements.
Yervoy (ipilimumab): May be considered medically necessary for multiple indications including unresectable/metastatic melanoma (≥12 years), adjuvant melanoma, brain metastases active against primary tumor, combination with Opdivo for intermediate/poor‑risk RCC, MSI‑H/dMMR colorectal cancer with nivolumab, HCC in combination with nivolumab, NSCLC combinations, and other listed uses.
PD‑L1 requirements may apply by indication.
Jemperli (dostarlimab-gxly): May be considered medically necessary for adults (≥18) for primary advanced or recurrent endometrial cancer in combination with carboplatin + paclitaxel; for recurrent/advanced dMMR endometrial cancer after platinum progression; and for recurrent/advanced dMMR solid tumors progressed after prior treatment when no satisfactory alternatives exist.
Agent-specific medical necessity indications (partial — per chunks provided)
Covered for the listed indication statements when the specific diagnostic, biomarker and prior therapy conditions (if any) described for each agent are met.
Keytruda Qlex indications (partial): Includes HCC secondary to hepatitis B after prior non‑PD‑1 systemic therapy; recurrent/metastatic Merkel cell carcinoma; RCC (first‑line with axitinib or lenvatinib; adjuvant for intermediate‑high/high risk); endometrial carcinoma (with lenvatinib or single agent for MSI‑H/dMMR); TMB‑H solid tumors (≥10 mut/Mb); and others. FDA‑approved testing for PD‑L1, EGFR/ALK/ROS1, or TMB‑H is required before coverage determination for Keytruda Qlex.TMB‑H ≥10 mut/Mb
Keytruda Qlex not approved for certain Keytruda indications (see policy).
Libtayo (cemiplimab): Medically necessary for CSCC (metastatic or locally advanced not candidate for curative therapy), high‑risk post‑surgery CSCC adjuvant use with specified pathologic features, basal cell carcinoma after hedgehog inhibitor or inappropriate, first‑line NSCLC for PD‑L1 TPS≥50% without EGFR/ALK/ROS1, and other listed indications.PD‑L1 TPS ≥50% for some NSCLC indications
Pathologic features required for high‑risk CSCC documented in policy.
Covered Indications (selected from document)
Covered indications listed in this portion of the policy include:
Non‑small cell lung cancer indications: Tecentriq Hybreza: first‑line treatment of adult individuals with metastatic non‑squamous NSCLC without EGFR or ALK aberrations in combination with paclitaxel protein‑bound and carboplatin; adjuvant treatment following resection and platinum‑based chemo for Stage II and IIIA NSCLC with PD‑L1 ≥1%; treatment of metastatic NSCLC with progression during/after platinum chemo (patients with EGFR/ALK/ROS1 aberrations should progress on targeted therapy first).PD‑L1 ≥1% mentioned for adjuvant NSCLC
Age/biomarker prerequisites apply per agent.
Small cell lung cancer: First‑line treatment of adult individuals with extensive‑stage SCLC in combination with carboplatin and etoposide; maintenance treatment in combination with lurbinectedin if disease not progressed after first‑line induction including atezolizumab‑containing regimens.
Includes maintenance indication when criteria met.
Hepatocellular carcinoma: Treatment of unresectable or metastatic HCC in adults not previously treated with systemic therapy when used in combination with bevacizumab (agent‑specific combinations also described elsewhere).
Evidence summaries by agent and indication
Evidence summaries and indication contexts (trial populations, endpoints, and outcomes):
Avelumab — Merkel cell carcinoma: JAVELIN Merkel 200 (n=88) multi‑center open‑label trial showed ORR 33% with CR 11.4% and median duration of response not reached; efficacy demonstrated irrespective of PD‑L1 status.
Histologically confirmed stage IV MCC refractory to chemotherapy in trial.
Durvalumab (Imfinzi) — gastric/GEJ (MATTERHORN): MATTERHORN randomized trial (n=948) in resectable Stage II–IVA GC/GEJC showed improved event‑free survival (HR 0.71) and higher pCR rate (19.2% vs 7.2%); trial excluded individuals with active/prior autoimmune disease or recent immunosuppression.
