CurrentmhnPolicy CP.PHAR.322

Pembrolizumab and Pembrolizumab/Berahyaluronidase Alfa-pmph (Keytruda, Keytruda Qlex) coverage criteria

Medical necessity criteria for initial and continued coverage of pembrolizumab (Keytruda) and pembrolizumab/berahyaluronidase alfa-pmph (Keytruda Qlex) across multiple FDA-approved and selected off-label oncology indications, including dosing limits and approval durations by line of business.

Policy Summary

Payermhn

PolicyPembrolizumab and Pembrolizumab/Berahyaluronidase Alfa-pmph (Keytruda, Keytruda Qlex) coverage criteria

Policy CodePolicy CP.PHAR.322

Change TypeMultiple FDA/NCCN updates; HCPCS and formulation additions

Effective Date03.01.17

Next Review Date

Key ActionProvider must submit documentation (office chart notes, lab results, other clinical information) supporting that member meets all approval criteria.

POLICY UPDATE CHANGES

RT4: criteria added for newly approved indications including esophageal/GEJ carcinoma, combination use for 1st line gastric or GEJ adenocarcinoma, locally advanced cutaneous squamous cell carcinoma, and high-risk early-stage TNBC; removed SCLC indication.

HCPCS code J3590 removed and J9999 added (12.02.25).

New SC formulation Keytruda Qlex added to policy and 400 mg every 6 week dosing conversion to full approval for certain adult indications (09.26.25).

Multiple annual RT4 updates from 2021-2025 added, removed, or clarified FDA-approved and NCCN-based indications (multiple dates).

Added new FDA approved indications including MPM and neoadjuvant/adjuvant HNSCC (2024-2025 entries).

Updated FDA-approved indication language to require PD-L1 (CPS ≥ 1) and/or HER2 status for certain gastric/GEJ and esophageal uses per PI.

18+Indications listed (partial count in this part)

24 monthsCommon max duration

6 / 12Commercial / Medicaid approvals

J3590→J9999HCPCS coding update

Keytruda QlexNew formulation

Coverage Summary

This policy establishes medical-necessity criteria for pembrolizumab (Keytruda) and pembrolizumab/berahyaluronidase alfa‑pmph (Keytruda Qlex) across multiple FDA‑approved oncology indications and selected NCCN/guideline‑supported off‑label uses, including initial and continuation requirements, dosing limits, and maximum treatment durations that vary by indication and line of business. Dosing themes include standard IV Keytruda maximums of 200 mg every 3 weeks or 400 mg every 6 weeks for adults (with specified pediatric weight‑based dosing where applicable) and SC Keytruda Qlex maximums of 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks; duration limits commonly range up to 24 months for many indications with shorter adjuvant or neoadjuvant limits for certain settings. Line‑of‑business differences (e.g., Medicaid/HIM typical approvals 12 months; Commercial typical approvals 6 months or to member renewal date) and jurisdictional step‑therapy exceptions are applied per policy. Specific numeric thresholds for approval (age, weight, PD‑L1 CPS/TPS, TMB) and indication‑specific criteria are detailed in the Medical‑Necessity Criteria section of the policy.

For prior authorization and documentation, providers must submit clinical information demonstrating that members meet all applicable criteria (including oncologist involvement where required); off‑label or guideline‑supported dosing/uses must be supported by submitted evidence per the policy.

Key thresholds and operational limits

AgeVaries by indication (examples: ≥12 years melanoma; ≥18 years for most adult indications; Keytruda pediatrics ≥6 months for some indications)

Weight for Keytruda Qlex> 40 kg required for Keytruda Qlex when pediatric/adolescent age criteria apply

PD-L1 TPS thresholdTPS ≥ 1% for certain NSCLC single-agent indications

PD-L1 CPS thresholdsCPS ≥ 1 or CPS ≥ 10 depending on indication (e.g., HNSCC, gastric/GEJ, cervical often CPS ≥1; GEJ squamous cell salvage CPS ≥10; TNBC CPS ≥10)

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

Common maximum durationMost indications: maximum common upper limit = 24 months

Approval duration by line of businessCommercial approvals: 6 months (or to member renewal date); Medicaid/HIM approvals: 12 months

Criteria for Initial and Continuation Coverage

General policy preface

Provider must submit documentation supporting that member has met all approval criteria. Keytruda/Keytruda Qlex are medically necessary when criteria below are met.

