OPDIVO, Nivolumab Form

Nivolumab (Opdivo®) is a programmed death receptor-1 (PD-1) blocking antibody. FDA Approved Indication(s) Opdivo is indicated for the treatment of: • Melanoma o Adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. o Adult and pediatric (12 years and older) patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma, in the adjuvant setting. • Non-small cell lung cancer (NSCLC) o Adult patients with resectable (tumors ≥ 4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. o Adult patients with metastatic NSCLC expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab. o Adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy.
o Adult patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Opdivo. • Malignant pleural mesothelioma o Adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab. • Renal cell carcinoma (RCC) o Adult patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. o Adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. o Adult patients with intermediate or poor risk advanced RCC, as a first-line treatment in combination with ipilimumab. Page 1 of 20

CLINICAL POLICY Nivolumab • Classical Hodgkin lymphoma (cHL) o Adult patients with cHL that has relapsed or progressed after:  autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or  3 or more lines of systemic therapy that includes autologous HSCT. • Squamous cell carcinoma of the head and neck (SCCHN) o Adult patients with recurrent or metastatic SCCHN with disease progression on or after a platinum-based therapy. • Urothelial carcinoma (UC) o Adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC. o Adult patients with locally advanced or metastatic UC who:  have disease progression during or following platinum-containing chemotherapy, or  have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. • Colorectal cancer o Adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab. • Hepatocellular carcinoma (HCC) o Adult patients with HCC who have been previously treated with sorafenib in combination with ipilimumab. • Esophageal cancer o As adjuvant treatment in adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy (CRT). o In combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). o In combination with ipilimumab for the first-line treatment of adult patients with unresectable advanced or metastatic ESCC. o Adult patients with unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. • Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma o Adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy. _ *This indication is approved under accelerated approval based on overall or tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Policy/Criteria Provider must submit documentation (including such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
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CLINICAL POLICY Nivolumab It is the policy of health plans affiliated with Centene Corporation® that Opdivo is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Melanoma (must meet all):

1. Diagnosis of melanoma that is either (a or b): a. Unresectable or metastatic; b. Resected stage IIB, IIC, or III;
2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 12 years;
   4. Request meets one of the following (a, b, or c): a. If prescribed as monotherapy (unresectable or metastatic disease, or adjuvant treatment), dose does not exceed any of the following (i or ii):
      i. Adult and pediatric members weighing ≥ 40 kg: 240 mg every 2 weeks or 480 mg every 4 weeks; ii. Pediatric members weighing < 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks (see Appendix E for dose rounding guidelines); b. If prescribed in combination with Yervoy® (unresectable or metastatic disease), dose does not exceed any of the following (i or ii; see Appendix E for dose rounding guidelines):
      i. Adult and pediatric members weighing ≥ 40 kg: 1 mg/kg every 3 weeks for 4 doses, followed by 240 mg every 2 weeks or 480 mg every 4 weeks;
      ii. Pediatric members weighing < 40 kg: 1 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 2 weeks or 6 mg/kg every 4 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. Non-Small Cell Lung Cancer (must meet all):
3. Diagnosis of resectable, recurrent, advanced, or metastatic NSCLC;
   
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Member has not previously progressed on a PD-1/PD-L1 inhibitor (e.g., Keytruda®, Tecentriq®, Imfinzi®);
4. For resectable NSCLC: Both of the following are met (a and b): a. Opdivo is prescribed as neoadjuvant treatment; b. Tumors ≥ 4 cm or node positive disease;

5. For recurrent, advanced, or metastatic NSCLC: Opdivo is prescribed in one of the following ways (a, b, or c): a. For use as a single agent, and disease has progressed on or after systemic therapy; b. For use as a single agent or in combination with Yervoy for tumors positive for the Tumor Mutation Burden (TMB) biomarker; c. For use in combination with Yervoy, and both of the following (i and ii): i. Request meets one of the following (a, b, or c): Page 3 of 20