Trial not designed to isolate neoadjuvant vs adjuvant effects.
Dostarlimab (Jemperli) — dMMR endometrial cancer: GARNET single‑arm cohort (n=71) in dMMR recurrent/advanced endometrial cancer after platinum progression showed confirmed ORR 42.3% and median DOR not reached; prior PD‑1/PD‑L1 therapy and recent systemic immunosuppression were exclusion criteria.
Dosing: 500 mg q3wk x4 then 1000 mg q6wk in trial.
Covered with criteria (selected indications and monitoring)
Coverage notes and supportive evidence summaries for specific drug indications described in this section
Accelerated approvals based on ORR and DOR: Several agents (e.g., nivolumab for advanced melanoma, atezolizumab for urothelial carcinoma and ASPS, retifanlimab for Merkel cell carcinoma) received accelerated approval based on objective response rate and duration of response; continued approval may require confirmatory trials.
See trial citations for ORR/DOR data.
Safety monitoring requirements: Immune‑mediated adverse reactions (pneumonitis, colitis, hepatitis, nephritis, endocrinopathies) occur and may necessitate corticosteroids, treatment delays, or discontinuation; monitor and manage per prescribing information.
PD‑L1 linked indications and testing: Certain indications and subgroup analyses depend on PD‑L1 expression assessed by the VENTANA PD‑L1 (SP142) Assay; documentation of PD‑L1 status may be required when coverage is tied to these subgroups.PD‑L1 ≥ specified thresholds as per trial (e.g., ≥5% IC, ≥50% TC, CPS thresholds)
Updated Coverage Criteria (selected highlights)
Policy was updated to add or revise coverage criteria for multiple agents and indications; specific coverage is agent- and indication-specific as detailed in the policy.
Imfinzi (durvalumab): Coverage criteria added for metastatic NSCLC in combination with Imjudo (tremelimumab‑actl); added for limited‑stage SCLC post concurrent chemoradiation; added for MIBC and resectable GC/GEJC with perioperative FLOT chemotherapy followed by single‑agent durvalumab.
Refer to drug‑specific sections for full eligibility and age limits.
Keytruda (pembrolizumab): Coverage criteria expanded to include HCC secondary to hepatitis B, primary advanced or recurrent endometrial carcinoma (including regardless of dMMR/MSI status for some indications), MIBC in combination with enfortumab vedotin for cisplatin‑ineligible individuals, and other new indications; follow PD‑L1 expression requirements where specified.
See updated history entries for effective dates and provider notification details.
Opdivo (nivolumab) and combinations: Added neoadjuvant/adjuvant indication for resectable NSCLC (tumors ≥4 cm or node positive) with platinum‑doublet chemo then adjuvant nivolumab; added Opdivo + Yervoy indications for HCC and MSI‑H/dMMR CRC; Hodgkin lymphoma staging and pediatric age threshold updates also added.
Summary of coverage criteria updates
Policy history documents additions and modifications to covered indications and criteria; coverage is tied to FDA‑approved indications and specified biomarker/tumor requirements as noted below.
PD‑L1 related requirement additions: Several indications were updated to require tumor PD‑L1 expression ≥1 for coverage (e.g., Yervoy for ESCC; Opdivo and Opdivo Qvantig for gastric/GEJ and esophageal adenocarcinoma; Opdivo Qvantig for first‑line ESCC).PD‑L1 ≥1 (where specified)
Changes effective with provider notification periods noted in history entries.
Age and weight limits: Tecentriq Hybreza coverage for ASPS updated to individuals aged ≥12 years who weigh at least 40 kg.age ≥12 and weight ≥40 kg
Effective dates and revisions documented in history.
Alaska exception: Site‑of‑Service Medical Necessity criteria does not apply to Alaska fully‑insured members per Alaska HB 226; only infusion drug Medical Necessity criteria applies.
Per Alaska HB 226, the Site-of-Service (SOS) Medical Necessity criteria described in this policy does not apply to Alaska fully‑insured members. For those members, only the standard infusion and injection drug medical necessity criteria apply; SOS review requirements and potential site-based denials outlined for other members are not used for Alaska fully‑insured members.
