Last Review Date: 12/01/2020

Date of Origin: 01/06/2015

Dates Reviewed: 03/2015, 07/2015, 10/2015, 11/2015, 02/2016, 05/2016, 08/2016, 10/2016, 11/2016, 02/2017, 05/2017, 08/2017, 10/2017, 01/2018, 02/2018, 05/2018, 08/2018, 09/2018, 10/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020, 04/2020, 06/2020, 07/2020, 09/2020, 11/2020, 12/2020

I. Length of Authorization 

Coverage will be provided for six months and may be renewed (unless otherwise specified).

• Adjuvant use in the treatment of melanoma can be authorized up to a maximum of 12 months of therapy.
• Use in the treatment of NSCLC in combination with ipilimumab can be authorized up to a maximum of 2 years of therapy.
• Use in the treatment of NSCLC in combination with ipilimumab and two (2) cycles of platinum-doublet chemotherapy can be authorized up to a maximum of 2 years of therapy.
• Use in the treatment of MPM as initial therapy in combination with ipilimumab can be authorized up to a maximum of 2 years of therapy.
• Use in the treatment of Vulvar Cancer can be authorized for up to a maximum of 2 years of therapy.

II. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

• Opdivo 40 mg/4 mL single-use vial: 2 vials per 14 days
• Opdivo 100 mg/10 mL single-use vial: 2 vials per 14 days
• Opdivo 240 mg/24 mL single-use vial: 4 vials per 14 days

2. Max Units (per dose and over time) [HCPCS Unit]:

3. Initial Approval Criteria ¹

Coverage is provided for the following conditions:

• Patient is at least 18 years of age (unless otherwise specified); AND

Universal Criteria

• Patient has not received previous therapy with a programmed death (PD-1/PD-L1)-directed therapy (e.g., cemiplimab, avelumab, pembrolizumab, atezolizumab, durvalumab, etc.) prior to initiation of therapy, unless otherwise specified; AND

Cutaneous Melanoma † Ф 

• Used as first-line therapy for unresectable or metastatic disease; AND
  • Used as a single agent or in combination with ipilimumab; OR
• Used as subsequent therapy for unresectable or metastatic* disease; AND
  • Used for retreatment of disease as re-induction as a single agent or in combination with ipilimumab in patients who experienced disease control (i.e., complete or partial response or stable disease) from prior checkpoint inhibitor therapy, but subsequently have disease progression/relapse > 3 months after treatment discontinuation; OR
  • Used after disease progression on first-line therapy or maximum clinical benefit from BRAF-targeted therapy (e.g., dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib, etc.); AND
    • Used as a single agent or in combination with ipilimumab if checkpoint inhibitor immunotherapy was not previously used; OR
    • Used in combination with ipilimumab for patients who progressed on single agent checkpoint inhibitor immunotherapy; OR
• Used as adjuvant treatment as a single agent; AND
  • Patient has lymph node involvement and has undergone complete resection, complete lymph node dissection (CLND), therapeutic lymph node dissection (TLND), or nodal basin ultrasound surveillance; OR
  • Patient has satellite/in-transit metastases or recurrence and has no evidence of disease after complete excision; OR
  • Patient has undergone TLND and/or complete resection of nodal recurrence; OR
  • Patient has undergone complete resection of distant metastatic disease

*Metastatic disease includes stage III clinical satellite/in transit metastases or local satellite/in-transit recurrence in patients with limited resectable and unresectable disease, unresectable nodal recurrence, and disseminated (unresectable) distant metastatic disease

Uveal Melanoma ‡ 

• Patient has distant metastatic disease; AND
• Used as a single agent or in combination with ipilimumab

Hepatocellular Carcinoma (HCC) † Ф 

• Patient has locally advanced, unresectable, inoperable, or metastatic disease; AND
• Used as subsequent therapy; AND
  • Patient has Child-Pugh Class A or B disease; AND
    • Used as a single agent; OR
  • Patient has Child-Pugh Class A disease; AND
    • Used in combination with ipilimumab

