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ModifiedBlue Cross Blue Shield - TennesseePolicy N/A

Pembrolizumab (Keytruda) — Oncology coverage criteria

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Defines covered oncology indications for pembrolizumab (Keytruda) for Blue Cross Blue Shield - Tennessee members when approval criteria are met; applies to providers requesting coverage for listed cancer indications.

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyPembrolizumab (Keytruda) — Oncology coverage criteria

Policy CodePolicy N/A

Change TypeMaterial — authorization criteria and biomarker thresholds added

Effective DateJun 30, 2026

Last ReviewJun 30, 2026

Next Review DateN/A

Key ActionObtain and submit required documentation (e.g., PD-L1, MSI-H/dMMR, or TMB lab reports) to support prior authorization for indicated oncology uses.

SourceLink

POLICY UPDATE CHANGES

Authorization of 6 months may be granted for multiple tumor types and biomarker-defined indications (e.g., MSI-H, dMMR, TMB-H) including specific combinations with chemotherapy or targeted agents.

20+distinct tumor-specific authorization entries

6 monthsstandard initial authorization duration

TMB ≥10TMB-H threshold

TPS ≥1%PD-L1 TPS threshold (selected NSCLC)

Pediatric CNS TMB-Hexplicit exclusion

Coverage Criteria and Indications

Covered Indications (list)

Covered when ALL of the following are met

General coverage requirement: Indication is FDA-approved or supported by compendia and all approval criteria are met

Member must have no exclusions to the prescribed therapy

Covered indications with criteria

Covered when the specific FDA-approved or compendial indication criteria are met; many authorizations are for 6 months where specified.

RCC: Keytruda in combination with lenvatinib or axitinib for first-line advanced renal cell carcinoma; Keytruda as adjuvant treatment for intermediate-high or high risk of recurrence following nephrectomy or nephrectomy plus resection of metastatic lesions

See chunk 18

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyPembrolizumab (Keytruda) — Oncology coverage criteria

Policy CodePolicy N/A

Change TypeMaterial — authorization criteria and biomarker thresholds added

Effective DateJun 30, 2026

Last ReviewJun 30, 2026

Next Review DateN/A

Key ActionObtain and submit required documentation (e.g., PD-L1, MSI-H/dMMR, or TMB lab reports) to support prior authorization for indicated oncology uses.

SourceLink

On This Page

Endometrial carcinoma:

Keytruda with carboplatin and paclitaxel (then single agent), or as single agent for MSI-H/dMMR advanced endometrial carcinoma after progression and not candidate for curative therapy; Keytruda with lenvatinib for pMMR/non–MSI-H after progression

TMB-H tumors: Keytruda for unresectable or metastatic TMB-H (≥10 mut/Mb) solid tumors that progressed following prior treatment and have no satisfactory alternative options (pediatric CNS TMB-H excluded)TMB-H ≥ 10 mut/Mb

See chunks 20 and 21

Cutaneous SCC: Keytruda for recurrent/metastatic or locally advanced cutaneous squamous cell carcinoma not curable by surgery or radiation

See chunk 22

Triple-negative breast cancer: Keytruda for high-risk early-stage TNBC with chemotherapy neoadjuvant then continued adjuvant single-agent; for locally recurrent unresectable/metastatic TNBC with PD-L1 CPS ≥10 in combination with chemotherapyPD-L1 CPS ≥10 for metastatic TNBC

See chunk 23

Classical Hodgkin lymphoma / PMBCL: Additional dosing regimen of 400 mg every 6 weeks indicated for adult classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma

See chunk 23 and 7

Compendial uses: Multiple tumor types listed as compendial uses (e.g., melanoma, head & neck, NSCLC, urothelial carcinoma, etc.) where coverage follows listed authorization guidance

See chunks 2, 29, 33, 34

NSCLC: Authorization may be granted for recurrent/advanced/metastatic NSCLC when there are no EGFR exon 19 or exon 21 L858R mutations or ALK rearrangements and for specified first-line PD-L1 positive disease or combinations with chemotherapy or pemetrexed maintenancePD-L1 TPS ≥1% for certain indications

See chunks 3 and 31

Head and neck cancer: Authorization for resectable stage III–IVa non-nasopharyngeal HNSCC when PD-L1 CPS ≥1 as neoadjuvant→adjuvant with RT ± cisplatin; other advanced HNSCC covered when PD-L1 CPS ≥1, MSI-H/dMMR, or TMB-H, or in combination with cetuximab/chemotherapyPD-L1 CPS ≥1 for certain indications

See chunk 5 and 32

Classic Hodgkin lymphoma regimens: Authorization for relapsed/refractory classic Hodgkin lymphoma as single agent or in combination with GVD, ICE, or decitabine/vorinostat if refractory to ≥3 prior lines

See chunk 33

Urothelial carcinoma: Authorization as single agent or in combination (e.g., with enfortumab vedotin) for various urothelial subtypes and settings including first-line for platinum-ineligible, subsequent therapy, adjuvant therapy, and high-risk BCG-unresponsive NMIBC when cystectomy will not be performed

See chunks 9 and 34

Solid tumors (biomarker-driven): Authorization for unresectable/metastatic solid tumors progressed after prior treatment and no satisfactory alternatives when tumor is TMB-H (≥10 mut/Mb) or MSI-H/dMMRTMB-H ≥ 10 mut/Mb

See chunks 10, 11, 20, 35

Anaplastic thyroid carcinoma: Authorization in combination with lenvatinib for stage IVC anaplastic thyroid carcinoma or as single agent for metastatic anaplastic thyroid carcinoma with TMB-H (≥10 mut/Mb)TMB-H ≥10 mut/Mb for single-agent metastatic use

See chunk 36

Radioiodine-refractory follicular/papillary/onocytic (Hürthle) thyroid carcinoma: Authorization when disease progressed on single-agent lenvatinib and pembrolizumab will be used in combination with lenvatinib; OR when disease is MSI-H, dMMR, or TMB-H (≥10 mut/Mb)TMB-H ≥10 mut/Mb

