CurrentNeighborhood Health Plan of Rhode IslandPolicy N/A

Keytruda (pembrolizumab) coverage policy

Defines clinical indications, continuation and exclusion criteria, coding, and utilization management approval authority for pembrolizumab (Keytruda) across multiple tumor types for members managed by the payer/UM vendor.

Policy Summary

PayerNeighborhood Health Plan of Rhode Island

PolicyKeytruda (pembrolizumab) coverage policy

Policy CodePolicy N/A

Change TypeNo material change

Effective Date

Next Review Date

Key ActionEvolent is responsible for processing all medication requests; requests must be supported by FDA labeling, CMS-recognized compendia, NCCN/ASCO guidelines, or acceptable peer-reviewed literature.

POLICY UPDATE CHANGES

No material changes

20+Tumor types/indications listed

3Biomarker-based thresholds

1Primary HCPCS code

Coverage Summary

Policy-level summary: This Evolent coverage policy for Keytruda (pembrolizumab) defines accepted indications, continuation and exclusion criteria, coding, and utilization management authority for pembrolizumab across multiple tumor types. Coverage stance: covered_with_criteria. Subject: Keytruda (pembrolizumab) coverage policy. Last review date: 2024-12-12.

Key Thresholds (policy-specified)

PD-L1 Combined Positive Score (CPS)>= 1% or >= 10% depending on indication

PD-L1 Tumor Proportion Score (TPS)>= 1% or >= 50% depending on indication

Tumor Mutational Burden (TMB-H)>= 10 mutations/megabase

MSI / dMMRMSI-High or deficient MMR confirmed by any standardized test

Adjuvant therapy duration limitMaximum 12 months for adjuvant melanoma or NSCLC (total 1 year in adjuvant melanoma)

Single dose limit200 mg every 3 weeks OR 400 mg every 6 weeks

Initial Therapy Criteria

Indication-specific Initial Approval Criteria

Cervical Cancer

Option 1
- Keytruda + Carboplatin or Cisplatin + Paclitaxel may be used as first-line or subsequent therapy
- Member has advanced/recurrent/metastatic cervical carcinoma whose tumors express PD-L1 CPS >= 1%PD-L1 CPS >= 1%
Option 2
- Keytruda as single agent as second-line or subsequent therapy following disease progression on or after prior chemotherapy
- Tumors express PD-L1 CPS >= 1%PD-L1 CPS >= 1%
- No prior exposure to Keytruda or another immune checkpoint inhibitor
Option 3
- Bevacizumab (or biosimilar) + Keytruda + cisplatin/carboplatin + paclitaxel may be used for initial treatment
- Member has PD-L1 positive (PD-L1 >= 1%) metastatic cervical cancerPD-L1 CPS >= 1%
Option 4
- Keytruda may be used in combination with chemoradiotherapy
- Member has newly diagnosed, previously untreated, high-risk locally advanced FIGO 2014 Stage III-IVA cervical cancerFIGO Stage III-IVA

Colorectal Cancer

Member has unresectable/metastatic colorectal cancer
Tumors show dMMR OR MSI-H confirmed by any standardized testMSI-H or dMMR
Keytruda may be used as single agent for initial or subsequent therapy

Cutaneous Squamous Cell Carcinoma (CSCC)

Member has recurrent, advanced, or metastatic CSCC and is not a candidate for curative surgery and/or curative radiation
Keytruda may be used as monotherapy

Endometrial Carcinoma

Option 1
- Keytruda may be used as first-line therapy in combination with carboplatin and paclitaxel for recurrent/metastatic (stage III or IV) endometrial carcinoma
Option 2
- Keytruda as single agent as subsequent-line systemic therapy for unresectable or metastatic MSI-H or dMMR tumors that progressed following prior treatmentMSI-H or dMMR
Option 3
- Keytruda may be used with Lenvima (lenvatinib) as subsequent therapy after progression on prior chemotherapy
- Member has not received prior therapy with an immune checkpoint inhibitor

Gastric / Esophageal / EGJ Cancers

Permitted uses
- Member has unresectable locally advanced, recurrent, or metastatic gastric cancer or esophageal/EGJ adenocarcinoma
- ANY of the following
  - First-line with fluoropyrimidine + platinum chemotherapy AND CPS >= 1%PD-L1 CPS >= 1%
  - First-line with fluoropyrimidine + platinum chemotherapy + trastuzumab for HER2-positive disease regardless of PD-L1HER2-positive
  - Second-line or subsequent single agent for esophageal squamous cell carcinoma with PD-L1 CPS >= 10