General requirements

General requirement for all requests: Provider submits documentation (office chart notes, lab results, other clinical information) supporting that member has met all approval criteria; Prescribed by or in consultation with an oncologist (or oncologist/hematologist where specified).

A. Melanoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of melanoma; Prescribed by or in consultation with an oncologist; Age ≥ 12 years; For Keytruda Qlex requests, member weighs > 40 kg; Disease is Stage IIB, IIC, III, recurrent, unresectable, or metastatic

Coding

HCPCS Covered/Informational CodesHCPCS

J9271	Injection, pembrolizumab, 1 mg
C9399	Unclassified drugs or biologicals
J9999	Not otherwise classified, antineoplastic drugs

Primary HCPCS codes referencedHCPCS

J9271	Injection, pembrolizumab, 1 mg
C9399	Unclassified drugs or biologicals
J9999	Not otherwise classified, antineoplastic drugs
J3590	Drug code removed (previously referenced)

Provider Actions & Billing Impact

Prior Authorization

Documentation required

Submit clinical documentation to support medical necessity and prior authorization requests. Include relevant office notes, infusion/administration records, pathology and radiology reports, laboratory results, and other clinical information demonstrating diagnosis, stage, prior therapies, biomarker results, and treatment intent.

Prior Authorization

Prior authorization may be required for co-therapies

Prior authorization may be required when pembrolizumab is used concurrently with other antineoplastic agents. Verify PA requirements for the listed co-therapies and include regimen details in the request.

Padcev (enfortumab vedotin)
Inlyta (axitinib)
Lenvima (lenvatinib)

Background & Evidence

Background: Pembrolizumab (Keytruda) is a PD‑1 blocking antibody. Keytruda Qlex combines pembrolizumab with berahyaluronidase alfa (an endoglycosidase) to provide a subcutaneous formulation. The policy enumerates applicable FDA‑approved indications for both Keytruda and Keytruda Qlex (see indications tables and sections I–VII) and permits certain NCCN or guideline‑supported off‑label uses when criteria are met.

Referenced evidence sources and guidance include the Keytruda Prescribing Information (Merck PI, Nov 2025), Keytruda Qlex PI, and NCCN compendia/guidelines (examples: NCCN Bladder Cancer Version 1.2025), which are cited in the policy and used to define indication, biomarker, dosing, and duration requirements.

Label	Value
NCCN Bladder Cancer Guidelines referenced	NCCN Bladder Cancer Version 1.2025 (accessed May 29, 2025)
Keytruda Prescribing Info	Merck Keytruda Prescribing Information; November 2025 (PI referenced)

Definitions & Key Terms

Definitions / Acronyms:

TMB‑H (Tumor Mutational Burden‑High): defined in the policy as ≥ 10 mutations per megabase (mut/Mb) for solid tumors and referenced in indication P (TMB‑H cancer).

CPS (Combined Positive Score): refers to the PD‑L1 Combined Positive Score used to determine PD‑L1 expression for multiple indications (e.g., CPS ≥ 1 or CPS ≥ 10 as specified by indication).

RT4: denotes the policy author's routine quarterly review/update cycle used to record revisions and updates to indications, dosing, and criteria.

Revision History

3Q 2021RT4 annual update

RT4: criteria added for newly approved indications including esophageal/GEJ carcinoma, combination use for 1st-line gastric or GEJ adenocarcinoma, locally advanced cutaneous squamous cell carcinoma, and high-risk early-stage TNBC; removed SCLC indication.

2021-2025 (multiple RT4 annual updates)RT4 annual updates

Multiple annual RT4 updates (2021–2025) added, removed, or clarified FDA-approved and NCCN-based indications (examples: RCC with lenvatinib, cervical cancer combinations, adjuvant NSCLC, MSI-H/dMMR approvals, HCC full approval updates, many NCCN off-label expansions).