Progression on lenvatinib required for combination path; see chunks 37 and 38

Anaplastic Thyroid Carcinoma

Covered when ANY of the following are met for anaplastic thyroid carcinoma:

Anaplastic Thyroid Carcinoma: Authorization of 6 months may be granted in combination with lenvatinib for stage IVC anaplastic thyroid carcinoma OR as a single agent for metastatic anaplastic thyroid carcinoma with tumor mutational burden-high (≥ 10 mut/Mb)TMB >= 10 mut/Mb

Combination with lenvatinib for stage IVC; single-agent pathway for TMB-H metastatic disease

Follicular/Papillary/Oncocytic (Hürthle cell) Thyroid Carcinoma

Covered when ALL/ANY (as specified) for follicular, papillary, and oncocytic (Hürthle cell) thyroid carcinoma not amenable to radioactive iodine:

Thyroid carcinoma not amenable to RAI: Authorization of 6 months may be granted when either: member progressed on single-agent lenvatinib and pembrolizumab will be used in combination with lenvatinib; OR disease is MSI-H, dMMR, or TMB-H (≥ 10 mut/Mb)TMB >= 10 mut/Mb

Progression on single-agent lenvatinib required for combination use

Colorectal Cancer / Small Bowel Adenocarcinoma

Covered when biomarker criteria are met:

Colorectal Cancer and Small Bowel Adenocarcinoma: Authorization of 6 months may be granted as single agent for MSI-H or dMMR tumors; for colorectal and small bowel, ultra-hypermutated POLE/POLD1 tumors with TMB > 50 mut/Mb are included (includes appendiceal carcinoma)TMB > 50 mut/Mb for ultra-hypermutated

See chunks 39 and 40

Merkel Cell Carcinoma

Merkel Cell Carcinoma: Authorization of 6 months may be granted as a single agent for locally advanced, recurrent or metastatic disease

See chunk 41

Gastric Cancer

Gastric cancer coverage contingent on biomarker status, surgical candidacy, and combination regimens:

Gastric Cancer - unresectable or not surgical candidates: 6-month authorization may be granted when: single-agent subsequent therapy for MSI-H/dMMR/TMB-H (≥10 mut/Mb); or first-line single agent or with chemotherapy for MSI-H/dMMR; or in combination with trastuzumab and chemotherapy for HER2+ with PD-L1 CPS ≥1; or with chemotherapy first-line for HER2-negative with PD-L1 CPS ≥1TMB >= 10 mut/Mb; PD-L1 CPS ≥1 for specified contexts

Separate criteria for medically fit for surgery and surgically unresectable locoregional disease (see chunks 42–43)

Esophageal and EGJ Cancer

Esophageal and esophagogastric junction (EGJ) cancer coverage:

Esophageal / EGJ Cancer: 6-month authorization may be granted as single agent for MSI-H/dMMR tumors or in combination with platinum+fluoropyrimidine chemotherapy for PD-L1 CPS ≥1 in surgical candidates; includes first-line and subsequent therapy options such as single-agent for squamous histology with CPS ≥10PD-L1 CPS ≥1 or CPS ≥10 for specific histologies; TMB ≥10 mut/Mb for some indications

See chunk 44 for histology- and CPS-specific details

Cervical Cancer

Cervical Cancer: 6-month authorization may be granted for recurrent/metastatic disease as single agent or with tisotumab vedotin if tumors express PD-L1 (CPS ≥1) or are MSI-H/dMMR; or with chemotherapy ± bevacizumab if PD-L1 CPS ≥1; or FIGO stage III–IVA with chemoradiationPD-L1 CPS ≥1

See chunk 45

Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer and related

Epithelial ovarian & related gynecologic tumors: 6-month authorization may be granted as single agent for recurrent/persistent MSI-H/dMMR or TMB-H (≥10 mut/Mb) tumors across multiple histologies; and in combination with oral cyclophosphamide and bevacizumab for recurrent/persistent diseaseTMB >= 10 mut/Mb

See chunk 47 for listed histologies

Uveal Melanoma

Uveal Melanoma: 6-month authorization may be granted as a single agent for unresectable or metastatic disease

See chunk 48

Testicular Cancer

Testicular Cancer (third-line): 6-month authorization may be granted as a single agent for third-line treatment in members with MSI-H, dMMR, or TMB-H (≥10 mut/Mb)TMB >= 10 mut/Mb

Third-line specified; see chunk 49

Endometrial Carcinoma

Endometrial Carcinoma: 6-month authorization may be granted in combination with lenvatinib for advanced/metastatic/recurrent disease when either the disease is pMMR OR dMMR with progression following prior platinum chemotherapy; also with carboplatin/paclitaxel then single-agent maintenance for stage III–IV or recurrent disease; or as single agent for recurrent unresectable/metastatic MSI-H/dMMR/TMB-H (≥10 mut/Mb)TMB >= 10 mut/Mb

See chunk 50

Anal Carcinoma

Anal Carcinoma: 6-month authorization may be granted as a single agent for subsequent treatment of metastatic anal carcinoma

See chunk 51

CNS Brain Metastases

CNS Brain Metastases: 6-month authorization may be granted as a single agent for treatment of CNS brain metastases in members with melanoma or PD-L1 positive NSCLCPD-L1 positive unspecified threshold

See chunk 52

Primary Mediastinal Large B-Cell Lymphoma

Primary Mediastinal Large B-Cell Lymphoma: 6-month authorization may be granted as a single agent or in combination with brentuximab vedotin for relapsed or refractory disease

See chunk 53

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma: 6-month authorization may be granted as a single agent for recurrent, locally advanced or metastatic pancreatic adenocarcinoma with MSI-H, dMMR, or TMB-H (≥10 mut/Mb)TMB >= 10 mut/Mb

See chunk 54

Biliary Tract Cancers

Biliary Tract Cancers: 6-month authorization may be granted as a single agent for unresectable or metastatic biliary tract cancers that are MSI-H, dMMR, or TMB-H (≥10 mut/Mb); or in combination with gemcitabine and cisplatin or carboplatin; or for neoadjuvant treatment of resectable locoregionally advanced gallbladder cancer with cisplatin+gemcitabine or as single agent for MSI-H/dMMRTMB >= 10 mut/Mb

See chunk 55

Tumor-agnostic biomarker indications

Authorization of 6 months may be granted when specific cancer-type and biomarker or therapy-context criteria are met.

