ModifiedmhnPolicy CP.PHAR.107

Regorafenib (Stivarga)

Defines medical necessity and prior authorization criteria for regorafenib (Stivarga) for multiple malignancies and off-label uses for members covered under Centene-affiliated health plans (Commercial, HIM, Medicaid). Applies to providers requesting coverage for regorafenib.

Policy Summary

Payermhn

PolicyRegorafenib (Stivarga)

Policy CodePolicy CP.PHAR.107

Change TypeMultiple clinical updates & additions (NCCN-aligned)

Effective DateDec 1, 2012

Next Review Date

Key ActionSubmit prior authorization with documentation showing member meets the listed criteria (diagnosis, prior therapies, age ≥18, dose ≤160 mg/day on days 1–21) and supporting clinical records.

SourceLink

POLICY UPDATE CHANGES

For HCC, removed requirement for Child-Pugh class A disease per NCCN.

Added off-label criteria set for uterine sarcoma per NCCN.

Commercial approval duration modified to '12 months or duration of request, whichever is less'.

Dosing clarified to allow 160 mg per day on days 1 to 21 of each 28-day cycle.

For CRC, appendiceal carcinoma was added as a coverable diagnosis with specified prior therapies by disease characteristics (pMMR/MSS, dMMR/MSI-H, POLE/POLD1) per NCCN.

For GIST, disease qualifiers were updated and Qinlock recommended if intolerant to Sutent for single-agent therapy; SDH mutation-positive revised to SDH-deficient per NCCN.

For soft tissue sarcoma, Stivarga was specified as subsequent therapy for pleomorphic rhabdomyosarcoma per NCCN.

For bone cancers, Ewing sarcoma, mesenchymal chondrosarcoma, dedifferentiated chondrosarcoma, and high-grade undifferentiated pleomorphic sarcoma were added as coverable cancer types with an additional disease qualifier of progressive per NCCN.

Glioblastoma was revised to central nervous system cancer and additional coverable CNS cancers (gliosarcoma, H3‑mutated high-grade glioma) and qualifier of progressive were added per NCCN.

For HCC, the requirement for Child-Pugh class A disease was removed per NCCN.

An off-label criteria set for uterine sarcoma was added per NCCN.

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Coverage Criteria

Initial Therapy — Colorectal Cancer

Covered when ALL of the following are met:

CRC initial: 1. Diagnosis of advanced or metastatic colorectal cancer (including appendiceal carcinoma); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Previously treated with one of the following: (a) for pMMR/MSS disease: systemic chemotherapy; OR (b) for dMMR/MSI-H or POLE/POLD1 mutation disease: checkpoint inhibitor immunotherapy unless ineligible; 5. Prescribed as a single agent; 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — GIST

Covered when ALL of the following are met:

GIST initial: 1. Diagnosis of gastrointestinal stromal tumor (GIST); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Disease is gross residual (R2 resection), unresectable, tumor rupture, recurrent, metastatic, or locally advanced; 5. Prescribed in one of the following ways: (a) as a single agent after prior imatinib and sunitinib (Qinlock if intolerant to sunitinib), unless clinically significant adverse effects or contraindicated; OR (b) for SDH-deficient disease (off-label) as a single agent; OR (c) in combination with everolimus after progression on approved therapies (imatinib, sunitinib, Qinlock) (off-label); 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — HCC

Covered when ALL of the following are met:

HCC initial: 1. Diagnosis of hepatocellular carcinoma (HCC); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Prescribed as a single agent; 5. Prescribed as second- or subsequent-line therapy; 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — Soft Tissue Sarcoma (off-label)

Covered when ALL of the following are met for specified sarcoma subtypes:

Soft tissue sarcoma initial: 1. Diagnosis of one of the following soft tissue sarcomas: (a) non-adipocytic sarcoma as subsequent therapy for advanced, metastatic, recurrent unresectable or recurrent stage IV disease; (b) pleomorphic rhabdomyosarcoma as subsequent therapy for advanced or metastatic disease; (c) angiosarcoma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Prescribed as a single agent; 5. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 6. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — Bone Cancer (off-label)