All uses of the listed agents that are not explicitly enumerated in this policy are considered investigational. The list of agents includes (but is not limited to) Bavencio, Imfinzi, Imjudo, Jemperli, Keytruda, Keytruda Qlex, Libtayo, Loqtorzi, Opdivo, Opdivo Qvantig, Opdualag, Tecentriq, Tecentriq Hybreza, Tevimbra, Unloxcyt, Yervoy, and Zynyz; requests for indications or regimens not specified in the policy may be denied as investigational.
Uses or indications for the immune checkpoint inhibitors named in this policy that are not listed in the coverage criteria are considered investigational. Providers should document that the requested use matches one of the policy's enumerated, indication‑specific criteria; otherwise the request will be evaluated as investigational per policy language.
Clinical trials cited in this policy commonly excluded individuals with active or prior autoimmune or inflammatory disorders and those who received systemic immunosuppressive medications shortly before enrollment (for example, durvalumab trials excluded those who used immunosuppressants within 14 days; dostarlimab trials excluded individuals requiring systemic immunosuppression within 2 years). These trial eligibility criteria reflect contexts in which immune checkpoint therapy may be inappropriate or require heightened caution when assessing coverage.
Over multiple annual updates the policy removed coverage for several FDA indications that were withdrawn or subsequently found to lack efficacy in confirmatory trials. Examples in the policy history include removal of Keytruda for small cell lung cancer and removal of certain Tecentriq and Imfinzi urothelial carcinoma indications after withdrawal for lack of efficacy. The policy aligns coverage with current FDA‑approved indications and deletes coverage where indications have been withdrawn.
Specific examples where coverage was removed or changed in the history include Keytruda's small cell lung cancer indication removed after follow‑up trials failed to confirm benefit, and withdrawal of certain Tecentriq and Imfinzi urothelial carcinoma indications leading to removal from coverage. Refer to the policy history entries for dates and affected indications.
Coverage for Tecentriq (atezolizumab) for locally advanced or metastatic urothelial carcinoma was removed from the policy following FDA withdrawal of that indication. The history notes this removal and records the change in coverage status concurrent with prescribing‑information updates.
Hospital‑based outpatient settings are considered medically necessary for infusion or injectable therapy only when the policy's site‑of‑service criteria are met. Examples where the hospital outpatient site is appropriate include the initial 90 days of an infusion course or re‑initiation after a treatment gap of ≥6 months, when there is no outpatient infusion center within 50 miles and no contracted home infusion service available, or when the individual has clinical conditions that increase the risk of complications (e.g., unstable cardiac or pulmonary disease, unstable renal function, difficult vascular access, severe prior anaphylaxis). When the SOS criteria are not met, hospital outpatient administration is considered not medically necessary.
Immune checkpoint inhibitors can cause immune‑mediated adverse events (irAEs) such as pneumonitis, colitis, hepatitis, nephritis, and endocrine disorders; serious immune‑mediated reactions occurred in clinical trials and may require corticosteroids, treatment delays, or discontinuation. These safety concerns and labeled warnings are referenced in the policy and should be considered when assessing eligibility and monitoring requirements for therapy.
Several indications were withdrawn from FDA approval or removed due to lack of efficacy and are no longer covered. The policy history documents these removals, including Keytruda for certain small cell lung cancer uses and durvalumab/Tecentriq urothelial carcinoma indications withdrawn after negative follow‑up data; such withdrawn indications are treated as not medically necessary in the policy.
Additional examples documented in the policy history include removal or modification of coverage for some Tecentriq indications (including certain urothelial carcinoma and TNBC uses) and edits to Keytruda and Opdivo indications as FDA labeling changed. The history entries list the affected agents, dates, and rationale (e.g., withdrawal or lack of confirmatory benefit).
Opdivo (nivolumab) coverage was removed for certain hepatocellular carcinoma indications previously treated with sorafenib following FDA withdrawal of those indications. The policy history notes the removal and associated coding updates tied to that change.