Tumor-agnostic biomarker-driven single-agent use: Single-agent use for recurrent/locally advanced/metastatic disease in members with MSI-H, dMMR, or TMB-H (≥10 mut/Mb)TMB ≥ 10 mut/Mb

Tumor-agnostic single-agent pathway; see chunk 54

Biliary tract cancers

Unresectable or metastatic biliary tract cancer: Single-agent authorization when tumor is MSI-H, dMMR, or TMB-H (≥10 mut/Mb); or in combination with gemcitabine + cisplatin or carboplatin for unresectable/R2/metastatic disease

See chunk 55

Neoadjuvant for resectable locoregionally advanced gallbladder cancer: Use with cisplatin + gemcitabine OR single-agent when tumor is MSI-H/dMMR

See chunk 55

Hepatocellular carcinoma

Unresectable or extrahepatic/metastatic HCC: Single-agent use in unresectable or extrahepatic/metastatic disease

See chunk 56

HCC with hepatitis B: Member with disease secondary to hepatitis B who received prior systemic therapy other than a PD-1/PD-L1-containing regimen and will use single-agent

See chunk 56

Vulvar cancer

Advanced/recurrent/metastatic vulvar cancer: Single agent or in combination with chemotherapy with or without bevacizumab for advanced, recurrent, or metastatic disease

See chunk 57

Renal cell carcinoma

RCC combination therapy: Subsequent or first-line treatment in combination with axitinib or lenvatinib for relapsed or stage IV disease (clear cell histology)

See chunk 58

Non-clear cell RCC: Single-agent use for relapsed or stage IV non-clear cell histology

See chunk 58

Adjuvant RCC: Single-agent adjuvant treatment for intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions

See chunk 18 and 58

Thymic carcinoma

Thymic carcinoma: Single-agent use for recurrent, unresectable, advanced, or metastatic disease, or pre/postoperative therapy in members who cannot tolerate first-line combination regimens

See chunk 59

Primary cutaneous lymphomas

Cutaneous lymphoma indications: Single-agent use for relapsed/refractory anaplastic large cell lymphoma (ALCL) or for mycosis fungoides/Sezary syndrome

See chunk 60

Extranodal NK/T-cell lymphoma

Relapsed/refractory ENKTL: Single-agent use for relapsed or refractory disease

See chunk 61

Gestational trophoblastic neoplasia

Chemotherapy-resistant GTN: Single-agent use for multi-agent chemotherapy-resistant disease when member has high-risk disease OR recurrent/progressive intermediate trophoblastic tumor (placental site or epithelioid)

See chunk 62

Neuroendocrine and adrenal tumors

Unresectable/locally advanced/metastatic NET/adrenal tumors: Authorization for treatment of unresectable, locally advanced or metastatic neuroendocrine and adrenal tumors

See chunk 63

Cutaneous squamous cell carcinoma

Locally advanced/recurrent/metastatic cSCC: Single-agent use for locally advanced, recurrent or metastatic cutaneous squamous cell carcinoma not curable by surgery or radiation

See chunk 64

Soft tissue sarcoma

STS specific histologies: Single-agent use for cutaneous angiosarcoma or dedifferentiated liposarcoma; single-agent or combined with axitinib for alveolar soft part sarcoma; single-agent for subsequent treatment of various sarcoma sites including rhabdomyosarcoma

See chunk 65

Occult primary cancer

Occult primary with biomarkers: Single-agent use for occult primary cancer in members with MSI-H, dMMR, or TMB-H (≥10 mut/Mb)TMB ≥ 10 mut/Mb

See chunk 66

Triple-negative breast cancer

Breast cancer (triple-negative)

TNBC with no response to preop therapy or recurrent/metastatic TNBC: Diagnosis must be triple-negative (ER-, PR-, HER2-); tumor must express PD-L1; agent may be single-agent or with chemotherapyPD-L1 required where specified

See chunk 67 for receptor testing documentation requirements

Locally advanced or high-risk TNBC (neoadjuvant/adjuvant): TNBC confirmed as ER-, PR-, HER2-; continued adjuvant single-agent use after surgery OR neoadjuvant use in combination with chemotherapy

See chunk 67

Prostate cancer

Castration-resistant metastatic prostate cancer: Single-agent subsequent therapy for castration-resistant distant metastatic prostate cancer in members with MSI-H, dMMR, or TMB ≥10 mut/Mb tumorsTMB ≥ 10 mut/Mb

See chunk 68

Small cell lung cancer

Relapsed/progressive SCLC: Single-agent subsequent therapy for relapsed or progressive disease

See chunk 69

Pediatric diffuse high-grade gliomas

Pediatric hypermutant diffuse HGG: Adjuvant treatment for hypermutant tumor pediatric diffuse high-grade glioma or for recurrent/progressive disease

See chunk 70

Ampullary adenocarcinoma

Ampullary adenocarcinoma with biomarkers: Single-agent use for MSI-H, dMMR, or TMB-H (≥10 mut/Mb) ampullary adenocarcinomaTMB ≥ 10 mut/Mb

See chunk 71

Kaposi sarcoma

Relapsed/refractory Kaposi sarcoma: Single-agent subsequent treatment for relapsed/refractory Kaposi Sarcoma

See chunk 72

Vaginal cancer

Vaginal cancer PD-L1 or biomarker-positive: Single-agent subsequent treatment for recurrent or metastatic PD-L1 positive disease OR MSI-H/dMMR tumors; combination with cisplatin/carboplatin + paclitaxel ± bevacizumab for recurrent/metastatic disease; subsequent treatment for unresectable/metastatic TMB-H (≥10 mut/Mb)TMB ≥ 10 mut/Mb

See chunk 73

Vaginal cancer

Covered when ANY of the following are met for vaginal cancer (authorization of 6 months):

Vaginal cancer coverage options: (1) Single-agent subsequent treatment for recurrent/metastatic disease that is PD-L1 positive or MSI-H/dMMR; (2) combination with cisplatin or carboplatin, paclitaxel, with or without bevacizumab for recurrent/metastatic disease; (3) subsequent treatment for unresectable/metastatic TMB-H (≥10 mut/Mb) tumors.