2023-2025 (PI clarifications)Prescribing Information clarifications

Policy Summary

Payermhn

PolicyPembrolizumab and Pembrolizumab/Berahyaluronidase Alfa-pmph (Keytruda, Keytruda Qlex) coverage criteria

Policy CodePolicy CP.PHAR.322

Change TypeMultiple FDA/NCCN updates; HCPCS and formulation additions

Effective Date03.01.17

Next Review Date

Key ActionProvider must submit documentation (office chart notes, lab results, other clinical information) supporting that member meets all approval criteria.

On This Page

Prescribed as one of the following

Single agent: A single agent
Combination options: In combination with Lenvima (lenvatinib) or Yervoy (ipilimumab)
BRAF mutation option: In combination with Mekinist (trametinib) and Tafinlar (dabrafenib) for disease with BRAF V600 activating mutation

Dose requirements (one of)

Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks (for a maximum of 12 months if adjuvant treatment)
Keytruda Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks (for a maximum of 12 months if adjuvant treatment)
Off-label dosing: Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)

Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

B. Non-Small Cell Lung Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of NSCLC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Disease status (one of)
- Resectable/resected: Disease is resectable or resected
- Recurrent/advanced/metastatic with biomarker options
  - Biomarker/mutation status (one of i-vi)
    i: Positive for EGFR exon 20, KRAS G12C, NRTK1/2/3, BRAF V600E, MET exon 14 skipping, RET rearrangement, or ERBB2 (HER2)
    ii: Positive for EGFR S768I, L861Q, and/or G719X, and member has received prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib
    Prior authorization may be required
    iii: Positive for EGFR exon 19 deletion or L858R, and member has received prior erlotinib ± (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, dacomitinib, or amivantamab-vmjw + lazertinib
    Prior authorization may be required
    iv: Positive for ROS1 rearrangement, and member has received prior crizotinib, entrectinib, or repotrectinib
    Prior authorization may be required
    v: Positive for ALK rearrangement, and member has received prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib
    Prior authorization may be required
    vi: Disease mutation status is negative for actionable biomarkers (EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, and ERBB2 [HER2])
Prescribed regimen (one of)
- PDL1+: For PDL1 positive disease (TPS ≥ 1%): in accordance with approved uses
- With chemotherapy: In combination with a chemotherapy regimen (see Appendix B)
- Neoadjuvant then adjuvant: In combination with a chemotherapy regimen as neoadjuvant treatment, followed by single-agent adjuvant treatment after surgery for resectable disease (tumors ≥ 4 cm or node positive)
- Continuation maintenance: As single-agent continuation maintenance therapy if previously given first line as part of a chemotherapy regimen
- Adjuvant:
Contraindication: Member does not have contraindications to PD-1/PD-L1 inhibitor therapy (see Appendix F)
Dose/duration limits (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum duration of: adjuvant 12 months; neoadjuvant then adjuvant 12 weeks neoadjuvant then 39 weeks adjuvant; all other requests 24 months
- Keytruda Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for maximum durations matching Keytruda (12 months adjuvant; 12w/39w neoadjuvant/adjuvant; 24 months others)
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

C. Malignant Pleural Mesothelioma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of MPM; Prescribed by or in consultation with an oncologist; Age ≥ 18 years; Disease is unresectable, advanced, or metastatic
Combination requirement: Keytruda or Keytruda Qlex is prescribed in combination with pemetrexed and platinum-containing chemotherapy
Dose/duration options (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Keytruda Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

D. Head and Neck Squamous Cell Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of HNSCC (includes paranasal sinuses, larynx, pharynx, lip, oral cavity, salivary glands; may be occult primary); Prescribed by or in consultation with an oncologist; Age ≥ 18 years; Disease is resectable, locally advanced, unresectable, recurrent/persistent, or metastatic
Unresectable/recurrent/persistent/metastatic options
- Chemo combinations: In combination with platinum-containing chemotherapy and either FU, docetaxel, or gemcitabine (Keytruda or Keytruda Qlex)
- Erbitux option: Keytruda: In combination with Erbitux (cetuximab) as first-line therapy or subsequent-line therapy (off-label)
- PD-L1 single agent: As a first-line single agent and tumor expresses PD-L1 with CPS ≥ 1 (Keytruda or Keytruda Qlex)
- Post-platinum single agent: As a single agent for disease that has progressed on or after platinum-containing chemotherapy
Resectable locally advanced pathway: For resectable locally advanced disease: Request is for Keytruda; Tumor expresses PD-L1 with a CPS of ≥ 1; Prescribed initially for neoadjuvant therapy as a single agent; Then continued as adjuvant therapy in combination with RT with or without cisplatin, then as a single agent
Nasopharyngeal carcinoma requirement (one of)
- Loqtorzi failure: Failure of Loqtorzi at up to maximally indicated doses, unless contraindicated or intolerable
- State regulation exemption: Request is for treatment associated with cancer for a state with regulations against step therapy in certain oncology settings (see Appendix G)
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks with maximums: neoadjuvant 6 weeks; adjuvant 1 year; all other requests 24 months
- Keytruda Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