Covered when ALL of the following are met for listed bone cancers:

Bone cancer initial: 1. Diagnosis of one of the following bone cancers: osteosarcoma; Ewing sarcoma; mesenchymal chondrosarcoma; dedifferentiated chondrosarcoma; high-grade undifferentiated pleomorphic sarcoma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Request is for second-line therapy for relapsed/refractory, progressive, or metastatic disease; 5. Prescribed as a single agent; 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — CNS Cancer (off-label)

Covered when ALL of the following are met for listed CNS cancers:

CNS cancer initial: 1. Diagnosis of one of the following central nervous system cancers: glioblastoma; gliosarcoma; H3‑mutated high‑grade glioma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Disease is recurrent or progressive; 5. Prescribed as a single agent; 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Initial Therapy — Uterine Sarcoma (off-label)

Covered when ALL of the following are met for listed uterine sarcomas:

Uterine sarcoma initial: 1. Diagnosis of one of the following uterine sarcomas: endometrial stromal sarcoma; undifferentiated uterine sarcoma; adenosarcoma; PEGoma; leiomyosarcoma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Disease is advanced, recurrent/metastatic, or inoperable; 5. Prescribed as a single agent; 6. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following: (a) dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Other indications / Off-label referral

Other indications not specifically listed:

Other uses: 1. If the drug has recently (within the last 6 months) undergone a label change that is not yet reflected in this policy, refer to the applicable formulary or non-formulary/no-coverage-criteria policy for the relevant line of business as specified; 2. If the requested use is not listed under section III (Diagnoses/Indications for which coverage is NOT authorized) and criterion 1 does not apply, refer to the off-label use policy for the relevant line of business (CP.CPA.09, HIM.PA.154, CP.PMN.53).

Continuation Therapy

Covered when ALL of the following are met for continuation:

Continuation: 1. Member is currently receiving medication via Centene benefit or documentation supports that member has received Stivarga for a covered indication for at least 30 days; 2. Member is responding positively to therapy; 3. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 4. If request is for a dose increase, new dose must meet one of: (a) does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

All Indications in Section I

Covered when ALL of the following are met:

All indications general requirements: 1. Currently receiving medication via Centene benefit, or documentation supports that member has received Stivarga for a covered indication for at least 30 days; 2. Member is responding positively to therapy; 3. For brand Stivarga requests, member must use generic regorafenib if available unless contraindicated or clinically significant adverse effects are experienced; 4. If request is for dose increase, new dose must either: (a) not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; OR (b) be supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA-approved or recommended by NCCN

Updated covered indications / disease qualifiers

Policy coverage updated to include the following NCCN-aligned conditions/qualifiers:

CRC_appendiceal: Appendiceal carcinoma added as a coverable diagnosis; prior therapies required depend on molecular status (pMMR/MSS, dMMR/MSI-H, POLE/POLD1) per NCCN.

Source: 2Q 2024 annual review

GIST_updates: GIST disease qualifiers updated; Qinlock recommended if intolerant to Sutent for single-agent therapy; terminology changed from SDH mutation-positive to SDH-deficient per NCCN.

Source: 2Q 2024 annual review

Soft_Tissue_Sarcoma: Stivarga specified as subsequent therapy for pleomorphic rhabdomyosarcoma per NCCN.

Source: 2Q 2024 annual review

Bone_Cancers:

If regorafenib has received a label change within the last 6 months that is not yet reflected in this policy (for example, a newly approved indication, age expansion, or dosing modification), follow the appropriate formulary or non‑formulary policy for the member's line of business rather than this clinical policy. See the listed policies for each line of business (e.g., CP.CPA.190, HIM.PA.33, CP.PMN.255 for formulary/no‑coverage criteria; CP.CPA.190, HIM.PA.103, CP.PMN.16 for non‑formulary) to determine coverage and requirements.