See chunk 73

Pleural or peritoneal mesothelioma

Covered when ALL of the following are met for pleural or peritoneal mesothelioma:

Mesothelioma first-line: Pembrolizumab used in combination with pemetrexed and platinum chemotherapy for first-line treatment of pleural or peritoneal mesothelioma (including pericardial and tunica vaginalis testis subtypes)

Authorization 6 months; see chunk 74

Histologic (Richter) transformation to DLBCL

Covered when ALL of the following are met for Histologic (Richter) transformation:

Richter transformation: Pembrolizumab as single agent or in combination with ibrutinib for treatment of Richter transformation to diffuse large B-cell lymphoma

Authorization 6 months; see chunk 75

Penile cancer

Covered when ANY of the following are met for penile cancer:

Penile cancer coverage options: (1) Single-agent subsequent therapy for unresectable/metastatic MSI-H, dMMR, or TMB-H (≥10 mut/Mb) tumors; (2) combination with fluorouracil and cisplatin or carboplatin followed by single-agent maintenance for recurrent/metastatic diseaseTMB ≥ 10 mut/Mb

Authorization 6 months; see chunk 76

Adjuvant and continued treatment

Reauthorization/continued treatment covered when ALL of the following are met for adjuvant or other listed indications:

Adjuvant continuation: Authorization of 6 months (up to specified total durations) may be granted for continued adjuvant treatment of cutaneous melanoma, HNSCC, TNBC, RCC, or NSCLC in members without disease recurrence or unacceptable toxicity; some indications allow up to 12 months total and others up to 24 months continuous use

See chunks 77–78 for details

Urothelial carcinoma

Covered when BOTH of the following are met for urothelial carcinoma reauthorization (up to 24 months):

Urothelial carcinoma reauthorization: (1) Requested medication used in combination with enfortumab vedotin-ejfv with no disease progression or unacceptable toxicity; (2) for high-risk BCG-unresponsive NMIBC only: disease is not persistent or recurrent

Authorization of 6 months; may be up to 24 months continuous use; see chunk 79

All other listed indications - continued treatment

Covered for continued treatment when ALL of the following are met for other listed indications:

Other indications continued treatment: Authorization of 6 months may be granted for continued treatment in members requesting reauthorization for an indication listed in the coverage criteria who have not experienced disease progression or an unacceptable toxicity

See chunk 80

Per the policy Keytruda is not recommended for patients with primary mediastinal large B‑cell lymphoma (PMBCL) who require urgent cytoreductive therapy. Providers should consider alternative urgent cytoreductive approaches in this clinical scenario rather than initiating pembrolizumab.

The policy explicitly excludes pediatric members with TMB‑H central nervous system cancers because safety and effectiveness have not been established in that population. Additionally, coverage is not provided for members who experienced disease progression while on a PD‑1/PD‑L1 inhibitor, except where specific subsequent‑therapy exceptions are listed (for example, certain melanoma combinations). Ensure documentation demonstrates the member does not meet these exclusions before requesting authorization.

Authorization for colorectal cancer is limited to tumors meeting the listed biomarker criteria (for example, MSI‑H/dMMR or ultra‑hypermutated POLE/POLD1 tumors with TMB > 50 mut/Mb). Requests for colorectal cancer that do not meet these biomarker requirements (e.g., non‑MSI‑H/dMMR and non‑ultra‑hypermutated POLE/POLD1 tumors) are not supported by the policy and therefore are not authorized under the colorectal cancer entry.

Coverage for cutaneous squamous cell carcinoma (cSCC) is limited to locally advanced, recurrent, or metastatic disease that is not curable by surgery or radiation. The policy does not support use of pembrolizumab for cSCC lesions that are amenable to curative surgical resection or radiotherapy.

Requests for continued treatment (reauthorization) will not be approved if the member has experienced disease progression or an unacceptable toxicity on therapy. For indications with specific reauthorization rules (for example, urothelial carcinoma combined with enfortumab vedotin), the policy requires documentation that no progression or unacceptable toxicity has occurred.

Use of pembrolizumab outside the specified biomarker thresholds (for example, PD‑L1 CPS/TPS cutoffs or TMB thresholds) or outside the listed combination/regimen contexts is not supported by the authorization statements in this policy. Prior authorization requires that the indicated biomarker and regimen criteria in the relevant disease section be met.