Non-Small Cell Lung Cancer (NSCLC) † 

• Used as a single-agent or in combination with ipilimumab as first-line therapy; OR
• Used for recurrent, advanced, or metastatic disease (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease) or mediastinal lymph node recurrence with prior radiation therapy; AND
  • Used as first-line therapy; AND
    • Used for one of the following:
      • Used in patients with PS 0-1 who have EGFR, ALK, ROS1, BRAF, MET exon skipping mutation, and RET rearrangement negative** tumors and PD-L1 expression <1%
      • Used in patients with PS 0-1 who are positive for one of the following molecular biomarkers:  BRAF V600E mutations, NTRK gene fusions, MET exon 14 skipping mutations, or RET rearrangements
      • Used in patients with PS 0-2 for PD-L1 expression-positive (PD-L1 ≥1%) tumors, as detected by an FDA or CLIA compliant testv, that are EGFR, ALK, ROS1, BRAF, MET exon skipping mutation, and RET rearrangement negative**; AND

• Used in combination with ipilimumab; OR
• Used in combination with ipilimumab and platinum-doublet chemotherapy (e.g., pemetrexed and either carboplatin or cisplatin for non-squamous cell histology, paclitaxel and carboplatin for squamous cell histology, etc.); OR
  • Used as subsequent therapy; AND
    • Used as a single agent; OR
    • Used for one of the following:
      • Used in patients with PS 0-1 who have EGFR, ALK, or ROS1 positive tumors and have received prior targeted therapy§
      • Used in patients with PS 0-1 who are positive for one of the following molecular biomarkers:  BRAF V600E mutations, NTRK gene fusions, MET exon 14 skipping mutations, or RET rearrangements; AND

• Used in combination with ipilimumab; OR
• Used in combination with ipilimumab, pemetrexed, and either carboplatin or cisplatin for non-squamous cell histology; OR
• Used in combination with ipilimumab, paclitaxel, and carboplatin for squamous cell histology

Renal Cell Carcinoma (RCC) † 

• Used in combination with ipilimumab for clear cell histology; AND
  • Used as first-line therapy in patients with advanced, relapsed, or stage IV disease with intermediate or poor risk; OR
  • Used as first-line therapy in patients with relapsed or stage IV disease with favorable risk; OR
  • Used as subsequent therapy in patients with relapsed or stage IV disease; OR
• Used as a single agent; AND
  • Used as subsequent therapy in patients with advanced, relapsed, or stage IV disease for clear cell histology; OR
  • Patient has relapsed or stage IV disease and non-clear cell histology

Classical Hodgkin Lymphoma (cHL) † Ф 

• Used as a single agent; AND
  • Patient age is 18 years and under; AND
    • Used as subsequent therapy for relapsed or refractory disease; AND
    • Used in patients heavily pretreated (with platinum or anthracycline-based chemotherapy) or if a decrease in cardiac function observed; OR
  • Patient is at least 18 years old and has received 2 or more prior lines of therapy OR used as palliative therapy in patients more than 60 years old; AND
    • Patient has relapsed or progressive disease after an autologous hematopoietic stem cell transplantation (HSCT) with or without brentuximab vedotin; OR
    • Patient has relapsed or refractory disease and is either transplant-ineligible based on comorbidities or has failure of second-line chemotherapy; OR
    • Patient is post-allogeneic stem-cell transplant; OR

• Used in combination with brentuximab vedotin for relapsed or refractory disease; AND
  • Patient is at least 18 years old; AND
    • Used as subsequent therapy (if not previously used); OR
  • Patient age is 18 years and under; AND
    • Used as subsequent therapy for relapsed or refractory disease; AND

• Used in patients heavily pretreated (with platinum or anthracycline-based chemotherapy) or if a decrease in cardiac function observed; OR
  • • Used as re-induction therapy; AND
• Used in patients heavily pretreated (with platinum or anthracycline-based chemotherapy) or if a decrease in cardiac function observed; OR
• Used with radiation therapy (ISRT) in highly favorable patients who may avoid autologous stem cell rescue (ASCR) (i.e., initial stage other than IIIB or IVB, no prior exposure to RT, duration of CR1 >1 year, absence of extranodal disease or B symptoms at relapse)

Squamous Cell Carcinoma of the Head and Neck (SCCHN) † 

• Used as single-agent therapy; AND
• Patient has unresectable, recurrent, persistent, or metastatic disease; AND
• Disease has progressed on or after platinum-based therapy; AND
• Patient does not have nasopharyngeal disease

Urothelial Carcinoma (Bladder Cancer) † 

• Used as a single agent; AND
• Used as subsequent systemic therapy after previous platinum treatment*; AND
• Patient has one of the following diagnoses:
  • Locally advanced or metastatic urothelial carcinoma; OR
  • Local bladder cancer recurrence or persistent disease in a preserved bladder ‡; OR
  • Local or metastatic bladder cancer recurrence post-cystectomy ‡; OR