   CLINICAL POLICY Nivolumab a) Disease mutation status is unknown or negative for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, and RET, and member has not received prior systemic therapy for advanced disease; b) Disease mutation status is positive for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, or NTRK gene fusion, and member has received mutation-specific treatment; c) Disease is positive for a RET rearrangement; ii. Request meets one of the following (a or b): a) Member has PD-L1 tumor expression of ≥ 1%; b) Opdivo is being used in combination with Yervoy ± a platinum-based regimen (see Appendix B); *Prior authorization may be required for Yervoy

   7. Request meets one of the following (a, b, c, d, or e): a. Monotherapy: Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; b. In combination with Yervoy: Dose does not exceed 3 mg/kg every 2 weeks (see Appendix E for dose rounding guidelines); c. In combination with Yervoy and platinum-doublet chemotherapy: Dose does not exceed 360 mg every 3 weeks; d. In combination with platinum-doublet chemotherapy, both of the following are met (i and ii): i. Dose does not exceed 360 mg every 3 weeks; ii. Request does not exceed 3 cycles; e. 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 (9 weeks for neoadjuvant NSCLC) C. Malignant Pleural Mesothelioma (must meet all):
6. Diagnosis of unresectable malignant pleural mesothelioma;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed in one of the following ways (a or b): a. As first-line therapy in combination with Yervoy; b. If not administered first-line, as subsequent therapy in combination with Yervoy or as a single agent;
7. Request meets one of the following (a or b): a. Dose does not exceed 360 mg every 3 weeks; b. 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 D. Renal Cell Carcinoma (must meet all):

8. Diagnosis of RCC;

   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
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   CLINICAL POLICY Nivolumab

9. Request meets one of the following (a, b, or c): a. Monotherapy or in combination with cabozantinib: Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; b. In combination with Yervoy: Dose does not exceed 3 mg/kg every 3 weeks for 4 doses, followed by 240 mg every 2 weeks or 480 mg every 4 weeks (see Appendix E for dose rounding guidelines); 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 E. Classical Hodgkin Lymphoma (must meet all):
10. Diagnosis of relapsed, refractory, or progressive cHL;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed as subsequent therapy;
    5. Request meets one of the following (a or b): a. Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; b. 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 F. Squamous Cell Carcinoma of the Head and Neck (must meet all):
11. Diagnosis of SCCHN;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed as a single agent;
    5. Disease has progressed on or after a platinum-containing regimen (e.g., cisplatin, carboplatin);
12. Request meets one of the following (a or b): a. Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; b. 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 G. Urothelial Carcinoma (must meet all):

13. Diagnosis of UC;

    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. One of the following (a, b, or c): a. Failure of a platinum-containing regimen (e.g., cisplatin, carboplatin), unless clinically significant adverse effects are experienced or all are contraindicated; b. Prescribed as adjuvant treatment and member is at high risk of recurrence after undergoing resection of UC; Page 5 of 20

    CLINICAL POLICY Nivolumab c. Member is at high risk of recurrence and did not previously receive a platinum- containing regimen;

14. Request meets one of the following (a or b): a. Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; b. 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 H. Colorectal Cancer (must meet all):
15. Diagnosis of unresectable or metastatic CRC;
    2. Tumor is characterized as MSI-H or dMMR;
    3. Prescribed by or in consultation with an oncologist;
    4. Age ≥ 12 years;
    5. Dose does not exceed one of the following (a, b, or c):
       a. Monotherapy: 240 mg every 2 weeks; b. In combination with Yervoy: 3 mg/kg every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks (see Appendix E for dose rounding guidelines); 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 I. Hepatocellular Carcinoma (must meet all):
16. Diagnosis of HCC;
    