Requests for uses that are not FDA‑approved and not specifically addressed in this policy are excluded unless the provider submits sufficient documentation of efficacy and safety consistent with the applicable off‑label use policy or evidence of coverage documents. Refer to the off‑label use policies for the relevant line of business (e.g., CP.CPA.09, HIM.PA.154, CP.PMN.53) for requirements to support coverage.

For members covered under Medicaid, state Medicaid coverage provisions take precedence when they conflict with this clinical policy. Providers should consult the applicable state Medicaid manual for the controlling coverage rules and any state‑specific requirements.

Use of regorafenib for non‑FDA approved indications without sufficient supporting off‑label evidence is considered not authorized. Such requests should be evaluated against the applicable off‑label policy and denied if the required documentation of efficacy and safety is not provided.

This clinical policy is intended as a guide to medical necessity to assist with coverage determinations and benefit administration. It does not constitute medical advice, guarantee coverage, or replace clinician judgment. Coverage decisions remain subject to the member's plan terms, exclusions, limitations, and applicable legal and regulatory requirements.

Provider Actions and Requirements

Denial Risk

Non‑FDA approved indications

Prior authorization is required for Stivarga (regorafenib). Requests for non‑FDA approved indications that are not specifically addressed in this policy will be denied unless the provider submits sufficient documentation of efficacy and safety consistent with the plan's off‑label use policies (CP.CPA.09 for commercial, HIM.PA.154 for Health Insurance Marketplace, and CP.PMN.53 for Medicaid) or other evidence of coverage documents.

Non‑FDA approved indications require supporting documentation per applicable off‑label policies: CP.CPA.09 (commercial), HIM.PA.154 (HIM), CP.PMN.53 (Medicaid).

Prior Authorization

Coverage contingent on NCCN‑specified qualifiers/prior therapies

Coverage for many indications is contingent on meeting NCCN‑specified disease qualifiers and prior‑therapy requirements. Requests that do not meet the disease‑specific prior therapy or qualifier requirements per NCCN (for example, prior systemic chemotherapy for pMMR/MSS colorectal cancer, checkpoint inhibitor therapy for dMMR/MSI‑H colorectal cancer when eligible, prior imatinib and sunitinib for GIST, or specified prior lines for HCC/bone/soft tissue cancers) will be denied.

Line of Therapy Requirements

second-line | subsequent

Line requirements: Colorectal cancer: prior systemic therapy requirements depend on molecular status (pMMR/MSS require systemic chemotherapy; dMMR/MSI-H or POLE/POLD1 require prior checkpoint inhibitor immunotherapy unless ineligible); Hepatocellular carcinoma: previously treated with sorafenib (second- or subsequent-line); Bone cancers: second-line therapy for relapsed/refractory/progressive/metastatic disease; GIST: previously treated with imatinib and sunitinib (Qinlock if intolerant to sunitinib).

subsequent therapy

GIST prior therapy requirement: For GIST, prior treatment with imatinib and sunitinib is required for single-agent regorafenib use; Qinlock should be used if intolerant to sunitinib for single-agent therapy per NCCN guidance.

subsequent therapy

Covered Regimens and Dosing

Regimen	Indication / Notes	Coverage Status
Regorafenib as single agent, standard dosing up to 160 mg daily on days 1-21 of each 28-day cycle
FDA-approved and NCCN-recommended regimens for listed indications (metastatic colorectal cancer, previously treated GIST, hepatocellular carcinoma, and specified off-label tumor types per NCCN updates)
Covered with criteria

Dose	Applies to	Maximum/day
160 mg PO once daily for the first 21 days of each 28-day cycle
Colorectal cancer (metastatic), Gastrointestinal stromal tumor (GIST), Hepatocellular carcinoma (HCC)
160 mg/day

Guidance / Recommendation	Clinical Context	Coverage Status
Use Qinlock (ripretinib) if patient is intolerant to sunitinib (Sutent) for GIST single-agent therapy; consider regorafenib (Stivarga) per NCCN as a subsequent-line option when indicated
Policy specifies Qinlock as the recommended alternative when intolerance to sunitinib exists; regorafenib remains a covered subsequent therapy for specified GIST scenarios per NCCN updates
Covered with criteria