E. Classical Hodgkin Lymphoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of cHL; Request is for Keytruda; Prescribed by or in consultation with an oncologist or hematologist; Age ≥ 6 months
Prescribed as (one of)
- Single agent: Single-agent therapy (adults or pediatrics)
- Combination adult regimens: In combination with GVD, ICE, decitabine and vorinostat (adults only)
Clinical intent (one of)
- Palliative therapy
- Post-transplant: Post-allogeneic hematopoietic cell transplant or post-autologous stem cell rescue
- Anthracycline ineligible: Member is not a candidate for anthracycline
- Relapsed/refractory: Disease relapsed or refractory to ≥ 1 line of systemic therapy (see Appendix B)
Dose/duration (one of)
- Adults dosing: Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Pediatrics dosing: Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

F. Primary Mediastinal Large B-Cell Lymphoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of PMBCL; Request is for Keytruda; Prescribed by or in consultation with an oncologist or hematologist; Age ≥ 6 months; Disease is refractory to or has relapsed after ≥ 1 line of systemic therapy (see Appendix B)
Prescribed regimen (one of)
- Single agent: As a single agent
- Pediatric combo: For age ≥ 6 months to < 18 years only, in combination with Adcetris
Dose/duration (one of)
- Adults dosing: Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Pediatrics dosing: Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

G. Urothelial Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of urothelial carcinoma; Prescribed by or in consultation with an oncologist or urologist; Age ≥ 18 years
Permitted regimens (one of)
- Combination with Padcev/Inlyta/Lenvima: In combination with Padcev, Inlyta, or Lenvima for locally advanced, relapsed, or metastatic disease (prior auth may be required for Padcev, Inlyta, Lenvima)
- Single agent advanced: As a single agent for locally advanced or metastatic disease, and member is ineligible for or has previously received platinum-containing chemotherapy or previously received other chemotherapy
- BCG-unresponsive NMIBC: As a single agent for BCG-unresponsive, high-risk NMIBC with CIS, and member is ineligible for or has elected not to undergo cystectomy
- Adjuvant: As a single agent for adjuvant therapy
- MIBC pathway: For MIBC: In combination with Padcev as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment; member is ineligible for cisplatin-containing chemotherapy
MIBC dosing specifics
- Keytruda neoadjuvant/adjuvant: Neoadjuvant: Keytruda dose does not exceed 200 mg every 3 weeks for a maximum of 3 doses; Adjuvant: Keytruda dose does not exceed 200 mg every 3 weeks for a maximum of 14 doses or 400 mg every 6 weeks for a maximum of 7 doses
- Qlex neoadjuvant/adjuvant: Keytruda Qlex: Neoadjuvant: 395 mg/4,800 units every 3 weeks for max 3 doses; Adjuvant: 395 mg/4,800 units every 3 weeks for max 14 doses or 790 mg/9,600 units every 6 weeks for max 7 doses
Dose/duration for other indications (one of)
- Keytruda other: Keytruda: For all other indications: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex other: Keytruda Qlex: For all other indications: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

