ERBITUX, Cetuximab Form

Cetuximab (Erbitux®) is an epidermal growth factor receptor (EGFR) antagonist.
FDA Approved Indication(s) Erbitux is indicated for treatment of: • Head and neck squamous cell carcinoma (HNSCC) o Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy for initial treatment o Recurrent locoregional disease or metastatic HNSCC in combination with platinum- based therapy with fluorouracil (5-FU) for first-line treatment o Recurrent or metastatic HNSCC progressing after platinum-based therapy, as a single agent
• Colorectal cancer (CRC) o K-Ras wild-type, EGFR-expressing, metastatic CRC as determined by an FDA-approved test
   In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy  As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan
o BRAF V600E mutation-positive metastatic CRC In combination with encorafenib, for the treatment of adult patients with metastatic CRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy Limitation(s) of use: Erbitux is not indicated for treatment of Ras-mutant CRC or when the results of the Ras mutation tests are unknown.
Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Erbitux is medically necessary when the following criteria are met:
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CLINICAL POLICY
Cetuximab I. Initial Approval Criteria
A. Head and Neck Squamous Cell Carcinoma (must meet all):

1. Diagnosis of HNSCC (see Appendix D for subtypes by location);
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is advanced, recurrent, or metastatic;
   5. Prescribed as one of the following (a or b):
      a. As a single agent; b. In combination with platinum-based therapy (e.g., cisplatin or carboplatin) or Opdivo®;Prior authorization may be required for platinum-based therapies.
2. Request meets one of the following (a, b, or c): a. Dose does not exceed an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly thereafter; b. Dose does not exceed 500 mg/m2 every 2 weeks; c. Dose 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 Approval duration: 6 months B. Colorectal Cancer (must meet all):
3. Diagnosis of CRC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is one of the following (a, b, or c): a. Wild-type RAS (defined as wild-type in both KRAS and NRAS); b. BRAF wild-type;
      c. BRAF V600E mutation positive;
4. Member has advanced, unresectable or metastatic CRC and one of the following (a or b): a. Request for use as a single agent or in combination with FOLFIRI, FOLFOX, CapeOX, or irinotecan in the initial or subsequent line setting; b. Prescribed in combination with Braftovi® if BRAF V600E mutation positive after prior therapy; Prior authorization may be required
5. For colon cancer that is KRAS/NRAS/BRAF wild-type: colon cancer is left-sided only (see Appendix E);

6. Request meets one of the following (a, b, or c): a. Dose does not exceed an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly thereafter; b. Dose does not exceed 500 mg/m2 every 2 weeks; c. Dose 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 Approval duration: 6 months Page 2 of 10

   CLINICAL POLICY
   Cetuximab C. Non-Small Cell Lung Cancer (off-label) (must meet all):

7. Diagnosis of recurrent, advanced, or metastatic non-small cell lung cancer;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Tumor is positive for a sensitizing EGFR mutation;
   5. Prescribed in combination with Gilotrif as subsequent therapy;Prior authorization may be required for Gilotrif
8. One of the following (a or b): a. Disease has progressed on or after an EGFR tyrosine kinase inhibitor (TKI) therapy (e.g., Tarceva®, Gilotrif®, or Iressa®); b. Tumor is T790M positive and disease has progressed on or after Tagrisso®; *Prior authorization may be required for Tagrisso and EGFR TKI therapies
9. 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
   Approval duration: 6 months D. Penile Cancer (off-label) (must meet all):
   
   1. Diagnosis of metastatic penile cancer;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Request is for use as a single agent as subsequent-line systemic therapy;
   5. 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 Approval duration: 6 months E. Squamous Cell Skin Cancer (off-label) (must meet all):
10. Diagnosis of squamous cell skin cancer;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Request is for use as a single agent;
    5. Disease is advanced, high-risk, very high-risk, metastatic, inoperable or not fully resectable;
11. 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 Approval duration: 6 months F. Other diagnoses/indications (must meet 1 or 2):

12. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): Page 3 of 10

    CLINICAL POLICY
    Cetuximab a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

13. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. All Indications in Section I (must meet all):
14. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Erbitux for a covered indication and has received this medication for at least 30 days;
15. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a or b):
       a. For HNSCC or CRC: New dose does not exceed 250 mg/m2 weekly or 500 mg/m2 every 2 weeks;
       b. New dose 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 Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
16. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

17. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
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    CLINICAL POLICY
    Cetuximab III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key 5-FU: fluorouracil CapeOX: capecitabine, oxaliplatin CRC: colorectal cancer EGFR: epidermal growth factor receptor FDA: Food and Drug Administration FOLFIRI: fluorouracil, leucovorin, irinotecan FOLFOXIRI: fluorouracil, leucovorin, oxaliplatin, irinotecan
    HER: human epidermal growth factor receptor HNSCC: head and neck squamous cell carcinoma
    KRAS: Kirsten rat sarcoma 2 viral oncogene FOLFOX: fluorouracil, leucovorin, homologue oxaliplatin NRAS: neuroblastoma RAS viral oncogene homologue Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Dosing Regimen Drug Name Dose Limit/ Maximum Dose See dosing regimen Modified FOLFOX 6 CapeOX FOLFIRI FOLFOXIRI CRC Day 1: oxaliplatin 85 mg/m2 IV Day 1: Folinic acid 400 mg/m2 IV Days 1–3: 5-FU 400 mg/m2 IV bolus on day 1, then 1,200 mg/m2/day × 2 days (total 2,400 mg/m2 over 46–48 hours) IV continuous infusion Repeat cycle every 2 weeks. CRC Day 1: Oxaliplatin 130 mg/m2 IV Days 1–14: Capecitabine 1,000 mg/m2 PO BID Repeat cycle every 3 weeks. CRC Day 1: Irinotecan 180 mg/m2 IV Day 1: Leucovorin 400 mg/m2 IV Day 1: Flurouracil 400 mg/m2 IV followed by 2,400 mg/m2 continuous IV over 46 hours Repeat cycle every 14 days. CRC Page 5 of 10 See dosing regimen See dosing regimen See dosing regimen

    CLINICAL POLICY
    Cetuximab Drug Name Dosing Regimen Dose Limit/ Maximum Dose Day 1: Irinotecan 165 mg/m2 IV, oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, flurouracil 1,600 mg/m2 continuous IV for 2 days (total 3,200 mg/m2) Repeat cycle every 2 weeks. 40 mg/day; 50 mg/day when on chronic concomitant therapy with a P-gp inducer 250 mg/day; 500 mg/day when used with a strong CYP3A4 inducer 80 mg/day; 160 mg/day when used with a strong CYP3A inducer 150 mg/day; 450 mg/day when used with a strong CYP3A4 inducer or 300 mg/day when used with a moderate CYP1A2 inducer See dosing regimen See dosing regimen Gilotrif (afatinib) Metastatic NSCLC 40 mg PO QD Iressa® (gefitinib) Metastatic NSCLC 250 mg PO QD Tagrisso® (osimertinib) NSCLC 80 mg PO QD erlotinib (Tarceva®) Metastatic NSCLC 150 mg PO QD TIP (paclitaxel, ifosfamide, cisplatin) 5-FU, cisplatin, carboplatin Penile Cancer Paclitaxel 175 mg/m2 IV on day 1; ifosfamide 1,200 mg/m2 IV on day 1-3; cisplatin 25 mg/m2 IV on day 1-3 Repeat every 3 to 4 weeks. HNSCC
    cisplatin 100 mg/m2 IV or carboplatin AUC 5 IV on day 1, plus 5-FU 1,000 mg/m2 IV on days 1, 2, 3, and 4, repeated every 3 weeks Penile Cancer 5-FU 800 - 1,000 mg/m2/day continuous IV on days 1-4 or 2-5; cisplatin 70-80 mg/m2 IV on day 1 Repeat every 3 to 4 weeks. Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): infusions reactions, cardiopulmonary arrest Page 6 of 10

    CLINICAL POLICY
    Cetuximab Appendix D: Head and Neck Squamous Cell Cancers by Location • Paranasal sinuses (ethmoid, maxillary) • Larynx (glottis, supraglottis) • Pharynx (nasopharynx, oropharynx, hypopharynx) • Lip and oral cavity • Major salivary glands (parotid, submandibular, sublingual) • Occult primary __ Squamous cell carcinoma, or a variant, is the histologic type in more than 90% of head and neck cancers. Appendix E: KRAS/NRAS/BRAF Wild-Type Colon Cancer • The NCCN Colon Cancer Guidelines recommend that cetuximab should only be used for left-sided tumors. The panel defines the left side of the colon as splenic flexure to rectum. Evidence suggests that patients with tumors originating on the right side of the colon (hepatic flexure through cecum) are unlikely to respond to cetuximab. Data on the response to cetuximab in patients with primary tumors originating in the transverse colon (hepatic flexure to splenic flexure) are lacking.
    V. Dosage and Administration
    Indication HNSCC, CRC Weekly schedule: initial dose 400 mg/m2 IV Dosing Regimen followed by 250 mg/m2 IV weekly Maximum Dose See dosing regimen Biweekly schedule: initial and subsequent doses 500 mg/m2 IV every 2 weeks VI. Product Availability
    Single-dose vials: 100 mg/50 mL, 200 mg/100 mL VII.