Head and Neck Cancer (non-nasopharyngeal)

ANY of the following
- First-line single agent
  - Single agent Keytruda for tumors that express PD-L1 (CPS or TPS) >= 1%PD-L1 CPS or TPS >= 1%
- First-line combination
  - Keytruda in combination with chemotherapy regardless of PD-L1 expression
- Subsequent therapy
  - Keytruda as single agent for disease progression on or after platinum-based chemotherapy regardless of PD-L1 expression

Hepatocellular Carcinoma (HCC)

Option 1
- Member has HCC and has not received prior therapy with an immune checkpoint inhibitor
- Member experienced disease progression on or after sorafenib, lenvatinib, or regorafenib unless intolerance/contraindication to these agents exists
Option 2
- Keytruda as single agent for progression after systemic treatment for unresectable/metastatic disease that is MSI-H and/or dMMRMSI-H or dMMR
NOTE: Use limited to members with liver function Child-Pugh Class A and B only, and no prior immune checkpoint inhibitor therapyChild-Pugh A or B; no prior checkpoint inhibitor

Hodgkin's Lymphoma

Member has refractory or relapsed Hodgkin's lymphoma and is not a candidate for hematopoietic stem cell transplant (HSCT)
Keytruda will be used as single agent

Malignant Pleural Mesothelioma (MPM)

Keytruda may be used in combination with pemetrexed and platinum chemotherapy as first-line treatment of adult members with unresectable advanced or metastatic MPM

Melanoma

Adjuvant
- Adult or pediatric members >=12 years as adjuvant therapy for stages IIb, IIc, and III following complete resection
  Maximum total duration of therapy is 1 year in the adjuvant setting
Neoadjuvant
- Neoadjuvant therapy for stage IIIB and IVC melanoma amenable to surgical resection (generally 3 cycles)
  May be followed by total of 15 additional cycles of adjuvant Keytruda
Unresectable/metastatic
- For unresectable or metastatic melanoma if member had no prior disease progression on a PD-L1/PD-1 inhibitor

Merkel Cell Carcinoma (MCC)

Keytruda may be used as single agent in members with recurrent, locally advanced, or metastatic MCC regardless of line of therapy

MSI-H / dMMR Solid Tumors (tumor-agnostic)

Member has metastatic/unresectable solid tumor that progressed following prior treatment including all satisfactory alternatives
Tumor is MSI-H or dMMR as confirmed by any standardized testMSI-H or dMMR
Keytruda may be used as single agent

Non-Muscle Invasive Bladder Cancer (High-risk BCG-unresponsive CIS)

Member has high-risk non-muscle invasive bladder cancer with carcinoma in situ (CIS), with or without papillary tumors
Member is refractory to intravesical BCG
Definition of refractory: loss of response within 12 months of maintenance therapy with at least the first course of induction (5-6 doses) followed by at least 2 doses of maintenance BCG OR loss of response with the second induction course (>=2 doses)
Keytruda used as monotherapy IV

Non-Small Cell Lung Cancer (NSCLC) - Squamous and Non-Squamous

First-line options
- As single agent if NSCLC negative for EGFR and ALK AND tumor PD-L1 (CPS or TPS) >= 50% (biomarkers not required for squamous histology)PD-L1 >= 50%; EGFR/ALK negative
- As single agent if EGFR and ALK negative AND PD-L1 >= 1% and concurrent chemotherapy cannot be given or is contraindicatedPD-L1 >= 1%; EGFR/ALK negative
- In combination with pemetrexed + platinum for nonsquamous histology if EGFR and ALK negative, regardless of PD-L1EGFR/ALK negative; nonsquamous
- In combination with carboplatin + paclitaxel or nab-paclitaxel (if severe allergy/intolerance to paclitaxel) for squamous histology, regardless of PD-L1

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Keytruda may be used as single agent in relapsed or refractory PMBCL

Renal Cell Carcinoma (RCC)