HCPCS, Dosing, and Coding References
Listed immune checkpoint inhibitors and formulationsmixed
pembrolizumab
Keytruda (and Keytruda Qlex)
durvalumab
Imfinzi
dostarlimab-gxly
Jemperli
nivolumab
Opdivo (including Opdivo Qvantig combination)
atezolizumab
Tecentriq (including Hybreza)
tremelimumab-actl
Imjudo
ipilimumab
Yervoy
cemiplimab
Libtayo
pembrolizumab+berahyaluronidase
Keytruda Qlex
HCPCS (part 1)HCPCS
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)
HCPCS (part 2)HCPCS
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
J9272
Injection, dostarlimab-gxly (Jemperli), 10 mg
J9275
Injection, cosibelimab-ipdl (Unloxcyt), 2 mg (new code effective 07/01/25)
J9289
Injection, nivolumab, 2 mg and hyaluronidase-nvhy (Opdivo Qvantig) (new code effective 07/01/25)
J9298
Injection, nivolumab and relatlimab-rmbw (Opdualag), 3 mg/1 mg
J9299
Injection, nivolumab (Opdivo), 1 mg
J9329
Injection, tislelizumab-jsgr (Tevimbra), 1mg
1–10 of 13
1/2
Documented trial dosing (atezolizumab)mixed
1200 mg every 3 weeks
Atezolizumab intravenous dosing used in trials
Documented trial dosing (nivolumab)mixed
3 mg/kg q2w
Nivolumab dosing in CheckMate-372
Pediatric dosing (atezolizumab)mixed
15 mg/kg q21d (pediatric max 1200 mg)
Atezolizumab pediatric dosing used in ASPS study
Policy historical HCPCS/Coding changesHCPCS
J9173
HCPCS code added for Tecentriq (as noted in historical updates)
J9023
HCPCS code added (referenced in history)
J9119
HCPCS code added (referenced in history)
J3590
HCPCS code used to report Imjudo; included/removed in history at points
J9272
HCPCS code added (referenced in history)
C9082
HCPCS code added/removed in history
C9147
HCPCS coding update added April 2023
HCPCS code changes and additionsHCPCS
J9298
HCPCS code added (documented)
J9272
HCPCS code with new effective date removed/changed (documented)
J3590
Added to report Imjudo and later for Keytruda Qlex
C9147
Termed/deleted HCPCS code (documented)
J9347
New HCPCS code added
J9345
New HCPCS code added
J9258
New HCPCS code added
J3263
New HCPCS code added effective 7/1/2024
J9329
New HCPCS code added effective 10/1/2024 for Tevimbra
C9399
Unlisted HCPCS added for Tecentriq Hybreza
1–10 of 14
1/2
PD-L1 expression thresholds
PD-L1 thresholds (tumor proportion)Tumor Proportion Score (TPS) ≥ 1% for many NSCLC and other indications
PD-L1 thresholds (combined)Combined Positive Score (CPS) ≥ 10 for selected indications (e.g., some TNBC and urothelial contexts)
Alternative PD-L1 cutoffsSome indications use CPS ≥ 1 or other trial-specified cutoffs; confirm indication-specific PD-L1 metric and threshold
Tumor mutational burden
TMB-H operational definitionTumor mutational burden–high defined as at least 10 mutations per megabase (mut/Mb)
Prior Authorization, Documentation, and Site-of-Service Actions
Prior Authorization
Medical necessity and site-of-service review
Site of Service (SOS) Medical Necessity and Prior Authorization: Site-of-service review applies to medical benefit administration of IV and injectable immune checkpoint inhibitors for all ages and to the site of service for individuals aged 13 and older. SOS review does NOT apply to Alaska fully-insured members (refer to infusion/injection drug criteria). The following agents are subject to site-of-service review except when administered concurrently with other infusion or injection cancer medications: Keytruda (pembrolizumab) IV, Imfinzi (durvalumab) IV, Jemperli (dostarlimab-gxly) IV, Opdivo (nivolumab) IV, Opdivo Qvantig (nivolumab and hyaluronidase-nvhy) SC, Tecentriq (atezolizumab) IV, Tecentriq Hybreza (atezolizumab-hyaluronidase-tqjs) SC, and other listed agents added in policy updates (e.g., Imfinzi, Jemperli, Opdivo Qvantig, Tecentriq, Tecentriq Hybreza). Reviewers will determine the medically necessary and most appropriate, safe, and cost-effective site: physician office, infusion center, home infusion, or hospital-based outpatient setting. Hospital-based outpatient setting may be considered medically necessary for the first 90 days for initial courses or for re-initiation after ≥6 months. Site-of-service exceptions exist for certain individuals receiving treatment for cytokine release syndrome (CRS).