H. Microsatellite Instability-High/Mismatch Repair Deficient Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of a solid tumor classified as MSI-H or dMMR (indicative of MMR gene mutation or loss of expression); Prescribed by or in consultation with an oncologist
Age/weight requirements (one of)
- Keytruda pediatric: Keytruda: Age ≥ 6 months
- Keytruda Qlex pediatric: Keytruda Qlex: Age ≥ 12 years AND Weight > 40 kg
Pediatric first-line restriction: For age ≥ 6 months to < 18 years, request is not for first-line therapy
Tumor types/lines (one of)
- Listed cancers first-line/subsequent: As first-line or subsequent therapy for ampullary adenocarcinoma, CRC, gallbladder cancer, gastric cancer, GEJ cancer, intrahepatic/extrahepatic cholangiocarcinoma, non-nasopharyngeal head and neck cancer, occult primary tumor, pancreatic adenocarcinoma, or small bowel adenocarcinoma
- Subsequent for others: As subsequent therapy for other solid tumors
Prescribed regimen (one of)
- Single agent: As a single agent
- Gastric/GEJ combo: For gastric or GEJ cancers: as a single agent or in combination with platinum- and fluoropyrimidine-based chemotherapy
Dose/duration (one of)
- Adults dosing: Keytruda Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Pediatrics dosing: Keytruda Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

I. Gastric, Esophageal, or GEJ Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of gastric cancer, esophageal cancer, or GEJ cancer; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Disease status (one of)
- Unresectable/etc: Disease is unresectable, locally advanced, recurrent, or metastatic
- Planned esophagectomy: Member is planned for esophagectomy
Tumor/therapy specific (one of)
- HER2+ trastuzumab combo: Keytruda or Keytruda Qlex with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for HER2-positive gastric or GEJ adenocarcinoma AND tumor expresses PD-L1 (CPS ≥ 1)
- HER2- platinum/fluoropyrimidine combo: Keytruda or Keytruda Qlex with platinum- and fluoropyrimidine-based chemotherapy for HER2-negative gastric or GEJ adenocarcinoma or esophageal carcinoma/GEJ squamous cell carcinoma AND tumor expresses PD-L1 (CPS ≥ 1); Step therapy exemption: failure of Tevimbra at up to maximally indicated doses unless contraindicated OR state regulations against step therapy (see Appendix G)
- Single agent after prior lines: Keytruda or Keytruda Qlex as a single agent after one or more prior lines of systemic therapy for tumors of squamous cell GEJ that express PDL1 (CPS ≥ 10)
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

J. Cervical Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of cervical cancer; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Permitted regimens (one of)
- Single agent recurrent/metastatic: As a single agent, and ALL of: tumor expresses PDL1 (CPS ≥ 1); disease is recurrent or metastatic; disease has progressed on or after ≥ 1 line of systemic therapy
- Combo with chemo: In combination with chemotherapy (with or without bevacizumab), AND tumor expresses PD-L1 (CPS ≥ 1); disease is persistent, recurrent, or metastatic
- Combo with Tivdak: In combination with Tivdak, and ALL of: tumor expresses PD-L1 (CPS ≥ 1) and has not received prior immuno-oncology therapy; disease is recurrent or metastatic; disease has progressed on or after ≥ 1 line of systemic therapy
- Combo with CRT: In combination with CRT, and disease is FIGO 2014 Stage III-IVA or FIGO 2018 stage III-IVA
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

K. Hepatocellular Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of HCC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Line of therapy (one of)
- Subsequent-line: Prescribed as subsequent-line systemic therapy AND member has not previously been treated with immune checkpoint inhibitor therapy (PD-L1/PD-1)
  Prior authorization may be required for Nexavar, Lenvima and Stivarga
- First-line: Prescribed as first-line treatment
Single agent: Prescribed as a single agent
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Co-therapy note: *Prior authorization may be required for Nexavar, Lenvima and Stivarga
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

L. Biliary Tract Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of BTC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Disease status (one of)
- Unresectable/metastatic/R2: Disease is locally advanced unresectable or resected gross residual (R2) disease, or metastatic
- Resectable neoadjuvant gallbladder: Disease is resectable locoregionally advanced and prescribed as neoadjuvant therapy for gallbladder cancer
Combination requirement: Prescribed in combination with gemcitabine and cisplatin
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