First-line combinations
- Keytruda + Lenvima (lenvatinib) may be used as first-line therapy for advanced/metastatic RCC
- Keytruda + Inlyta (axitinib) may be used as first-line for IMDC favorable risk advanced/metastatic RCC in members who have not had prior progression on axitinib or a PD-L1/PD-1 inhibitor
Adjuvant
- Keytruda may be used as single agent for adjuvant therapy in resected RCC if any ONE of the following: Stage II disease with grade 4 histology or sarcomatoid differentiation; Stage III or higher disease; Regional nodal metastases; M1 NED (resectable metastases at diagnosis with surgical resection within 1 year of nephrectomy and no evidence of metastatic disease prior to starting Keytruda)

Triple-Negative Breast Cancer (TNBC)

Neoadjuvant/Adjuvant high-risk early-stage
- Keytruda as part of neoadjuvant therapy in combination with chemotherapy and subsequent adjuvant therapy for newly diagnosed high-risk early-stage TNBC (tumor size > 2 cm regardless of nodal involvement)
  Keytruda may be used in adjuvant therapy ONLY if member received pembrolizumab in neoadjuvant setting
Recurrent/metastatic PD-L1+
- Keytruda for locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 CPS >= 10PD-L1 CPS >= 10%
NOTE: Keytruda + Abraxane (nab-paclitaxel) regimen is not supported for recurrent unresectable or metastatic breast cancer per policy

Tumor Mutational Burden-High (TMB-H) Cancer

Member has unresectable or metastatic solid tumors with TMB-H >= 10 mut/MbTMB >= 10 mut/Mb
Tumor progressed following anti-cancer treatment and no satisfactory alternative anti-cancer options exist
Keytruda may be used as single agent

Urothelial Carcinoma (including upper urinary tract and urethra)

Platinum-ineligible or progression after platinum
- Keytruda monotherapy may be used in members with recurrent/metastatic urothelial cancer who are not eligible for platinum-based chemotherapy OR who have disease progression during or after platinum-containing chemotherapy
Combination first-line
- Keytruda + Enfortumab vedotin (Padcev) may be used as first-line therapy for locally advanced/metastatic urothelial carcinoma

Continuation Therapy Criteria

General Continuation Exemption

Continuation requests for a not-approvable medication shall be exempt provided ALL of the following are met:

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Continuation and administration constraints: Continuation requests are governed by the policy's continuation exemptions and may be allowed when criteria are met; specific treatment duration limits apply in the adjuvant setting including a maximum total duration of 1 year (12 months) for adjuvant melanoma and an adjuvant duration limit of up to 12 months for resected NSCLC. Single-dose administration limits that may lead to claim exclusion are 200 mg every 3 weeks (q3w) or 400 mg every 6 weeks (q6w).

Unproven / Not Supported Uses

Not Supported / Exclusions

Small Cell Lung Cancer (SCLC) exclusion: Single-agent Keytruda is NOT supported for metastatic SCLC following progression on platinum-based chemotherapy and/or at least one other line of therapy (e.g., topotecan, irinotecan, paclitaxel, docetaxel)

Rationale: FDA indication withdrawn/confirmatory study KEYNOTE-604 failed to meet OS endpoint

Soft Tissue Sarcoma exclusions: Single-agent Keytruda is NOT supported for the following sarcomas: cutaneous angiosarcoma; undifferentiated sarcomas; myxofibrosarcoma; undifferentiated pleomorphic sarcoma

Rationale: lack of Level 1 evidence showing superior outcomes

Unsupported combinations: Keytruda + cetuximab combination is not supported for initial and subsequent treatment of non-nasopharyngeal head and neck cancers

Lack of Level 1 evidence

NSCLC unsupported combo: Keytruda + Carboplatin + Abraxane (nab-paclitaxel) is not supported for NSCLC per policy

Based on KEYNOTE-407 results showing equivalent PFS and OS with Abraxane and Taxol

TNBC unsupported combo: Keytruda + Abraxane (nab-paclitaxel) regimen is not supported for recurrent unresectable or metastatic breast cancer per policy

Based on KEYNOTE-355 results showing equivalent outcomes with Abraxane and Taxol

Other exclusions and provider action notes: Providers must submit requests supported by FDA labeling, CMS-recognized compendia, NCCN/ASCO guidelines, or acceptable peer-reviewed literature and document required biomarkers. The policy notes withdrawn or unsupported FDA indications (for example, single-agent pembrolizumab is not supported for metastatic SCLC following progression) and lists other unsupported uses (selected soft tissue sarcomas and certain combinations). Final coverage decisions vary by member benefit and are subject to Evolent utilization management processing and plan terms.