Site-of-service review applies to medical benefit IV/injectable drugs; SOS review for ages ≥13
SOS review does not apply to Alaska fully-insured members
SOS not required when drug is given concurrently with other infusion/injection cancer medications
Background and Clinical Context
Immune checkpoint inhibitors are systemic immunotherapies that block tumor immune‑evasion pathways (for example, PD‑1/PD‑L1 and CTLA‑4) to restore T‑cell‑mediated antitumor activity. These agents are typically large monoclonal antibodies administered intravenously, with some subcutaneous formulations now available; they carry class‑specific risks of immune‑mediated adverse events and require indication‑specific biomarker and prior‑therapy assessments as described in the policy.
Definitions and Key Terms
Site of service (SOS) definition
DefinitionSite of service (SOS) is the location where the drug is administered (eg, hospital-based outpatient, infusion center, physician's office, or at home)
SOS medical necessity scopeSOS Medical Necessity criteria applies only to medical benefit reviews and to individuals aged 13 years and older (Alaska fully‑insured exception applies)
Preferred sitesPhysician office, infusion center, or home infusion are preferred medically necessary sites; hospital‑based outpatient setting reserved for specific criteria
Distance/time criteriaHospital‑based outpatient may be necessary when no outpatient infusion center or contracted home infusion agency will travel within 50 miles
Cytokine Release Syndrome (CRS) grade 3 or 4 definition
Grade 3–4 CRS criteria
Policy Summary
PayerPremera Bluecross
PolicyImmune Checkpoint Inhibitors
Policy CodePolicy N/A
Change TypeMultiple additions, removals, and updates to indications and site-of-service reviews
Effective DateMar. 1, 2026
Next Review DateN/A
Key ActionSubmit prior authorization and site-of-service documentation for IV or injectable immune checkpoint inhibitors for individuals aged 13 and older; follow required biomarker and clinical documentation per indication.
Treatment regimens and dosing per prescribing information.
Keytruda (pembrolizumab) and Keytruda Qlex: May be considered medically necessary for numerous indications (melanoma, NSCLC across settings with PD‑L1 criteria, HNSCC, cHL, PMBCL, urothelial cancer, gastric/GEJ, cervical, HCC, Merkel cell carcinoma, RCC, endometrial carcinoma including with lenvatinib, TMB‑H ≥10 mut/Mb tumors, TNBC with CPS thresholds, biliary tract cancer, and others). Keytruda Qlex requires FDA‑approved testing (PD‑L1, EGFR/ALK/ROS1, or TMB) before coverage determination and is not approved for some Keytruda indications (e.g., cHL, PMBCL).PD‑L1 TPS/CPS thresholds; TMB‑H ≥10 mut/Mb
Tecentriq (atezolizumab) and related formulations: Multiple PD‑L1/PD‑1 inhibitors have indication‑specific criteria; many require combinations with chemotherapy or targeted agents per indication (e.g., Tecentriq Hybreza SC for NSCLC indications, Tecentriq IV for adult‑only HCC).
Tecentriq Hybreza has age/weight limits for some pediatric indications.
Opdivo (nivolumab) and formulations: Medically necessary for multiple malignancies including melanoma (adjuvant and unresectable/metastatic), resectable NSCLC in neoadjuvant/adjuvant settings, metastatic NSCLC with PD‑L1 criteria and absence of EGFR/ALK/ROS1, RCC, cHL after HSCT/brentuximab or ≥3 lines, urothelial indications, MSI‑H/dMMR cancers, HCC in combination with Yervoy, and others per drug‑specific sections.
Opdivo Qvantig SC and IV formulations have overlapping but distinct listed indications.