M. Merkel Cell Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of MCC; Prescribed by or in consultation with an oncologist
Age/weight (one of)
- Keytruda age: Keytruda: Age ≥ 6 months
- Qlex age/weight: Keytruda Qlex: Age ≥ 12 years AND Weight > 40 kg
Disease status: Disease is recurrent, locally advanced, or metastatic
Regimen: Prescribed as a single agent
Dose/duration (one of)
- Adults dosing: Keytruda Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Pediatrics dosing: Keytruda Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

N. Renal Cell Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of RCC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Prescribed in one of the following ways (a,b,c)
- Combination with Inlyta/Lenvima: Keytruda or Keytruda Qlex: In combination with Inlyta or Lenvima, and disease is advanced (relapsed or stage IV) (prior auth may be required for Inlyta and Lenvima)
- Adjuvant monotherapy: Keytruda or Keytruda Qlex: As single-agent adjuvant treatment, and member is at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions
- Non-clear cell off-label: Keytruda: As a single agent for relapsed or stage IV disease with non-clear cell histology (off-label)
Dose/duration (one of)
- Keytruda combination vs mono: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months (combination) or 12 months (monotherapy)
- Qlex combination vs mono: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months (combination) or 12 months (monotherapy)
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

O. Endometrial Carcinoma (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of endometrial carcinoma; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Prescribed in one of the following (a or b)
- Lenvima combination pMMR: In combination with Lenvima AND both: disease is pMMR or not MSI-H; progressed following prior systemic therapy (e.g., carboplatin/paclitaxel)
  Prior authorization may be required for Lenvima
- Carboplatin/paclitaxel pathway: In combination with carboplatin and paclitaxel and continued as a single agent for maintenance therapy for advanced, recurrent, or Stage III-IV disease
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

P. Tumor Mutational Burden-High Cancer (must meet all)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of a solid tumor classified as TMB-H (≥ 10 mutations/megabase); Prescribed by or in consultation with an oncologist
See Appendix E for examples of TMB-H solid tumors
Age/Agent requirements (one of)
- Keytruda age: Keytruda: Age ≥ 6 months
- Qlex requirements: Keytruda Qlex: Age ≥ 12 years AND Weight > 40 kg
Disease status: Disease is unresectable or metastatic
Line/setting (one of)
- Progressed following prior treatment: Disease has progressed following prior treatment
- First-line exceptions: Prescribed as a first-line therapy for ampullary adenocarcinoma or pancreatic adenocarcinoma
Regimen: Prescribed as a single agent
Dose/duration (one of)
- Adults dosing: Keytruda Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Pediatrics dosing: Keytruda Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence)
Exclusion note: Limitations: Pediatric CNS TMB-H cancers: safety and effectiveness not established (pediatric CNS exclusion)
Regimen requirement: *Prescribed regimen must be FDA-approved or recommended by NCCN.

Q. Cutaneous Squamous Cell Carcinoma (start of criteria present)

Covered when ALL of the following are met; document fragment ends mid-sentence in source.

ALL of the following

General: Diagnosis of cSCC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Further criteria truncated in this document part

P. Tumor Mutational Burden-High Cancer (TMB-H)

Duplicate/overlap entry of TMB-H criteria present elsewhere; include as separate group if distinct — source appears identical to criteria_trees[16].

ALL of the following

Reference: See P. Tumor Mutational Burden-High Cancer criteria

Q. Cutaneous Squamous Cell Carcinoma (cSCC)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of cSCC; Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Curative intent ineligible: Member is not a candidate for curative surgery or radiation
Single agent: Prescribed as a single agent
Documented single-agent use only
Dose/duration (one of)
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks for a maximum of 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Regimen requirement: Prescribed regimen must be FDA-approved or recommended by NCCN

R. Triple Negative Breast Cancer (TNBC)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of TNBC (ER/PR negative and HER2-negative); Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Disease/regimen options (one of)
- High-risk early-stage neoadjuvant/adjuvant: Disease is high-risk early-stage, prescribed in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery
- Locally recurrent/metastatic: Disease is locally recurrent unresectable or metastatic, and tumor expresses PDL1 (CPS ≥ 10), prescribed in combination with chemotherapy
- Preoperative systemic therapy: Prescribed as preoperative systemic therapy in combination with carboplatin and docetaxel
Dose/duration options
- Keytruda dosing: Keytruda: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks; High-risk early-stage: 24 weeks neoadjuvant and 27 weeks adjuvant; Locally recurrent/metastatic: 24 months
- Qlex dosing: Keytruda Qlex: Dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks; High-risk early-stage: 24 weeks neoadjuvant and 27 weeks adjuvant; Locally recurrent/metastatic: 24 months
- Off-label dosing: Dose supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Regimen requirement: Prescribed regimen must be FDA-approved or recommended by NCCN