Medication Dosing, Biomarker Thresholds, and Codes

Medication dosing regimensmixed

200mg every 3 weeks	Pembrolizumab intravenous dosing regimen
400mg every 6 weeks	Pembrolizumab intravenous dosing regimen
2mg/kg every 3 weeks	Pediatric dosing (up to max 200 mg) for selected indications
4mg/kg every 6 weeks	Weight-based dosing option listed for selected indications

Medication dosing regimens (alternate listings)mixed

200mg every 3 weeks	Pembrolizumab intravenous dosing regimen (listed across multiple indications)
400mg every 6 weeks	Pembrolizumab intravenous dosing regimen (listed across multiple indications)
2mg/kg every 3 weeks	Pediatric weight-based dosing (up to a maximum of 200 mg)
4mg/kg every 6 weeks	Weight-based dosing option for selected indications

PD-L1 Tumor Proportion Score (TPS)

Threshold>= 1% (PD-L1 Tumor Proportion Score, TPS)

Test methodAs determined by an FDA‑approved test

Primary useEligibility for selected NSCLC first‑line and subsequent‑line single‑agent indications

PD-L1 Combined Positive Score (CPS)

Common threshold>= 1 (PD-L1 Combined Positive Score, CPS)

Higher threshold for some indicationsCPS >= 10 required for certain squamous esophageal single‑agent settings and for metastatic TNBC

Test methodAs determined by an FDA‑approved test

Tumor Mutational Burden

Threshold≥ 10 mutations/megabase (mut/Mb)

Test methodAs determined by an FDA‑approved test; submit laboratory report confirming TMB where applicable

ScopeUsed for tumor‑agnostic and multiple tumor‑specific indications for unresectable/metastatic solid tumors

PD-L1 Combined Positive Score (TNBC)

ThresholdCPS ≥ 10 (PD‑L1 Combined Positive Score) for metastatic triple‑negative breast cancer

ContextRequired when pembrolizumab is used in combination with chemotherapy for locally recurrent unresectable or metastatic TNBC

DocumentationProvider must document PD‑L1 expression by an FDA‑approved test

PD-L1 thresholds (selected indications)

Typical thresholdsCPS ≥ 1 for many gastric, esophageal, cervical, and HNSCC indications; use PD‑L1 positive/CPS thresholds where specified

Indication examplesGastric/GEJ first‑line (CPS ≥1), esophageal/EGJ (CPS ≥1 or CPS ≥10 for some squamous histologies), HNSCC (CPS ≥1 for selected settings)

Test methodAs determined by an FDA‑approved test; submit PD‑L1 tumor expression documentation where applicable

Tumor mutational burden (TMB)

TMB‑High (TMB‑H)≥ 10 mut/Mb

Ultra‑hypermutated phenotype> 50 mut/Mb (eg, POLE/POLD1 ultra‑hypermutated tumors)

Use casesApplied for colorectal ultra‑hypermutated entries and tumor‑agnostic single‑agent indications

Tumor mutational burden (TMB)

Threshold≥ 10 mut/Mb (TMB‑H)

ApplicabilityUsed for tumor‑agnostic indications and multiple tumor‑specific single‑agent authorizations (e.g., pancreatic, ampullary, occult primary)

DocumentationLab report confirming high TMB must be submitted where applicable

Tumor Mutational Burden

Threshold≥ 10 mut/Mb (TMB‑H)

IndicationsSupported for biliary tract cancers, solid tumors after prior treatment, and other biomarker‑defined settings

ExclusionsPediatric TMB‑H central nervous system cancers excluded from coverage

Prior Authorization, Documentation, and Denial Risks

Prior Authorization

Prior authorization for approved indications — Coverage is provided for FDA-approved indications and compendial uses provided all approval criteria are met and the member has no exclusions to the prescribed therapy.

Coverage is provided for FDA-approved indications and compendial uses when all approval criteria are met and the member has no exclusions to the prescribed therapy. Providers must document indication and confirm absence of exclusion criteria when submitting prior authorization requests.

Prior authorization is required for listed oncology indications; approvals are commonly for 6 months.
Provide documentation supporting FDA-approved indication or compendial use and that all approval criteria are met.

Prior Authorization

Prior authorization required for listed oncology indications — Prior authorization may be granted (commonly for 6 months) for multiple tumor-specific indications including melanoma, NSCLC, head and neck, urothelial, and other solid tumors.

Prior authorization may be granted (commonly for 6 months) for multiple tumor-specific indications including melanoma, NSCLC, head and neck cancers, urothelial carcinoma, and many biomarker-driven solid tumors. Specific tumor and biomarker criteria apply per indication.

Authorization lengths typically 6 months for tumor-specific and biomarker-driven indications.
Requests for biomarker-driven indications must include corresponding lab reports (PD-L1, MSI-H/dMMR, TMB).

Prior Authorization

6-month prior authorization required — Prior authorization for 6 months is required for use across specified tumor types and biomarker-defined indications; approvals typically require documentation of prior therapies and biomarker testing.

Prior authorization for 6 months is required for use across specified tumor types and biomarker-defined indications; approvals typically require documentation of disease status, prior therapies, and relevant biomarker results.

Many indications require absence of specific driver mutations (e.g., EGFR exon 19 deletions/exon 21 L858R or ALK rearrangements in NSCLC) unless testing is not feasible.
For hepatocellular carcinoma, prior systemic therapy other than a PD-1/PD-L1–containing regimen is required for one criterion.

Prior Authorization

6-month authorization for biomarker-driven single-agent use — A 6-month authorization may be granted for indicated single-agent use in MSI-H, dMMR, or TMB-H (≥10 mut/Mb) tumors, depending on cancer type and other criteria.

A 6-month authorization may be granted for indicated single-agent use in MSI-H, dMMR, or TMB-H (≥10 mut/Mb) tumors, depending on cancer type and other criteria.

Submit lab report confirming MSI-H, dMMR, or TMB-H (≥10 mut/Mb) when requesting biomarker-driven single-agent use.

Prior Authorization

6-month authorization for combination therapy — A 6-month authorization may be granted for certain cancers when used in combination with specified chemotherapy regimens or targeted agents.

A 6-month authorization may be granted for certain cancers when used in combination with specified chemotherapy regimens or targeted agents (e.g., combinations with gemcitabine/cisplatin for biliary tract cancers, with lenvatinib for select thyroid cancers).

When seeking combination therapy with lenvatinib for follicular, papillary, or oncocytic (Hürthle cell) thyroid carcinomas, documentation must show the member experienced disease progression on single-agent lenvatinib prior to approval.
For combination regimens, include documentation of prior therapies and rationale for combination use.