Opdivo + Yervoy combinations: Medically necessary for unresectable/metastatic melanoma, NSCLC first‑line with PD‑L1≥1% without EGFR/ALK/ROS1, malignant pleural mesothelioma, intermediate/poor‑risk RCC, MSI‑H/dMMR colorectal cancer, ESCC, HCC, and other listed indications. Note: Opdivo when used in combination with Yervoy is NOT subject to site‑of‑service review in some contexts.PD‑L1 ≥1% for select NSCLC/ESCC indications
Combination regimens have specific age and prior therapy criteria.
Other PD‑1/PD‑L1 agents: Tevimbra, Loqtorzi, Libtayo, Bavencio, Imfinzi, Tecentriq, Unloxcyt, Zynyz, and others each have enumerated cancer‑specific indications (ESCC, gastric/GEJ, NPC, urothelial carcinoma, MCC, HCC, NSCLC, SCLC, BTC, endometrial carcinoma, ASPS, etc.) with conditions such as age limits, PD‑L1 thresholds, combination regimens, and prior therapy requirements described per agent.
All other uses not listed in policy are investigational.
Some HCC indications limited to adults for certain formulations.
Melanoma: Treatment of BRAF V600 mutation–positive unresectable or metastatic melanoma when used in combination with cobimetinib and vemurafenib (atezolizumab example); multiple agents have melanoma indications detailed in drug sections.
BRAF mutation status referenced for specific combinations.
Unloxcyt (cosibelimab‑ipdl) for cutaneous squamous cell carcinoma: May be considered medically necessary for metastatic or locally advanced cutaneous squamous cell carcinoma when ALL of the following are met: individual is aged ≥18; not a candidate for curative surgery or radiation; has not received prior anti‑PD‑1/PD‑L1 or other immune checkpoint inhibitor; prescribed as monotherapy.
Agent‑specific eligibility criteria must be documented.
Zynyz (retifanlimab‑dlwr): May be considered medically necessary for metastatic/recurrent locally advanced Merkel cell carcinoma (no prior systemic therapy), first‑line inoperable locally recurrent/metastatic SCAC in combination with carboplatin + paclitaxel, and for locally recurrent or metastatic SCAC with progression/intolerance to platinum chemo as single agent.
Pembrolizumab (Keytruda) — multiple indications: KEYNOTE program (multiple randomized and single‑arm trials) demonstrated improvements in ORR, PFS, OS, or disease‑free survival across melanoma, NSCLC, HNSCC, cHL, urothelial carcinoma, MSI‑H/dMMR tumors, and perioperative settings; dose/regimen and prior therapy requirements vary by indication.
Keytruda trial results cited include KEYNOTE‑006, KEYNOTE‑024, KEYNOTE‑087, KEYNOTE‑052, etc.
Loqtorzi (toripalimab) — JUPITER‑02: JUPITER‑02 Phase 3: Loqtorzi + chemo reduced progression/death by 48% and reduced risk of death by 37% vs chemo; higher rates of irAEs and treatment discontinuation observed.
Significant Grade ≥3 irAEs increase noted.
Nivolumab (Opdivo) — melanoma and safety: Accelerated approval based on response rate and durability in unresectable/metastatic melanoma trials (CheckMate data); immune‑mediated adverse events include pneumonitis, colitis, hepatitis, nephritis, and endocrinopathies; discontinuation in 9%, serious adverse reactions in 41% in cited data.
Responses observed irrespective of BRAF mutation status in cited trials.
Trial‑specified PD‑L1 cutpoints referenced in Tecentriq and other agents.
Site‑of‑service review additions noted for several drugs effective Oct 3, 2025 and other dates.
Tecentriq (atezolizumab) & Tecentriq Hybreza: Tecentriq Hybreza (SC) product added; age/weight criteria for ASPS updated to include individuals aged ≥12 years and weighing ≥40 kg; Tecentriq IV HCC use limited to adults.age ≥12 yrs and weight ≥40 kg for Hybreza in ASPS
Administration time differs (IV 30–60 min vs SC ~7 min).