S. Pediatric Glioma (off-label)

Covered when ALL of the following are met:

ALL of the following

General: Diagnosis of hypermutant tumor diffuse high-grade glioma; Request is for Keytruda; Prescribed by or in consultation with an oncologist; Age ≥ 6 months and < 18 years
Dosing guidance: Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

T. NCCN Recommended Uses (off-label)

Preserved top-level NCCN recommended uses and required supporting evidence.

ALL of the following

General: Diagnosis of one of the listed NCCN-recommended cancers (see policy for full list of examples); Prescribed by or in consultation with an oncologist; Age ≥ 18 years
Evidence: Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

U. Other diagnoses/indications

Routing logic for other diagnoses or indications not directly covered in Section I.

ANY of the following

Recent label change - formulary: For drugs on the formulary/PDL, refer to no coverage criteria policy for relevant line of business: CP.CPA.190 (commercial), HIM.PA.33 (HIM), CP.PMN.255 (Medicaid)
If recent label change within 6 months
Not on formulary: For drugs NOT on formulary/PDL, refer to non-formulary policy: CP.CPA.190 (commercial), HIM.PA.103 (HIM), CP.PMN.16 (Medicaid)
If not on formulary
Off-label policy referral: If requested use is NOT specifically listed under section III AND criterion 1 above does not apply, refer to the off-label use policy: CP.CPA.09 (commercial), HIM.PA.154 (HIM), CP.PMN.53 (Medicaid)

A. Continuation / All Indications in Section I (renewal criteria)

Continuation/renewal criteria applicable to all indications in Section I.

ALL of the following

Current therapy: Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Keytruda or Keytruda Qlex for a covered indication and has received this medication for at least 30 days
Keytruda requirement for certain indications: For cHL, PMBCL, pediatric glioma, and other off-label indications (see Section I.T), request is for Keytruda
Response: Member is responding positively to therapy
Has NOT received maximum duration of therapy
- Adjuvant melanoma or RCC monotherapy: Adjuvant melanoma treatment or RCC monotherapy: up to 12 months
- TNBC high-risk: High-risk, early stage TNBC: up to 24 weeks if neoadjuvant treatment, followed by 27 weeks as adjuvant treatment
- NSCLC options: adjuvant 12 months; neoadjuvant then adjuvant 12 weeks then 39 weeks; all other NSCLC requests 24 months
- HNSCC options: neoadjuvant 6 weeks; adjuvant 1 year; all other requests 24 months
- MIBC options: neoadjuvant 3 doses; adjuvant 14 doses (q3w) or 7 doses (q6w)
- Other FDA-approved indications: All other FDA-approved indications: up to 24 months
If request is for a dose increase
- Keytruda adult dose increase: Adults: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks
- Keytruda pediatric dose increase: Keytruda Pediatrics: New dose does not exceed 2 mg/kg up to 200 mg every 3 weeks
- Keytruda Qlex dose increase: Keytruda Qlex: New dose does not exceed 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks
- Off-label dose increase evidence: New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Regimen requirement: Prescribed regimen must be FDA-approved or recommended by NCCN

Stivarga (regorafenib)

Documentation Required

PD-L1 / biomarker test documentation

Document PD-L1, TMB, MSI-H/dMMR, or relevant mutation status when clinically indicated. Specify the test used and that it is an FDA-approved or guideline-recommended assay where applicable.

Step Therapy

Step therapy for some indications

Step therapy applies for some indications — prior failure of specified alternatives is required before approval. Note state-level exemptions where applicable.

Required failures may include listed agents such as Loqtorzi and Tevimbra where the policy indicates step requirements.
State-specific exemptions apply (see Appendix G and IL HB 5395 for Illinois step-therapy bypass provisions).