Coding and Dose Key Values

Regorafenib dosing schedule — inv-17

Standard dosing160 mg PO QD for the first 21 days of each 28-day cycle

Maximum daily doseMaximum 160 mg/day (on days 1–21 of each 28-day cycle)

Administration routeOral (PO)

Cycle length28-day cycle (treatment on days 1–21)

Biomarker and Diagnostic Requirements

dMMR/MSI-H; POLE/POLD1 — inv-44

Required biomarker (CRC pathway)dMMR/MSI-H or POLE/POLD1 mutation status used to identify patients for checkpoint inhibitor prior therapy pathway

Role in prior therapy decisiondMMR/MSI-H or POLE/POLD1 → checkpoint inhibitor immunotherapy expected unless ineligible

Terminology sourceDefined per NCCN-based policy criteria and Appendices

pMMR/MSS, dMMR/MSI-H, POLE/POLD1 — inv-45

Biomarker categories referencedpMMR/MSS, dMMR/MSI-H, POLE/POLD1

UseStratifies required prior therapies for colorectal and appendiceal carcinoma per NCCN guidance

Definitions

Regorafenib (Stivarga) — inv-32

Drug class/descriptionA kinase/vascular endothelial growth factor receptor (VEGFR) inhibitor

FDA-approved indicationsMetastatic colorectal cancer (previously treated), advanced GIST (previously treated with imatinib and sunitinib), and hepatocellular carcinoma (previously treated with sorafenib)

Dosage form infoOral tablets; standard regimen 160 mg PO QD on days 1–21 of each 28-day cycle

Policy contextUsed as single-agent therapy in most covered indications per policy criteria

pMMR/MSS and dMMR/MSI-H — inv-33

DefinitionpMMR/MSS and dMMR/MSI-H refer to mismatch repair proficiency status used to guide prior therapy requirements in colorectal cancer

Background

Regorafenib (Stivarga) is an oral multikinase inhibitor with activity against vascular endothelial growth factor receptors (VEGFR) and other kinases. It is FDA‑approved for certain previously treated malignancies including metastatic colorectal cancer, advanced gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma after prior therapy. The standard dosing regimen referenced in this policy is 160 mg PO once daily for the first 21 days of each 28‑day cycle (maximum 160 mg/day on treatment days).

Documentation Required

Required documentation for continuation and brand requests

For continuation or brand‑name Stivarga requests, the provider must submit documentation that the member is currently receiving regorafenib through the Centene benefit or evidence that the member has received Stivarga for at least 30 days for a covered indication, and that the member is responding to therapy. For brand requests, documentation must also justify why generic regorafenib is not being used (contraindication or clinically significant adverse effects). If requesting a dose increase, provide documentation supporting the new dose (must not exceed 160 mg/day on days 1–21 of each 28‑day cycle unless supported by practice guidelines or peer‑reviewed literature).

Documentation examples: office chart notes, treatment start date, progress notes showing clinical response, prior authorization or pharmacy claims showing prior supply (≥30 days).
Brand request justification: clinical rationale or intolerance to generic regorafenib.
Dose increase: supporting literature or guideline citation if exceeding standard dosing limits.

Step Therapy

Prior‑line therapy requirements

Prior‑line therapy requirements apply across indications and must be documented at the time of the request. Examples include prior systemic chemotherapy for pMMR/MSS colorectal cancer, prior checkpoint inhibitor therapy for eligible dMMR/MSI‑H or POLE/POLD1 colorectal cancer, prior imatinib and sunitinib (or Qinlock if intolerant to sunitinib) for GIST, and required second‑line or subsequent‑line status for certain bone, soft tissue, uterine sarcoma, and HCC indications. Providers must submit prior treatment history (agents, dates, and reasons for discontinuation if applicable).

Include prior regimen names, start/stop dates, response or intolerance details, and documentation that alternative recommended agents were tried unless contraindicated.
See Appendix B for therapeutic alternatives and typical regimens to support prior therapy documentation.