Zynyz (pembrolizumab?) — indications for select solid tumors
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Defines coverage and prior authorization requirements for Zynyz for specified cancer indications and biomarker-driven uses for BlueCross BlueShield of Tennessee members.
No material clinical or coverage changes in this revision.
Coverage Criteria for Zynyz
FDA-indicated uses
Covered indications when FDA-approved or compendial uses and approval criteria are met:
dMMR/MSI-H / POLE/POLD1 ultra-hypermutated tumors
Covered tumor types for biomarker-driven single-agent use when all biomarker criteria met:
SCAC initial and subsequent therapy criteria
SCAC treatment scenarios that may be authorized:
Reauthorization — criteria and maximum combined authorization durations
Reauthorization criteria
Coverage will not be provided for members who have experienced disease progression while on a PD‑1 or PD‑L1 inhibitor agent; such members are excluded from authorization for Zynyz.
Indications not specifically listed in this policy — other than treatment of Merkel cell carcinoma (MCC), squamous cell carcinoma of the anal canal (SCAC), and the specified biomarker‑selected appendiceal, colorectal, and small bowel tumors — are considered experimental/investigational and are outside the scope of coverage for Zynyz.
Requests for Zynyz for any other tumor types or clinical situations not described in this policy will be considered not medically necessary because they are experimental or investigational per the policy statements.
Covered Regimens and Treatment Settings
| Regimen | Indication / line of therapy | Authorization notes |
|---|---|---|
| Zynyz + carboplatin + paclitaxel | First‑line treatment of inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) | Authorization of 6 months may be granted for primary metastatic or recurrent disease; reauthorization permitted per policy (combination therapy reauthorization up to 12 months total) |
| Regimen | Indication / line of therapy | Authorization notes |
|---|---|---|
| Zynyz (single‑agent) | Locally recurrent or metastatic SCAC after progression on or intolerance to platinum‑based chemotherapy (subsequent therapy) | Authorization of 6 months may be granted; reauthorization for single‑agent SCAC allowed up to 24 months total when no unacceptable toxicity or progression is present |
| Zynyz (single‑agent) | Metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) | Authorization of 6 months may be granted as a single agent; reauthorization allowed per policy (up to 24 months total for single‑agent indications) |
| Zynyz (single‑agent) | Biomarker‑selected gastrointestinal tumors (appendiceal neoplasms, colorectal cancer, small bowel adenocarcinoma) with dMMR/MSI‑H or POLE/POLD1 mutation and ultra‑hypermutated TMB (>50 mut/Mb) | Authorization of 6 months may be granted; reauthorization for listed single‑agent indications allowed up to 24 months total when no unacceptable toxicity or progression is present |
Provider Actions, Documentation, and Prior Authorization
Prior Authorization Required
Prior authorization is required for both initial requests and reauthorizations. Typical initial and reauthorization periods are 6 months. Reauthorization may be granted when there is no evidence of unacceptable toxicity or disease progression while on the current regimen; duration limits vary by indication (see policy for indication-specific total duration limits).
- Initial authorization period: typically 6 months.
- Reauthorization: typically 6-month intervals; indication-specific cumulative limits apply (e.g., SCAC combination up to 12 months total; SCAC single-agent up to 24 months total; other indications up to 24 months total).
SCAC Sequencing / Combination
For Squamous Cell Carcinoma of the Anal Canal (SCAC), document the intended sequencing or combination: the medication may be used in combination with carboplatin and paclitaxel for primary metastatic or recurrent disease, or as single-agent subsequent therapy for locally recurrent or metastatic disease after progression on or intolerance to platinum-based chemotherapy. Reauthorization for SCAC in combination with carboplatin and paclitaxel may be granted for continued treatment (up to 12 months total) if no unacceptable toxicity or disease progression has occurred; single-agent reauthorization may be granted (up to 24 months total) under the same conditions.
- Combination use: with carboplatin + paclitaxel for primary metastatic or recurrent SCAC.
- Single-agent use: subsequent therapy for locally recurrent/metastatic SCAC after progression on or intolerance to platinum-based chemotherapy.
- Reauthorization limits: combination SCAC — up to 12 months total; single-agent SCAC — up to 24 months total, contingent on absence of progression/toxicity.
Required Biomarker Documentation
Submit laboratory documentation confirming tumor biomarker status when applicable. A lab report or pathology report must demonstrate one of the following: microsatellite instability-high (MSI-H), deficient mismatch repair (dMMR), or polymerase epsilon/delta (POLE/POLD1) mutation associated with an ultra-hypermutated tumor mutational burden (TMB > 50 mutations/megabase).
- Acceptable documentation: laboratory or pathology report showing MSI-H or dMMR status.
- When claiming POLE/POLD1 ultra-hypermutated phenotype: submit molecular testing showing POLE or POLD1 mutation with TMB > 50 mut/Mb.
- Documentation must be included with the prior authorization request.
Prior PD-1/PD-L1 Progression Exclusion
Coverage will be denied for members who experienced disease progression while on prior PD-1 or PD-L1 inhibitor therapy.
- Exclude members with documented progression on PD-1 or PD-L1 inhibitors.
Biomarker Requirements and Thresholds
Include lab reports and numeric TMB values for biomarker evidence
Include the laboratory report(s) showing the biomarker test results with the prior authorization request: clearly document MSI-H or dMMR status, POLE/POLD1 mutation when required, and the numeric TMB value when claiming an ultra-hypermutated phenotype (>50 mut/Mb).
- Attach the specific lab report(s) (not just a summary) demonstrating MSI-H or dMMR and/or POLE/POLD1 mutation.
- When relying on ultra-hypermutated status, include the reported TMB numeric value and testing methodology showing >50 mut/Mb.
Line of Therapy Specifications
first-line
First-line coverage criteria:
second-line
Second-line coverage criteria:
Coding and Billing
| No codes listed |
Background
Zynyz is indicated for multiple advanced or metastatic solid tumor types in specific settings, including Merkel cell carcinoma (MCC) and squamous cell carcinoma of the anal canal (SCAC). For certain gastrointestinal tumors (appendiceal, colorectal, small bowel), single‑agent use is limited to tumors with documented dMMR/MSI‑H or POLE/POLD1 mutation and an ultra‑hypermutated tumor mutational burden (TMB > 50 mut/Mb). Prior authorization is required and treatments are authorized only when the policy’s specified clinical and biomarker criteria are met.
Definitions
Revision History
Medical Policy Manual approved; effective date 2026-07-31 (do not implement until this date).
Zynyz package insert (Incyte Corporation) dated May 2025 added to references supporting indications and labeling.
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