Yervoy was FDA approved for the treatment of unresectable or metastatic melanoma in pediatric patients 12 years of age and older. Yervoy was evaluated in 45 pediatric patients across two clinical trials. One trial was a dose finding trial. The median age was 13 years, and 20 patients were > 12 years of age. Patients received 1, 3, 5, and 10 mg/kg IV over 90 minutes every 3 weeks for 3 doses and then every 12 weeks thereafter until progression or treatment discontinuation. Yervoy was also evaluated in an open-label, single-arm, trial in 12 pediatric patients > 12 years of age with previously untreated, unresectable, stage 3 or 4 malignant melanoma. Patients received either 3mg/kg or 10mg/kg over 9 minutes every 3 weeks for 4 doses. Of the 17 patients > 12 years of age, two experience objective responses including one partial response that was sustained for 16 months. The overall safety profile was consistent with the safety profile in adults.

Further analysis of progression-free survival in CheckMate-067 showed a benefit in all patients regardless of BRAFV600 mutation status, leading to accelerated FDA approval for BRAFV600 mutation-positive in addition to BRAFV600 wild-type. The addition of this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

In April 2018, the FDA approved Yervoy, in combination with Opdivo (nivolumab), for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma. The safety and efficacy of Yervoy for this use were demonstrated in a randomized, open-label, phase 3 trial of Opdivo plus Yervoy followed by Opdivo monotherapy versus Sutent (sunitinib) monotherapy. Patient included in the trial had measurable disease, and a Karnofsky performance-status score of at least 70. The co-primary endpoints were overall survival, overall response rate, and overall survival. The median overall survival has not yet been reached. The overall response rate was 41.6% for Opdivo and Yervoy compared to 26.5% with Sutent (P<0.0001). There was not a statistically significant improvement in progression free survival (11.6 months Opdivo + Yervoy vs. 8.4 months Sutent). Grade 3 or 4 events occurred in 46% of patients treated Opdivo and Yervoy compared to 63% of the Sutent group. 22% of patients discontinued treatment in the Opdivo and Yervoy group compared to 12% in the Sutent group.

In July 2018, the FDA approved Yervoy, in combination with Opdivo (nivolumab), for the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The approval was based on the results from a multicenter, non-randomized, multiple parallel-cohort, open-label study (CHECKMATE 142) in patients with dMMR or MSI-H mCR whose disease progressed during or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Patients were eligible to enter the trial if they were 18 years of age or older with recurrent or metastatic colorectal cancer, ECOG Performance Status of 0 or 1, and absence of active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Of the 6 different treatment arms, the 2 of interest that led to the FDA approval were 1) Yervoy 1mg/kg by IV infusion in combination with Opdivo 3mg/kg IV every 3 weeks for 4 doses, followed by Opdivo 3mg/kg IV as a single agent every 2 weeks, and 2) Opdivo monotherapy 3mg/kg IV every 2 weeks. Treatment was continued until unacceptable toxicity or radiographic progression. Efficacy outcome measures were overall response rate (ORR) and duration of response (DOR). The overall response rate was 46% for Yervoy and Opdivo compared to 28% with Opdivo monotherapy. Response duration of ≥ 6 months was also higher in the arm treated with Yervoy and Opdivo compared to Opdivo alone (89% vs. 67%). The most common adverse reactions (≥20%) in those receiving Yervoy and Opdivo are fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, dyspnea, decreased appetite, and vomiting. Efficacy for adolescent patients (12 years and older) with MSI-H or dMMR metastatic CRC is extrapolated from the results in the respective adult population. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

On March 10, 2020, the FDA granted accelerated approval to the combination of nivolumab and ipilimumab (Opdivo and Yervoy) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Efficacy of the combination was investigated in Cohort 4 of CHECKMATE-040, (NCT01658878) a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. A total of 49 patients received nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity. The main efficacy outcome measures were overall response rate and duration of response. ORR was 33% (n=16; 95% CI: 20, 48), with 4 complete responses and 12 partial responses. Response duration ranged from 4.6 to 30.5+ months, with 31% of responses lasting at least 24 months. The most common adverse reactions (20%) with nivolumab in combination with ipilimumab are: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness. For HCC, the recommended doses are nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