Prior Authorization

Prior authorization required with supporting evidence for off-label uses

Prior authorization is required for off-label uses and for doses or regimens outside FDA-approved labeling. Provide supporting evidence such as clinical practice guidelines or peer-reviewed literature when requesting coverage for off-label indications or dosing.

Reference off-label policy numbers (submit guideline or peer-reviewed literature with the PA request).

Documentation Required

Prescriber/oncologist consultation documentation

Document involvement of the prescribing oncologist or specialist when required by the indication or plan rules. Include consultation notes or documented oncology oversight in the medical record.

Billing Rule

Adhere to listed dose and duration limits

Adhere to the policy's listed dose and duration limits when billing and ordering therapy. Use the specified maximums and frequencies to avoid denials or billing adjustments.

Example adult dosing: 200 mg every 3 weeks or 400 mg every 6 weeks (per current labeling).
Keytruda Qlex subcutaneous formulation: follow the policy's specified maximum dose and administration frequency for SC formulation.

Denial Risk

Coverage not authorized for certain situations

Coverage is not authorized for certain scenarios; requests lacking indication alignment with FDA-approved or policy-listed indications may be denied. Pediatric CNS tumors are excluded from TMB-H/MSI-H pediatric coverage per policy; off-label routes follow off-label review.

Non‑FDA indications not listed in the policy are generally not covered without strong supportive evidence.
Pediatric CNS tumors are excluded from TMB-H/MSI-H pediatric approvals.
Off-label uses should be routed through the off-label prior authorization pathway with supporting literature.

Prior Authorization

Approval duration varies by line of business

Prior authorization and approval durations vary by line of business. Confirm the expected approval length and submit reauthorization requests in advance of expiration to avoid coverage gaps.

Commercial: typical approval durations are longer (e.g., 6–12 months) depending on indication and response — verify plan-specific authorization length.
Medicaid/HIM: approval durations are often shorter (e.g., 3 months) and may require earlier reauthorization.
Submit reauthorization requests with updated clinical status and documentation before the current approval expires.

Documentation Required

Use up-to-date coding guidance

Use current coding guidance when submitting claims or PA requests. Codes listed in the policy are informational; verify payer-specific billing requirements.

J9271 (pembrolizumab)
C9399 (drug, antineoplastic, chemotherapy administration — plan-specific use)
J9999 (not otherwise classified drugs — plan/contract guidance)

Billing Rule

HCPCS code changes

HCPCS code changes have been made; implementers must update billing systems to reflect current code sets and remove retired codes.

J3590 (unclassified drug code) was removed.
J9999 was added (effective 12/02/2025).
See policy codes array for full code set and statuses.

Step Therapy

Step therapy bypass

Step-therapy bypass provisions may apply by jurisdiction. For Illinois, IL HB 5395 provides a step-therapy bypass mechanism — follow jurisdictional application guidance when processing requests.

Illinois step-therapy bypass per IL HB 5395 — apply when provider documents medical necessity for bypass.

Billing Rule

New subcutaneous formulation

New subcutaneous Keytruda Qlex formulation is included in this policy. Account for differences in administration route, supplies, and billing pathway (SC vs IV) when submitting claims and authorizations.

Keytruda Qlex (pembrolizumab/berahyaluronidase alfa) — ensure billing and administration codes reflect SC formulation and associated supplies.

Multiple clarifications across 2023–2025 reflecting PI changes, including updates requiring PD-L1 (CPS ≥ 1) and/or HER2 status for certain gastric/GEJ and esophageal uses and other label-aligned criteria refinements.

09.26.25New formulation / dosing update

New subcutaneous formulation Keytruda Qlex added to policy; 400 mg every 6 week adult IV dosing conversion noted to full approval for certain adult indications.

12.02.25HCPCS / approval duration changeLatest

HCPCS code J3590 removed and J9999 added; initial approval duration for a maintenance medication (MIBC) extended from 6 to 12 months and HCPCS coding updated accordingly.

01.01.26 (policy note)Jurisdictional step therapy exceptionLatest

Step therapy bypass added for Illinois per IL HB 5395 for gastric, esophageal, and GEJ cancers (applies to HIM requests in IL).

As single-agent adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA disease