Applicable Codes

Primary HCPCS code for pembrolizumabHCPCSCovered

J9271

Injection, pembrolizumab, mg

Provider Actions / Prior Authorization

Prior Authorization

Authorization required and UM processing

Evolent is responsible for processing all medication requests; medications not authorized may be deemed not approvable and not reimbursable. Requests must be supported by FDA-approved product labeling, CMS-recognized compendia, NCCN/ASCO guidelines, or acceptable peer‑reviewed literature.

Documentation Required

Biomarker documentation

For indication-specific requests, document relevant biomarker results to meet coverage criteria. Examples include PD‑L1 (CPS or TPS) per indication thresholds (e.g., CPS/TPS ≥1% or ≥50% as required), MSI‑High or dMMR confirmed by a standardized test, tumor mutational burden (TMB) ≥10 mut/Mb, and EGFR/ALK negative status when required for first‑line NSCLC.

Denial Risk

Exclusion for dosing/length limits

Claims may be excluded when dosing or treatment duration exceed policy limits. Single‑dose limits are 200 mg every 3 weeks or 400 mg every 6 weeks. Adjuvant treatment duration in the resected melanoma or NSCLC settings is limited to a maximum of 12 months. Affected HCPCS code: J9271.

Denial Risk

Exclusion for prior progression / withdrawn indications

Avoid uses that the policy excludes to prevent claim denials. Examples of unsupported or withdrawn/unsuitable uses include single‑agent pembrolizumab for metastatic SCLC following progression on platinum‑based chemotherapy and/or additional lines of therapy, certain soft tissue sarcoma subtypes (cutaneous angiosarcoma, undifferentiated sarcomas, myxofibrosarcoma, undifferentiated pleomorphic sarcoma), and combinations or indications not supported by FDA labeling, CMS compendia, or acceptable peer‑reviewed evidence.

Clinical Evidence & References

References cited: Primary evidence sources include multiple KEYNOTE trials and publications (KEYNOTE-826, KEYNOTE-859, KEYNOTE-671, KEYNOTE-604, KEYNOTE-407, KEYNOTE-522, KEYNOTE-426 and others), articles in NEJM and Lancet, NCCN guidance, and the Keytruda prescribing information (2024).

Background

Background and policy scope: The policy defines accepted indications for pembrolizumab including FDA-approved uses and select off-label uses supported by compendia and guidelines. Evolent Clinical Guidelines are used for utilization management but do not constitute medical advice; final coverage varies by member benefit and plan terms.

Definitions

Refractory to BCG (bladder)Loss of response within 12 months of maintenance therapy with at least the first induction (5-6 doses) followed by >=2 maintenance doses OR loss of response with the second induction course (>=2 doses).

M1 NED (RCC adjuvant)Member with resectable metastases at diagnosis and surgical resection of primary and metastatic lesions within 1 year of nephrectomy and no evidence of metastatic disease prior to starting Keytruda.

Policy Summary

PayerNeighborhood Health Plan of Rhode Island

PolicyKeytruda (pembrolizumab) coverage policy

Policy CodePolicy N/A

Change TypeNo material change

Effective Date

Next Review Date

On This Page

Tumors are MSI-stable or MMR-proficient (not MSI-H/dMMR)

Second-line or subsequent therapy for MSI-H or dMMR tumorsMSI-H or dMMR

NOTE: Keytruda + cetuximab combination is not supported for initial/subsequent treatment of non-nasopharyngeal cancers

Continuation maintenance

As continuation maintenance in combination with pemetrexed (non-squamous only) or as single agent for members who achieved CR/PR/SD following first-line therapy that included chemotherapy + Keytruda

Subsequent therapy

As single agent for tumors with PD-L1 >= 1% and member had no prior progression on a PD-L1/PD-1 inhibitorPD-L1 >= 1%

Neoadjuvant/adjuvant

Neoadjuvant therapy with platinum-based chemotherapy for 4 cycles for locally advanced stages II, IIB, IIIA; may be followed by up to 13 additional cycles of Keytruda as continuation/adjuvant therapy
Adjuvant monotherapy up to 12 months following complete resection and platinum-based chemotherapy for stage IB (tumors >=4 cm), II, or IIIA regardless of PD-L1 statusMax 12 months adjuvant

OpenPayer