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. One of the following (a or b): a. Documentation of Child-Pugh Class A status and both of the following (i and ii): i. Member has had disease progression following treatment with Nexavar®, Lenvima®, Tecentriq® + bevacizumab (Mvasi® and Zirabev™ are preferred), or Imfinzi®; *Prior authorization may be required for Nexavar, Lenvima, Tecentriq, bevacizumab, and Imfinzi. ii. Prescribed in combination with Yervoy; b. Documentation of Child-Pugh Class B status and prescribed as a single agent
       (off-label);

17. Dose does not exceed one of the following (a or b):
    a. In combination with Yervoy: 1 mg/kg every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks (see Appendix E for dose rounding guidelines); b. 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 6 of 20

    CLINICAL POLICY Nivolumab J. Esophageal Cancer (must meet all):

18. Diagnosis of one of the following (a or b): a. Completely resected esophageal cancer or gastroesophageal junction (esophagogastric junction; EGJ) cancer; b. Unresectable advanced, recurrent, or metastatic ESCC;
19. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. For completely resected esophageal cancer or EGJ cancer, member meets both of the following (a and b): a. Member has residual pathologic disease; b. Member has previously received CRT;
20. For ESCC, one of the following (a or b):
    a. For unresectable advanced or metastatic disease: Prescribed in combination with Yervoy or with fluoropyrimidine- and platinum-containing chemotherapy; b. For unresectable advanced, recurrent, or metastatic disease: Member has had previous treatment with a fluoropyrimidine-based (e.g., 5-fluorouracil, capecitabine) and platinum-based (e.g., carboplatin, cisplatin, oxaliplatin) chemotherapy;
21. Request meets one of the following (a, b, or c):
    a. ESCC in combination with Yervoy: Dose does not exceed 3 mg/kg every 2 weeks or 360 mg every 3 weeks; b. Other indications: Dose does not exceed 240 mg every 2 weeks or 480 mg every 4 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 K. Gastric and Esophageal Adenocarcinomas (must meet all):
22. Diagnosis of gastric cancer, EGJ cancer, or esophageal adenocarcinoma;
    2. Member meets one of the following (a or b): a. Disease is advanced, recurrent, or metastatic; b. For EGJ cancer or esophageal adenocarcinoma: member meets one of the following (i or ii):
       i. Member is post-operative following chemoradiation; ii. Disease is advanced, recurrent, or metastatic;
    3. Prescribed by or in consultation with an oncologist;
    4. Age ≥ 18 years;
    5. For advanced, recurrent, or metastatic disease: both of the following are met (a and b):
       a. Prescribed in combination with a fluoropyrimidine- (e.g., 5-fluorouracil, capecitabine) and platinum-containing (e.g., carboplatin, cisplatin, oxaliplatin) chemotherapy; b. Disease is HER2-negative;

23. Request meets one of the following (a or b):*
    a. Dose does not exceed 240 mg every 2 weeks or 360 mg every 3 weeks; Page 7 of 20

    CLINICAL POLICY Nivolumab b. 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 L. Off-label NCCN Compendium Recommended Indications (must meet all):

24. Diagnosis of one of the following (a-o): a. Squamous cell anal carcinoma that is metastatic; b. Merkel cell carcinoma; c. Gestational trophoblastic neoplasia; d. Uveal melanoma that is metastatic; e. Small bowel adenocarcinoma that is advanced or metastatic; f. Extranodal NK/T-cell lymphoma, nasal type, that is relapsed or refractory; g. Pediatric Hodgkin lymphoma, as subsequent therapy; h. Vulvar cancer - HPV-related advanced, recurrent, or metastatic disease, as second-line treatment; i. Cervical cancer; j. Endometrial carcinoma that is recurrent or metastatic;
    k. Small cell lung cancer, as subsequent therapy; l. Bone cancer (e.g., Ewing Sarcoma, chordoma, osteosarcoma, chondrosarcoma);
    m. Central nervous system (CNS) cancer (e.g., brain metastases); n. Pediatric primary mediastinal large B-cell lymphoma; o. Pediatric diffuse high-grade gliomas;
25. Prescribed by or in consultation with an oncologist;
    3. For anal carcinoma: prescribed as second line or subsequent therapy (examples of prior therapy include 5-FU/cisplatin, carboplatin/paclitaxel, FOLFOX, FOLFCIS);
    4. For gestational trophoblastic neoplasia: prescribed as a single agent for multi-agent chemotherapy-resistant disease (see Appendix B) in one of the following settings (a or b): a. Recurrent or progressive intermediate trophoblastic tumor following treatment with a platinum-containing regimen (e.g., cisplatin, carboplatin); b. High-risk disease (see Appendix D);
26. For pediatric primary mediastinal large B-cell lymphoma: prescribed as one of the following (a or b):
    a. As a single agent as second line therapy after failure of induction therapy/initial treatment (see appendix B);
    b. Combination with brentuximab vedotin as consolidation/additional therapy;
    