• • Recurrent or metastatic primary carcinoma of the urethra ‡; AND
    • Patient does not have recurrence of stage T3-4 disease or palpable inguinal lymph nodes; OR
  • Metastatic upper genitourinary (GU) tract tumors ‡; OR

• • Metastatic urothelial carcinoma of the prostate ‡

Small Cell Lung Cancer (SCLC) † Ф 

• Used as subsequent systemic therapy; AND
  • Used as a single agent for metastatic disease with progression after platinum-based treatment and at least one other line of therapy †; OR

• • Used as a single agent ‡; AND
    • Used for relapse within 6 months following complete response, partial response, or stable disease with initial treatment; AND
      • Patient did not relapse while on maintenance atezolizumab or durvalumab; OR
    • Used for primary progressive disease

Colorectal Cancer (CRC) † 

• Patient is at least 12 years of age; AND
• Patient’s disease must be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR); AND
  • • Used as a single agent or in combination with ipilimumab as subsequent therapy for advanced or metastatic disease that progressed following treatment with a fluoropyrimidine-, oxaliplatin-, and/or irinotecan-based chemotherapy; OR
    • Used as a single agent or in combination with ipilimumab as primary treatment for unresectable or metastatic disease after previous adjuvant FOLFOX (fluorouracil, leucovorin and oxaliplatin) or CapeOX (capecitabine-oxaliplatin) in the past 12 months ‡; OR
    • Used as a single agent as primary treatment for unresectable or metastatic disease in patients who are not candidates for intensive therapy ‡; OR
    • Used as a single agent for unresectable or metastatic disease that remains unresectable after primary treatment in patients who are not candidates for intensive therapy ‡

Merkel Cell Carcinoma ‡ 

• Used as a single agent; AND
• Patient has disseminated metastatic disease

Central Nervous System (CNS) Cancer ‡ 

• Used in one of the following treatment settings:
  • Used as initial treatment in patients with small asymptomatic brain metastases; OR
  • Used for relapsed disease in patients with limited brain metastases and stable systemic disease or reasonable treatment options; OR
  • Patient has recurrent limited brain metastases; OR
  • Used for recurrent disease in patients with extensive brain metastases and stable systemic disease or reasonable systemic treatment options; AND
• Used as a single-agent or in combination with ipilimumab for the treatment of brain metastases in patients with melanoma; OR
• Used as a single-agent for the treatment of brain metastases in patients with PD-L1 positive non-small cell lung cancer (NSCLC)

Anal Carcinoma ‡ 

• Patient has metastatic squamous cell disease; AND
• Used as a single agent for subsequent therapy

Gestational Trophoblastic Neoplasia ‡ 

• Used as single-agent therapy for multiagent chemotherapy resistant disease; AND
  • Patient has intermediate placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT); AND
    • Patient has recurrent or progressive disease; AND
    • Patient was previously treated with a platinum/etoposide containing regimen; OR
  • Patient has methotrexate-resistant high risk disease (i.e., FIGO stages II-III and ≥7 Prognostic score OR FIGO stage IV disease)

Malignant Pleural Mesothelioma † ‡ 

• Used as a single agent or in combination with ipilimumab as subsequent therapy; OR
• Used in combination with ipilimumab as first-line therapy in patients with unresectable disease

Small Bowel Adenocarcinoma ‡ 

• Patient has advanced or metastatic disease that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR); AND
• Used as a single agent or in combination with ipilimumab in one of the following settings:
  • As subsequent therapy; OR
  • As initial therapy in patients with prior oxaliplatin exposure in the adjuvant setting or contraindication

Extranodal NK/ T-Cell Lymphoma ‡ 

• Used as a single agent for relapsed or refractory nasal type disease; AND

• Disease progressed following additional treatment with an alternative asparaginase-based chemotherapy regimen not previously used; AND

• Participation in a clinical trial is unavailable

Esophageal Squamous Cell Carcinoma (ESCC) † Ф 

• Used as a single agent; AND
• Used as subsequent therapy for unresectable advanced (or is not a surgical candidate), recurrent, or metastatic disease

Endometrial Carcinoma (Uterine Neoplasms) ‡ 

• Used as a single agent; AND
• Used as second-line therapy for mismatch repair deficient (dMMR) recurrent, metastatic, or high-risk disease