Documentation Required

Required documentation for prior authorization — Submit documentation of PD-L1 tumor expression where applicable; lab reports confirming high TMB (≥10 mut/Mb), MSI-H/dMMR, or receptor status where applicable.

Providers must submit specific documentation to initiate prior authorization review. Requests missing required documentation or showing exclusions may be denied.

Documentation of PD-L1 tumor expression where applicable.
Laboratory report confirming high tumor mutational burden (≥10 mut/Mb) where applicable.
Laboratory report confirming MSI-H, dMMR, or POLE/POLD1 tumor status where applicable.
Documentation that the cancer cells are negative for estrogen receptor, progesterone receptor, and HER-2 where applicable to confirm triple-negative breast cancer.
Documentation of presence or absence of EGFR exon 19 deletions/exon 21 L858R mutations or ALK rearrangements where applicable.
For reauthorization requests (e.g., urothelial carcinoma with enfortumab vedotin-ejfv), documentation must show no disease progression and no unacceptable toxicity.

Denial Risk

Prior authorization requirement — Authorization of 6 months may be granted for listed indications; requests failing to meet criteria or with exclusions will be denied.

Coverage is excluded for certain clinical scenarios and progression while on specific therapies. Requests that do not meet approval criteria or that document exclusions may be denied.

Coverage excluded for pediatric members with TMB-H central nervous system cancers.
Coverage excluded for members who progressed while on PD-1 or PD-L1 inhibitor therapy (except where subsequent therapy is explicitly allowed, e.g., metastatic or unresectable melanoma in combination with ipilimumab or lenvatinib).
Requests for continued treatment where the member has experienced disease progression or unacceptable toxicity may be denied.

Documentation Required

TNBC receptor status documentation — Documentation must support receptor-negative status for triple-negative breast cancer (negative for estrogen, progesterone, and HER-2) and PD-L1 status where applicable.

Providers must confirm receptor-negative status when requesting treatment for triple-negative breast cancer (TNBC).

Documentation must support that cancer cells test negative for estrogen receptor, progesterone receptor, and HER-2 to meet TNBC criteria.
Tumor PD-L1 expression must be documented where PD-L1 positivity is required.

Documentation Required

For certain thyroid and oncocytic carcinoma indications, progression on single-agent lenvatinib is required before approval of combination with lenvatinib.

For certain unresectable or metastatic follicular, papillary, and oncocytic (Hürthle cell) thyroid carcinoma indications, approval for combination therapy with lenvatinib requires prior progression on single-agent lenvatinib.

Provide documentation that the member experienced disease progression on single-agent lenvatinib when requesting combination therapy with lenvatinib for anaplastic, follicular, papillary, or oncocytic thyroid carcinomas as applicable.

Permitted Combination Regimens

Regimen	Indication / Setting	Coverage Status
Keytruda + carboplatin + paclitaxel
NSCLC (first-line metastatic squamous) — Keytruda in combination with carboplatin and paclitaxel is FDA-indicated
Keytruda + pemetrexed + platinum chemotherapy
NSCLC (first-line metastatic nonsquamous) — Keytruda in combination with pemetrexed and platinum chemotherapy is FDA-indicated
Keytruda + pemetrexed + platinum
Malignant pleural mesothelioma (first-line) — Keytruda in combination with pemetrexed and platinum chemotherapy is FDA-indicated
Keytruda + trastuzumab + fluoropyrimidine + platinum
HER2‑positive gastric/GEJ adenocarcinoma (first-line) — combination with trastuzumab and chemotherapy for PD‑L1 ≥1 is FDA-indicated
Keytruda + gemcitabine + cisplatin
Biliary tract cancer (locally advanced unresectable or metastatic) — Keytruda in combination with gemcitabine and cisplatin is FDA-indicated
Keytruda + lenvatinib
Renal cell carcinoma (first-line advanced) and advanced endometrial carcinoma (pMMR) — Keytruda in combination with lenvatinib is FDA-indicated
Keytruda + carboplatin + paclitaxel (endometrial sequence)
Endometrial carcinoma (primary advanced/recurrent) — combination with carboplatin and paclitaxel followed by single‑agent Keytruda is FDA‑indicated

Regimen	Indication / Setting	Coverage Status
Keytruda + lenvatinib
RCC (first-line advanced) and endometrial carcinoma (pMMR after prior therapy); anaplastic thyroid (stage IVC in combination) — FDA‑approved combinations
Keytruda + axitinib
Renal cell carcinoma (first-line or subsequent in combination) — FDA‑approved combination
Keytruda + carboplatin + paclitaxel → Keytruda (sequence)
Endometrial carcinoma — combination with carboplatin and paclitaxel followed by single‑agent Keytruda (maintenance) is indicated
Keytruda + pemetrexed ± platinum
NSCLC — first‑line or maintenance settings with pemetrexed (nonsquamous) per FDA‑labeled regimens
Keytruda + cetuximab or chemotherapy
Head and neck squamous cell carcinoma — combinations with cetuximab or chemotherapy where specified in indications

Regimen	Indication / Setting	Coverage Status
Keytruda + lenvatinib
Anaplastic thyroid carcinoma (stage IVC) — combination with lenvatinib; and advanced endometrial carcinoma when pMMR or dMMR with prior platinum progression (endometrial) per FDA labeling/policy

Regimen	Indication / Setting	Coverage Status
Keytruda + platinum + fluoropyrimidine-based chemotherapy
Gastric and esophageal/EGJ cancer (first-line or surgical-candidate settings) — combination with platinum and fluoropyrimidine per PD‑L1 / MSI criteria is indicated
Keytruda + trastuzumab + chemotherapy
HER2+ gastric/GEJ adenocarcinoma — combination with trastuzumab and fluoropyrimidine/platinum chemotherapy for PD‑L1 ≥1 tumors is indicated
Keytruda + gemcitabine + cisplatin or carboplatin
Biliary tract cancers — Keytruda in combination with gemcitabine and cisplatin (or carboplatin) for unresectable/metastatic disease is indicated