    6. For pediatric diffuse high-grade gliomas: prescribed as a single agent for adjuvant therapy or for recurrent/progressive disease;
27. For uveal melanoma, bone cancer, CNS cancer: prescribed as a single agent or in combination with Yervoy; *Prior authorization may be required for Yervoy.
28. For cervical cancer: prescribed as second line or subsequent therapy for PD-L1 tumor expression of ≥ 1%;

29. 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).* Page 8 of 20

    CLINICAL POLICY Nivolumab *Prescribed regimen must be FDA-approved or recommended by NCCN
    Approval duration: 6 months M. Other diagnoses/indications (must meet 1 or 2):

30. 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
31. 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):
32. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Opdivo for a covered indication and has received this medication for at least 30 days;

33. Member is responding positively to therapy;

    3. If request is for a dose increase, request meets one of the following (a, b, c, d, e, or f):* a. NSCLC in combination with Yervoy: New dose does not exceed 3 mg/kg every 2 weeks; b. Malignant pleural mesothelioma in combination with Yervoy, and gastric and esophageal adenocarcinomas: New dose does not exceed 360 mg every 3 weeks; c. ESCC in combination with Yervoy: New dose does not exceed 3 mg/kg every 2 weeks or 360 mg every 3 weeks; d. Melanoma (i or ii):
       i. If prescribed as monotherapy (unresectable or metastatic disease, or adjuvant treatment), new dose does not exceed any of the following (a or b):
       a) Adult and pediatric members weighing ≥ 40 kg: 240 mg every 2 weeks or 480 mg every 4 weeks; b) Pediatric members weighing < 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks; ii. If prescribed in combination with Yervoy (unresectable or metastatic disease), new dose does not exceed any of the following (a or b):
       a) Adult and pediatric members weighing ≥ 40kg: 1 mg/kg every 3 weeks for 4 doses, followed by 240 mg every 2 weeks or 480 mg every 4 weeks;
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    CLINICAL POLICY Nivolumab b) Pediatric members weighing < 40 kg: 1 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks; e. Other indications: New dose does not exceed 240 mg every 2 weeks or 480 mg every 4 weeks; f. 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):

34. 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

35. 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.
    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 ALK: anaplastic lymphoma kinase BRAF: B-Raf proto-oncogene, serine/threonine kinase CHL: classic Hodgkin lymphoma CNS: central nervous system CRC: colorectal cancer dMMR: mismatch repair deficient
    EGFR: epidermal growth factor receptor EGJ: esophagogastric junction ESCC: esophageal squamous cell carcinoma FDA: Food and Drug Administration HCC: hepatocellular carcinoma HER-2: human epidermal growth factor receptor-2 HSCT: hematopoietic stem cell
    transplantation MET: mesenchymal-epithelial transition MSI-H: microsatellite instability-high NSCLC: non-small cell lung cancer PD-1: programmed death receptor-1 PD-L1: programmed death-ligand 1 Page 10 of 20