Vulvar Cancer (Squamous Cell Carcinoma) ‡ 

• Used as a single agent; AND
• Used as second-line therapy for HPV-related advanced, recurrent, or metastatic disease

v If confirmed using an immunotherapy assay-http://www.fda.gov/CompanionDiagnostics

† FDA Approved Indication(s); ‡ Compendia recommended indication(s); Ф Orphan Drug

4. Renewal Criteria ^{1,2,4-6,15-42,49}

Authorizations can be renewed based on the following criteria:

• Patient continues to meet universal and other indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: severe infusion reactions, complications of allogeneic hematopoietic stem cell transplantation (HSCT), severe immune-mediated adverse reactions (i.e. pneumonitis, colitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, adverse skin reactions/rash, encephalitis), etc.; AND
• Disease response with treatment defined as stabilization of disease or decrease in size of tumor or tumor spread; AND

Cutaneous Melanoma (adjuvant therapy)

• • • • Patient has not exceeded a maximum of twelve (12) months of therapy

NSCLC (in combination with ipilimumab or in combination with ipilimumab and two (2) cycles of platinum-doublet chemotherapy)

• • • • Patient has not exceeded a maximum of two (2) years of therapy

MPM (initial therapy in combination with ipilimumab)

• • • • Patient has not exceeded a maximum of two (2) years of therapy

Vulvar Cancer

• Patient has not exceeded a maximum of two (2) years of therapy

Cutaneous Melanoma Re-induction ‡

4. • • • Refer to Section III for criteria (see Melanoma – Used for retreatment of disease as re-induction)

V. Dosage/Administration

VI. Billing Code/Availability Information

HCPCS Code:

• J9299 - Injection, nivolumab, 1 mg; 1 billable unit = 1 mg

NDC:

• Opdivo 40 mg/4 mL single-use vial: 00003-3772-xx
• Opdivo 100 mg/10 mL single-use vial: 00003-3774-xx
• Opdivo 240 mg/24 mL single-use vial: 00003-3734-xx

VII. References

1. Opdivo [package insert]. Princeton, NJ; Bristol-Myers Squibb Company; November 2020. Accessed November 2020.
2. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) nivolumab. National Comprehensive Cancer Network, 2020. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed November 2020.
3. Scherpereel A, Mazieres J, Greillier L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. [Abstract]. J Clin Oncol 2017;35: Abstract LBA 8507.
4. Walocko FM, Scheier BY, Harms PW, et al. Metastatic Merkel cell carcinoma response to nivolumab. J Immunother Cancer. 2016 Nov 15;4:79.
5. Tawbi HA-H, Forsyth PAJ, Algazi AP, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204. J Clin Oncol 2017;35(15_suppl):abstr 9507.
6. Morris VK, Salem ME, Nimeiri H, et al.  Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Apr;18(4):446-453. doi: 10.1016/S1470-2045(17)30104-3. Epub 2017 Feb 18.
7. Zhao X, Ivaturi V, Gopalakrishnan M, et al. Abstract CT 101: A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types. Cancer Res July 1 2017 (77) (13 Supplement) CT101; DOI: 10.1158/1538-7445.AM2017-CT101.
8. Zhao X, Suryawanshi M, Hruska M, et al. Assessment of nivolumab benefit-risk profile of a 240 mg flat dose relative to a 3 mg/kg dosing regimen in patients with advanced tumors. Ann Oncol2017; 28:2002-2008.
9. Feng Y, Xiaoning W, Bajaj G, et al. Nivolumab exposure-response analyses of efficacy and safety in previously treated squamous or nonsquamous non-small cell lung cancer. ClinCa Res 2017;23(18): 5394-5405.
10. Gupta S, Sonpavde G, Grivas P, et al. Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2019 Mar 1;37(7_suppl):451.

11. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378:2093-2104.
12. Fahrenbruch R, Kintzel P, Bott AM, et al. Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. J Oncol Pract. 2018 Mar;14(3):e130-e136.
13. Hematology/Oncology Pharmacy Association (2019). Intravenous Cancer Drug Waste Issue Brief. Retrieved from http://www.hoparx.org/images/hopa/advocacy/Issue-Briefs/Drug_Waste_2019.pdf
14. Bach PB, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016 Feb 29;352:i788.

15. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. doi: 10.1016/S1470-2045(15)70076-8. Epub 2015 Mar 18.
16. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16.
17. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31.
18. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10.
19. Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016 Nov 15;122(21):3344-3353. doi: 10.1002/cncr.30258. Epub 2016 Aug 17.
20. Piulats JM, Cruz-Merino LDL, Garcia MTC, et al. Phase II multicenter, single arm, open label study of nivolumab in combination with ipilimumab in untreated patients with metastatic uveal melanoma (GEM1402.NCT02626962). J Clin Oncol 2017; 35 Abstr 9533.
21. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.
22. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.
23. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.
24. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5. Epub 2016 Jun 4.
25. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.
26. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.
27. Armand P, Engert A, Younes A, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol. 2018 May 10;36(14):1428-1439. doi: 10.1200/JCO.2017.76.0793. Epub 2018 Mar 27.
28. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. doi: 10.1056/NEJMoa1411087. Epub 2014 Dec 6.
29. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. Epub 2016 Oct 8.
30. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. doi: 10.1016/S1470-2045(17)30065-7. Epub 2017 Jan 26.
31. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9. Epub 2017 Jul 19.
32. Overman MJ, Lonardi S, Wong KYM, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779. doi: 10.1200/JCO.2017.76.9901. Epub 2018 Jan 20.
33. Topalian SL, Bhatia S, Hollebecque A, et al. Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC). DOI: 10.1158/1538-7445.AM2017-CT074 Published July 2017.
34. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018 May;19(5):672-681. doi: 10.1016/S1470-2045(18)30139-6. Epub 2018 Mar 27.
35. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Anal Carcinoma. Version 2.2020. National Comprehensive Cancer Network, 2020. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed October 2020.
36. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Gestational Trophoblastic Neoplasia. Version 3.2020. National Comprehensive Cancer Network, 2020. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed October 2020.
37. Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 2019 Feb;20(2):239-253. doi: 10.1016/S1470-2045(18)30765-4. Epub 2019 Jan 16.
38. Disselhorst MJ, Quispel-Janssen J, Lalezari F, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med. 2019 Mar;7(3):260-270. doi: 10.1016/S2213-2600(18)30420-X. Epub 2019 Jan 16.
39. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Small Bowel Adenocarcinoma. Version 2.2020. National Comprehensive Cancer Network, 2020. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed October 2020.
40. Chan TSY, Li J, Loong F, et al. PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol. 2018 Jan;97(1):193-196. doi: 10.1007/s00277-017-3127-2. Epub 2017 Sep 6.
41. Goldman JW, Crino L, Vokes EE, et al. Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets). J Clin Oncol 34, no. 15_suppl (May 20, 2016) 9038-9038. DOI: 10.1200/JCO.2016.34.15_suppl.9038.
42. Gauvain C, Vauleon E, Chouaid C, et al. Intracerebral efficacy and tolerance of nivolumab in non–small-cell lung cancer patients with brain metastases. Lung Cancer. 2018 Feb; 116:62-66. doi: 10.1016/j.lungcan.2017.12.008.
43. Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Non-Small Cell Lung Cancer. Version 8.2020. National Comprehensive Cancer Network, 2020. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed October 2020.
44. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(11):1506‐1517. doi:10.1016/S1470-2045(19)30626-6.

45. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231.
46. Reck M, Ciuleanu T-E, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA [abstract]. J Clin Oncol 2020;38:Abstract 9501-9501.
47. Zalcman G, Peters S, Mansfield AS, et al. Checkmate 743: A phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma. Journal of Clinical Oncology 2017 35:15_suppl, TPS8581-TPS8581
48. Azad NS, Gray RJ, Overman MJ, et al. Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers: Results From Arm Z1D-A Subprotocol of the NCI-MATCH (EAY131) Study. J Clin Oncol. 2020 Jan 20;38(3):214-222.
49. Naumann RW, Hollebecque A, Meyer T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019 Nov 1;37(31):2825-2834.
50. National Government Services, Inc. Local Coverage Article: Billing and Coding: Nivolumab (A54862). Centers for Medicare & Medicaid Services, Inc. Updated on 09/25/2020 with effective date 10/01/2020. Accessed October 2020.
51. Palmetto GBA. Local Coverage Article (LCA): Billing and Coding: Chemotherapy (A56141). Centers for Medicare & Medicaid Services, Inc. Updated on 05/26/2020 with effective date 04/30/2020. Accessed October 2020.

Appendix 1 – Covered Diagnosis Codes