Regimen	Indication / Setting	Coverage Status
Keytruda (single‑agent) or Keytruda + oral cyclophosphamide + bevacizumab
Recurrent or persistent epithelial ovarian, fallopian tube, primary peritoneal cancer and related histologies — single‑agent for MSI‑H/dMMR/TMB‑H tumors or in combination with oral cyclophosphamide and bevacizumab for recurrent/persistent disease

Regimen	Indication / Setting	Coverage Status
Gemcitabine + cisplatin or carboplatin; cisplatin or carboplatin + paclitaxel ± bevacizumab (with Keytruda)
Biliary tract cancers — combination with gemcitabine + cisplatin or carboplatin for unresectable/metastatic disease; Vaginal cancer — combination with platinum + paclitaxel ± bevacizumab for recurrent/metastatic disease as specified

Regimen	Indication / Setting	Coverage Status
Keytruda + axitinib
Renal cell carcinoma — in combination with axitinib for first‑line or subsequent therapy of advanced/relapsed/stage IV clear‑cell RCC per FDA‑labeled uses

Regimen	Indication / Setting	Coverage Status
Keytruda + cisplatin/carboplatin + paclitaxel ± bevacizumab
Vaginal cancer — combination with platinum + paclitaxel ± bevacizumab for recurrent/metastatic disease; Mesothelioma — combination with pemetrexed + platinum for first‑line pleural/peritoneal mesothelioma; Penile cancer — combination with fluorouracil + cisplatin/carboplatin followed by maintenance; Urothelial carcinoma reauthorization — combination with enfortumab vedotin‑ejfv per reauthorization criteria

Line of Therapy Guidance

inv-91: mixed

mixed: Authorization of 6 months may be granted for multiple tumor-specific settings including adjuvant, neoadjuvant, first-line, and subsequent therapy per indication-specific language

See chunk 29 and related entries

inv-92: mixed

First-line RCC and NSCLC: First-line combinations for RCC (with lenvatinib or axitinib) and first-line NSCLC for PD-L1 positive disease where specified

See chunks 18 and 31

Adjuvant / neoadjuvant: Adjuvant use in RCC post-nephrectomy for intermediate-high/high risk; neoadjuvant→adjuvant pathways for TNBC, melanoma, NSCLC and select HNSCC described

See chunks 18, 29, 31, 67

Subsequent / later-line: Used as subsequent therapy for progressed metastatic/unresectable disease across multiple tumor types including MSI-H/dMMR/TMB-H biomarker-driven uses

See chunks 35 and related entries

inv-93: salvage

salvage: Third-line single-agent use for testicular cancer with MSI-H, dMMR, or TMB-H tumorsTMB ≥ 10 mut/Mb

See chunk 49

inv-94: first-line

first-line: First-line single agent or in combination with chemotherapy for MSI-H/dMMR tumors or with chemotherapy for PD-L1 CPS ≥1 in gastric and esophageal/EGJ cancersPD-L1 CPS ≥1; TMB ≥10 mut/Mb where specified

See chunks 42 and 44

inv-95: subsequent therapy

subsequent therapy: Authorization for subsequent therapy in relapsed/recurrent or stage IV settings where specified (e.g., RCC combination or SCLC subsequent therapy)

See chunks 58 and 69

inv-96: first-line

first-line: Neoadjuvant use in combination with chemotherapy or continued adjuvant single-agent after surgery for TNBC

See chunk 67

inv-97: first-line

first-line: First-line pemetrexed plus platinum combination with pembrolizumab for pleural or peritoneal mesothelioma

See chunk 74

inv-98: second-line

subsequent/combination: Combination with cisplatin/carboplatin + paclitaxel ± bevacizumab for vaginal cancer; combination with pemetrexed + platinum for mesothelioma; combination with fluorouracil + cisplatin/carboplatin followed by maintenance in penile cancer; combination with enfortumab vedotin-ejfv for urothelial reauthorization

See chunks 73, 76, 74, 79

Biomarker Thresholds and Testing Requirements

PD-L1 (TPS)

Threshold>= 1% (PD‑L1 TPS)

Clinical roleSpecifies eligibility for selected NSCLC first‑line and subsequent settings where no EGFR/ALK alterations are present

Test methodAs determined by an FDA‑approved test; document PD‑L1 TPS where applicable

PD-L1 (CPS)

General CPS threshold>= 1 (PD‑L1 CPS) for many indications

Higher CPS exampleCPS ≥ 10 required for specific esophageal squamous single‑agent settings and metastatic TNBC

ContextCPS used to define PD‑L1 positivity for gastric/GEJ, esophageal, cervical, HNSCC and other tumor types

MSI-H / dMMR

RequirementMSI‑H or dMMR as determined by an FDA‑approved test

ScopePan‑tumor eligibility for unresectable or metastatic MSI‑H/dMMR solid tumors and specific colorectal indications

DocumentationSubmit laboratory report confirming MSI‑H or dMMR status where applicable

PD-L1 — CPS and selected thresholds

TNBC thresholdCPS ≥ 10 for metastatic triple‑negative breast cancer (with chemotherapy)

Other PD‑L1 usesCPS ≥1 or PD‑L1 ≥1 applied to select HNSCC, gastric/GEJ, esophageal and cervical indications

Testing notePD‑L1 expression must be determined by an FDA‑approved test and documented for prior authorization

TMB‑H

ThresholdTMB‑H defined as ≥ 10 mut/Mb

Test methodAs determined by an FDA‑approved test; provide lab confirmation where applicable

Use casesReferenced for tumor‑agnostic approval and multiple tumor‑specific single‑agent authorizations

MSI‑H / dMMR (and related exclusions)

Exclusion notePediatric members with TMB‑H central nervous system cancers are excluded from coverage