    CLINICAL POLICY Nivolumab RCC: renal cell carcinoma ROS1: ROS proto-oncogene 1 SCLC: small cell lung cancer TMB: tumor mutational burden UC: urothelial carcinoma 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 and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose 800 mg/day 12 mg/day See regimen Varies Varies Varies Varies sorafenib (Nexavar) Lenvima (lenvatinib) Tecentriq (atezolizumab) + bevacizumab (Avastin®, Mvasi, Zirabev) Imfinzi (durvalumab)* First-line therapies (e.g., 5- FU/cisplatin, carboplatin/paclitaxel, FOLFOX, FOLFCIS) First-line therapies (e.g., platinum/etoposide-containing regimen) platinum-containing regimens HCC: 400 mg PO BID until clinical benefit ceases or unacceptable toxicity occurs HCC: 12 mg PO QD (patients ≥ 60 kg) or 8 mg PO QD (patients < 60 kg) until disease progression or unacceptable toxicity HCC Tecentriq: 840 mg IV every 2 weeks, 1,200 mg IV every 3 weeks, or 1,680 mg IV every 4 weeks
    Bevacizumab: 15 mg/kg IV every 3 weeks HCC Varies Metastatic anal carcinoma: Varies Gestational trophoblastic neoplasia: Varies NSCLC – squamous cell carcinoma: paclitaxel + carboplatin
    dose varies NSCLC – nonsquamous cell carcinoma: pemetrexed + [carboplatin or cisplatin]
    dose varies Multiagent chemotherapy regimens examples:
    EMA/CO (etoposide, methotrexate, UC, SCCHN: Varies Gestational Trophoblastic Neoplasia: Varies Varies Page 11 of 20

    CLINICAL POLICY Nivolumab Drug Name Dosing Regimen Dose Limit/ Maximum Dose dactinomycin/cyclophosphamide, vincristine), EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, cisplatin) Dose-adjusted-EPOCH-R, R- CHOP with radiation therapy, or LMB-modified B/C chemotherapy with rituximab Yervoy (ipilimumab)
    Pediatric primary mediastinal large B- cell lymphoma: Varies Varies Melanoma, HCC: 3 mg/kg IV every 3 weeks for a maximum of 4 doses See regimen RCC, CRC: 1 mg/kg IV every 3 weeks for a maximum of 4 doses NSCLC, malignant pleural mesothelioma, ESCC: 1 mg/kg IV every 6 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. *Off-label Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • High-risk disease in gestational trophoblastic neoplasia is defined as having a FIGO stage IV or a prognostic score ≥ 7 o FIGO staging system: Stage I II III IV Criteria Tumor confined to uterus Tumor extends to other genital structures (ovary, tube, vagina, broad ligaments) by metastasis or direct extension Lung metastasis All other distant metastases o Prognostic Scoring Index  The total score is obtained by adding the individual scores for each prognostic factor (low risk is indicated by a score < 7 and high risk is indicated by a score ≥ 7) Prognostic factor Age (years) Risk score 0 < 40 1 ≥ 40 2 -- 4 -- Page 12 of 20

    CLINICAL POLICY Nivolumab Prognostic factor Antecedent pregnancy Interval from index pregnancy (months) Pretreatment hCG (IU/L) Largest tumor size, including uterus (cm) Site of metastases Number of metastases identified Previous failed chemotherapy Total score Risk score 0 Hydatidiform mole < 4 1 Abortion 2 Term pregnancy 4 -- 4 to 6 7 to 12