Tevimbra (tislelizumab-jsgr): Coverage criteria added for first‑line treatment of unresectable/metastatic HER2‑negative gastric/GEJ adenocarcinoma with PD‑L1 ≥1 in combination with platinum and fluoropyrimidine chemotherapy and expanded uses per prescribing information.PD‑L1 ≥1 for gastric/GEJ first‑line
Refer to prescribing information for regimen specifics and effective dates.
Policy text and history clarify applicability.
CRS exception: An exception to site‑of‑service requirements exists for certain individuals receiving treatment for cytokine release syndrome (CRS) when inpatient admission is expected.CRS grade 3 or 4 criteria apply
Documented in policy and history.
FDA label alignment: Medications listed are subject to FDA dosage and administration; coverage criteria were updated to align with FDA‑approved indications and to remove indications withdrawn by FDA where applicable.
History documents multiple additions/removals and HCPCS code changes across 2018–2026.
Use contextTMB-H requirement applies for certain indications (e.g., adult and pediatric individuals aged ≥12 or ≥18 with TMB-H solid tumors) before coverage determination
Testing requirementFDA‑approved testing confirming TMB-H is required prior to coverage determination in relevant indications
TMB-H threshold
Numeric thresholdTMB‑H defined as at least 10 mutations per megabase (mut/Mb)
NotationExpressed as mut/Mb (mutations per megabase)
Indication linkageApplied where specific agent indications require TMB-H for eligibility (see agent criteria)
Hospital outpatient considered necessary for first 90 days for initial therapy or re-initiation after ≥6 months
Exception for CRS patients
Prior Authorization
Authorization length and re-authorization
Providers must obtain prior authorization when required by the plan. Initial and re-authorization lengths: non-formulary exception reviews may be approved up to 12 months. All other initial and re-authorization approvals may be approved up to 12 months when drug-specific coverage criteria are met and documentation shows continued clinical benefit.
Non-formulary exception approvals: up to 12 months
All other authorizations and re-authorizations: up to 12 months if criteria and clinical response documented
Documentation Required
Required clinical documentation
Required documentation for all reviews: submit office visit notes documenting diagnosis, relevant history, physical exam, medication history, histologic confirmation when applicable, prior treatment history (including prior targeted therapies when required by indication), PD-L1 or other FDA-approved biomarker test results when indicated, and notes documenting clinical response for re-authorization. For agents and indications that require specific companion diagnostic testing (e.g., PD-L1, EGFR/ALK/ROS1, BRAF, MSI-H/dMMR, TMB-H), include FDA-approved test results per General Medical Necessity Criteria for Companion Diagnostics.
Office visit notes with diagnosis, history, exam, medication list
Histologic confirmation and prior treatment history
Documentation of required biomarker testing (FDA-approved assay and result) when indicated
PD-L1 testing documentation when required (e.g., VENTANA SP142 or other FDA-approved assay)
Document prior targeted therapy for genomic tumor aberrations when policy requires
Prior Authorization
Indication- and prior-treatment-based prior authorization
Prior-treatment and indication-based requirements: some indications require prior exposure or progression on FDA-approved targeted therapies for specific genomic aberrations (e.g., EGFR, ALK/ROS1) before immune checkpoint inhibitor coverage. Combination regimen requirements must be documented when therapy is prescribed as part of a combination (for example, Opdivo + Yervoy; durvalumab + Imjudo; pembrolizumab with chemotherapy or enfortumab vedotin where indicated).
Document prior FDA-approved therapy for genomic aberrations before coverage if the policy lists this prerequisite
Document combination regimen components and indication-specific sequencing
Denial Risk
Investigational uses and prescribing information
Investigational or off-label uses not listed in this policy are considered investigational and may be denied. Follow the product's FDA prescribing information for dosing and administration; coverage is tied to FDA-labeled indications and policy criteria. Site-of-service review may affect the authorization decision.
Uses not listed in policy = investigational (denial risk)
Follow FDA prescribing information for dosing/documentation
Site-of-service review outcome may change authorization
Billing Rule
Billing/coding reminders
Provider billing and coding notes: use updated HCPCS and J-codes per policy history (e.g., J9024, J9329, J9329 additions, and removal of J9258; unlisted HCPCS codes C9399 and J9999 added for Tecentriq Hybreza). Verify current coding effective dates when submitting claims.