Ultra‑hypermutated qualifierPOLE/POLD1 ultra‑hypermutated colorectal tumors considered when TMB > 50 mut/Mb

DocumentationLaboratory confirmation of POLE/POLD1 status and TMB required where applicable

EGFR / ALK — NSCLC testing/absence requirement

NSCLC testing considerationAbsence of EGFR exon 19 deletions/exon 21 L858R mutations or ALK rearrangements required for many NSCLC pembrolizumab uses (unless testing not feasible)

RoleEnsures appropriate sequencing of targeted therapy before PD‑1 therapy in NSCLC

DocumentationDocument presence/absence of EGFR/ALK alterations where applicable

TMB — thresholds and ultra‑hypermutated phenotype

TMB thresholds≥ 10 mut/Mb for TMB‑H; > 50 mut/Mb for ultra‑hypermutated (POLE/POLD1)

ApplicabilityUsed across many single‑agent tumor‑agnostic and tumor‑specific indications (e.g., anaplastic thyroid, colorectal ultra‑hypermutated)

DocumentationLaboratory confirmation of TMB level required for prior authorization

MSI‑H / dMMR (referenced)

MSI‑H / dMMR requirementMSI‑H or dMMR status determined by an FDA‑approved test required for tumor‑agnostic and colorectal MSI‑H indications

DocumentationSubmit lab report confirming MSI‑H/dMMR status for prior authorization

ScopeApplies to adult and pediatric patients where indicated (except pediatric CNS TMB‑H exclusion)

PD‑L1 (CPS) — common thresholds

CPS general usePD‑L1 CPS ≥1 for many indications; CPS ≥10 for select squamous esophageal and metastatic TNBC settings

IndicationsGastric/GEJ, esophageal/EGJ, cervical, HNSCC, TNBC among others use CPS thresholds to determine eligibility

TestingPD‑L1 testing by FDA‑approved assay required and must be documented

TMB — ≥ 10 mut/Mb

Threshold≥ 10 mut/Mb (TMB‑H)

Use casesReferenced repeatedly for tumor‑agnostic and tumor‑specific indications including pancreatic, ampullary, occult primary, and others

DocumentationProvide laboratory report confirming high TMB for prior authorization

MSI‑H / dMMR (referenced)

MSI‑H / dMMRMSI‑H or dMMR as determined by an FDA‑approved test

Indication examplesColorectal MSI‑H/dMMR, and other unresectable/metastatic MSI‑H solid tumors are eligible

DocumentationLab confirmation required for prior authorization

PD‑L1 (referenced)

PD‑L1 rolePD‑L1 expression (TPS or CPS) used to determine eligibility in multiple tumor types; thresholds vary by indication

ExamplesTPS ≥1% for NSCLC; CPS ≥1 or ≥10 for gastric, esophageal, HNSCC, cervical, TNBC as specified

Testing noteDocument PD‑L1 results from an FDA‑approved assay for prior authorization

PD‑L1 (referenced)

PD‑L1 importancePD‑L1 CPS/TPS thresholds determine eligibility for TNBC, HNSCC, NSCLC and other indications

TNBC specificMetastatic TNBC requires CPS ≥10 when used with chemotherapy

DocumentationPD‑L1 test results must be submitted when applicable

MSI‑H / dMMR (and TMB‑H cross‑reference)

TMB‑H threshold≥ 10 mut/Mb

Ultra‑hypermutated> 50 mut/Mb for POLE/POLD1 ultra‑hypermutated tumors

Clinical useApplied for tumor‑agnostic approvals and select tumor‑specific entries (colorectal ultra‑hypermutated, anaplastic thyroid, etc.)

TMB‑H — ≥ 10 mut/Mb

TMB‑H numeric cutoff≥ 10 mut/Mb

Dosing contextTMB‑H indications use standard pembrolizumab dosing (eg, 200 mg q3w or 400 mg q6w) as listed in dosing regimens

TestingLaboratory report confirming TMB ≥10 mut/Mb required for prior authorization

Background and Definitions

Pembrolizumab (Keytruda) is an anti‑PD‑1 immune checkpoint inhibitor with multiple FDA‑approved and compendial oncology indications. The policy documents tumor‑specific and tumor‑agnostic uses including biomarker‑directed indications such as MSI‑H/dMMR and TMB‑H (≥ 10 mut/Mb), PD‑L1 biomarker‑defined uses, adjuvant and metastatic settings, and numerous combination regimens with chemotherapy or targeted agents. Prior authorization is required and many authorizations are issued for an initial period of 6 months when the approval criteria are met.

PD‑L1 expression thresholds (summary)

PD‑L1 expression (TPS/CPS)PD‑L1 referenced using TPS ≥ 1% for certain NSCLC settings and CPS thresholds for other tumor types

Clinical implicationPD‑L1 thresholds guide first‑line single‑agent use and neoadjuvant/adjuvant pathways in NSCLC and HNSCC

Testing requirementPD‑L1 must be determined by an FDA‑approved test and documented for prior authorization when applicable

MSI‑H / dMMR

DefinitionMicrosatellite instability‑high (MSI‑H) or mismatch repair deficient (dMMR) tumors as determined by an FDA‑approved test

EligibilitySupports tumor‑agnostic and multiple tumor‑specific pembrolizumab indications (including colorectal MSI‑H)

DocumentationProvide laboratory confirmation of MSI‑H/dMMR for prior authorization

TMB‑H definition

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

Test methodDetermined by an FDA‑approved test; lab report required for authorization

UseCriterion for tumor‑agnostic approvals and many tumor‑specific single‑agent indications

PD‑L1 CPS (definition and thresholds)

CPS meaningCombined Positive Score (CPS) for PD‑L1 tumor expression used to determine eligibility in several tumor types

Key thresholdsExamples include CPS ≥10 for TNBC and CPS ≥1 for many gastric, esophageal, cervical, and HNSCC indications

TestingPD‑L1 CPS must be determined by an FDA‑approved assay and provided in documentation when required