    12 < 103 < 3 Lung 0 -- -- 103 to < 104 104 to 105 ≥ 105 3 to 5 5 Spleen, kidney 1 to 4 Gastrointestinal tract 5 to 8 Brain, liver 8 -- -- Single drug -- Two or more drugs -- Appendix E: Dose Rounding Guidelines Weight-based Dose Range ≤ 41.99 mg 42 mg-104.99 mg
    105 mg-146.99 mg 147 mg-209.99 mg 210 mg-251.99 mg 260 mg-293.99 mg 294 mg-356.99 mg 357 mg-503.99 mg This is part of a dose rounding guideline on select drug classes as part of an initiative conducted on a larger scale with multiple references and prescriber feedback.
    Vial Quantity Recommendation 1 vial of 40 mg/4 mL 1 vial of 100 mg/10 mL 1 vial of 40 mg/4 mL and 100 mg/10 mL 2 vials of 100 mg/10 mL 1 vial of 240 mg/24 mL 1 vial of 40 mg/4 mL and 240 mg/24 mL 1 vial of 100 mg/4 mL and 240 mg/24 mL 2 vials of 240 mg/24 mL V. Dosage and Administration
    Indication Melanoma (unresectable or metastatic) Dosing Regimen Monotherapy:
    • Adult and pediatric patients weighing ≥ 40 kg: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks • Pediatric patients weighing < 40 kg: 3 mg/kg IV every 2 weeks or 6 mg/kg IV every 4 weeks Maximum Dose See regimen
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    CLINICAL POLICY Nivolumab Indication Melanoma (adjuvant treatment) RCC - advanced with previous anti- angiogenic therapy, cHL, SCCHN, UC
    Dosing Regimen With ipilimumab:
    • Adult and pediatric patients weighing ≥ 40 kg: 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks
    • Pediatric patients weighing < 40 kg: 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then nivolumab 3 mg/kg IV every 3 weeks or 6 mg/kg mg IV every 6 weeks • Adult and pediatric patients weighing ≥ 40 kg: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks • Pediatric patients weighing < 40 kg: 3 mg/kg IV every 2 weeks or 6 mg/kg IV every 4 weeks 240 mg IV every 2 weeks or 480 mg IV every 4 weeks MSI-H/dMMR CRC Monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks RCC - advanced previously untreated HCC With ipilimumab: 3 mg/kg IV, followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks Monotherapy or with cabozantinib: 240 mg IV every 2 weeks or 480 mg every 4 weeks With ipilimumab: 3 mg/kg IV, followed by ipilimumab 1 mg/kg IV on the same day every 3 weeks for 4 doses, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks With ipilimumab: nivolumab 1 mg/kg IV, followed by ipilimumab 3 mg/kg IV on the same day, every 3 weeks for a maximum of 4 doses, then as single-agent nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks until disease progression or unacceptable toxicity Maximum Dose See regimen 480 mg/dose Monotherapy: 480 mg/dose With ipilimumab: 3 mg/kg/dose 480 mg/dose 480 mg/dose Page 14 of 20

    CLINICAL POLICY Nivolumab Indication NSCLC Esophageal cancer Maximum Dose Monotherapy: 480 mg/dose With ipilimumab: 3 mg/kg/dose With platinum- doublet with or without ipilimumab: 360 mg/dose See regimen Dosing Regimen Monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks until disease progression or unacceptable toxicity With ipilimumab: nivolumab 3 mg/kg IV every 2 weeks and ipilimumab 1 mg/kg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression With ipilimumab and platinum-doublet chemotherapy: nivolumab 360 mg IV every 3 weeks and ipilimumab 1 mg/kg IV every 6 weeks and histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression With platinum-doublet chemotherapy: nivolumab 360 mg IV every 3 weeks with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles Adjuvant treatment of resected esophageal or GEJ cancer: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for a total treatment duration of 1 year ESCC: until disease progression, unacceptable toxicity, or up to 2 years: • As a single agent or in combination with • fluoropyrimidine- and platinum- containing chemotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks In combination with ipilimumab: nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks Gastric cancer, EGJ cancer, and esophageal adenocarcinoma Malignant pleural mesothelioma 240 mg every 2 weeks or 360 mg every 3 weeks 360 mg/dose With ipilimumab: nivolumab 360 mg every 3 weeks and ipilimumab 1 mg/kg every 6 weeks With ipilimumab: 360 mg/dose Page 15 of 20

    CLINICAL POLICY Nivolumab VI. Product Availability
    Single-dose vials: 40 mg/4 mL, 100 mg/10 mL, 120 mg/12 mL, 240 mg/24 mL VII.