Confirm HCPCS/J-code changes (historic and effective dates) before billing
Use unlisted codes added for Tecentriq Hybreza where applicable
CRS grade 3 or 4: temperature ≥ 38 °C; hypotension requiring one or more vasopressors; and hypoxia requiring high‑flow oxygen or positive pressure support (eg, CPAP, BiPAP, intubation, or mechanical ventilation)
Admission conditionHospital‑based outpatient setting is considered medically necessary when grade 3 or 4 CRS is present AND the individual will be admitted inpatient as soon as possible
Examples of hypoxia supportHigh‑flow nasal cannula, face mask, non‑rebreather, Venturi mask, CPAP, BiPAP, intubation, mechanical ventilation
MSI-H / dMMR definition
DefinitionMSI‑H (microsatellite instability‑high) or dMMR (mismatch repair deficient) status denotes tumors with high microsatellite instability or deficient mismatch repair and is required for coverage of certain indications
Age scopeApplies in adult and pediatric individuals (eg, ≥12 years) for some agent indications requiring MSI‑H/dMMR
Indication examplesRequired for coverage in select endometrial, colorectal, and other solid tumor indications as specified in agent criteria
TMB-H definition
DefinitionTMB‑H (tumor mutational burden‑high) indicates tumors with a high number of somatic mutations; for policy purposes defined as ≥10 mutations/megabase (mut/Mb)
Coverage useTMB‑H status is required for eligibility in specified solid tumor indications that progressed after prior treatment and lack satisfactory alternatives
TestingFDA‑approved testing confirming TMB‑H is required before coverage determination in relevant indications
PD-1 definition
PD‑1 (protein)Programmed Cell Death Protein 1 (PD‑1, CD279) is a cell‑surface protein that down‑regulates immune responses by promoting apoptosis of antigen‑specific T cells and reducing apoptosis in regulatory T cells
Clinical relevancePD‑1 is an immune checkpoint targeted by multiple systemic cancer immunotherapies to enhance antitumor T‑cell activity
PD-L1 definition
PD‑L1 (protein)Programmed Death‑Ligand 1 (PD‑L1, CD274) is a transmembrane protein that suppresses immune responses by binding PD‑1 and B7.1, inhibiting antigen‑specific T‑cell proliferation and affecting regulatory T‑cell survival
Clinical roleTumor PD‑L1 expression is used as a biomarker for eligibility in multiple agent‑ and indication‑specific coverage criteria
Yervoy (ipilimumab) description
Agent class and actionYervoy (ipilimumab) is a human CTLA‑4–blocking monoclonal antibody that augments T‑cell activation and proliferation by blocking CTLA‑4 interaction with CD80/CD86
Immunologic effectBlockade of CTLA‑4 can reduce regulatory T‑cell function and increase antitumor T‑cell responsiveness
Zynyz (retifanlimab-dlwr) description
Agent class and actionZynyz (retifanlimab‑dlwr) is a programmed death receptor‑1 (PD‑1) blocking antibody that binds PD‑1 and blocks interaction with PD‑L1 and PD‑L2
Indication contextUsed for indications such as metastatic/recurrent Merkel cell carcinoma and other PD‑1–sensitive tumors per prescribing information
Immune-related adverse events (irAEs) examples
Common irAEsImmune‑related adverse events include pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, and endocrinopathies (eg, hyper‑ or hypothyroidism)
Management implicationsirAEs may require corticosteroids, treatment delays, or drug discontinuation; serious adverse reactions reported in trials (eg, nivolumab)
Incidence examplesNivolumab trials reported discontinuation for adverse reactions in ~9% and serious adverse reactions in ~41% of individuals
Site of Service Medical Necessity definition
DefinitionSite of Service Medical Necessity is a review process added to evaluate the appropriateness of the care location for administration of IV or injectable immune checkpoint inhibitors and may affect authorization
ApplicabilityApplies to medical benefit reviews for individuals aged 13 years and older; does not apply to Alaska fully‑insured members per Alaska HB 226
Effect on authorizationFailure to meet SOS criteria may render a hospital‑based outpatient site not medically necessary and may trigger denial or different payment considerations