On May 15, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as first-line treatment for patients with metastatic non-small cell lung cancer whose tumors express PD-L1(≥1%), as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Efficacy was investigated in CHECKMATE-227 (NCT02477826), a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC and no prior anticancer therapy. In Part 1a of the trial, 793 patients with PD-L1 tumor expression ≥1% were randomized to receive either the combination of nivolumab plus with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397). The trial demonstrated a statistically significant improvement in overall survival (OS) for patients with PD-L1 tumor expression ≥1% receiving nivolumab plus ipilimumab compared to those treated with  platinum-doublet chemotherapy. Median OS was 17.1 months (95% CI: 15, 20.1) versus 14.9 (95% CI: 12.7, 16.7) (HR 0.79; 95% CI: 0.67, 0.94; p=0.0066). Median progression-free survival (PFS) per blinded independent central review (BICR) was 5.1 months (95% CI: 4.1, 6.3) in the nivolumab plus ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm (HR 0.82; 95% CI: 0.69, 0.97). Confirmed overall response rate (ORR) per BICR was 36% (95% CI: 31, 41) and 30% (95% CI: 26, 35), respectively. Median response duration was 23.2 months in the nivolumab plus  ipilimumab arm and 6.2 months in the platinum-doublet chemotherapy arm. The most common adverse reactions in ≥20% of patients receiving the combination of nivolumab plus ipilimumab in CHECKMATE-227 were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, pruritis, nausea, and hepatitis. The recommended doses for metastatic NSCLC are nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

On May 26, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) and 2 cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Efficacy was investigated in CHECKMATE-9LA (NCT03215706), a randomized, open-label trial in patients with metastatic or recurrent NSCLC. Patients were randomized to receive either the combination of nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy for 4 cycles (n=358). The trial demonstrated a statistically significant benefit in overall survival (OS) for patients treated with nivolumab plus ipilimumab plus chemotherapy compared to those who received chemotherapy. Median OS was 14.1 months (95% CI: 13.2, 16.2) versus 10.7 months (95% CI: 9.5, 12.5), HR 0.69; 96.71% CI: 0.55, 0.87). Median progression-free survival (PFS) per blinded independent central review (BICR) was 6.8 months (95% CI: 5.6, 7.7) in the nivolumab plus ipilimumab and chemotherapy arm and 5 months (95% CI: 4.3, 5.6) in the chemotherapy arm (HR 0.70; 95% CI: 0.57, 0.86). Confirmed overall response rate (ORR) per BICR was 38% (95% CI: 33, 43) and 25% (95% CI: 21, 30) respectively. Median response duration was 10 months in the nivolumab plus ipilimumab and chemotherapy arm, and 5.1 months in the chemotherapy arm. The most common adverse reactions in ≥20% of patients receiving nivolumab in combination with ipilimumab and platinum-doublet chemotherapy were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. The recommended nivolumab dose for this indication is 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. The nivolumab and ipilimumab is continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

[INFORMATIONAL NOTE: In KEYNOTE-059 trial, PD-L1 expression was evaluated by the PD-L1 IHC 22C3 pharmDx Kit (Dako) and PD-L1 positivity was based on a combined positive score (CPS) ≥ 1. CPS is determined by the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by total number of tumor cells evaluated, multiplied by 100. The PD-L1 IHC 22C3 pharmDx (Dako) is used to select patients with gastric cancer for treatment with pembrolizumab. If PD-L1 expression is not detected in an archival gastric cancer specimen, FDA recommends assessing the feasibility of a fresh tumor biopsy. D-L1 protein expression in gastric or GEJ adenocarcinoma is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 1001. The specimen should be considered to have PD-L1 expression if CPS ≥ 1. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying gastric or GEJ adenocarcinoma patients for treatment with Keytruda (pembrolizumab).]

[INFORMATIONAL NOTE: As per the FDA approved package insert, withhold scheduled dose of Ipilimumab (Yervoy) for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or 3 equivalent per day, resume YERVOY at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier.
Permanently discontinue Ipilimumab (Yervoy) for any of the following:

• Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
• Failure to complete full treatment course within 16 weeks from administration of first dose.
• Severe or life-threatening adverse reactions, including any of the following:
  o Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation
  o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal
  o Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations
  o Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
  o Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)
  o Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.
• Upon discontinuation of ipilimumab for any of these severe or life-threatening adverse reactions, initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent and upon improvement or control of the reaction, initiate corticosteroid taper and continue to taper over at least 1 month
  o For immune-mediated enterocolitis: withhold ipilimumab dosing for moderate enterocolitis. Administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
  o For immune-mediated hepatitis: across the clinical development program for ipilimumab, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold ipilimumab in patients with Grade 2 hepatotoxicity.
  o For immune-mediated neuropathies: withhold ipilimumab dosing in patients with moderate neuropathy (not interfering with daily activities)
  o For immune-mediated endocrinopathies, initiate appropriate hormone replacement therapy. Withhold ipilimumab dosing in patients with moderate to severe signs and symptoms.

• For treatment of unresectable or metastatic melanoma
  • Member is over the age of 12 AND
  • Member has an ECOG performance score of 0-1 AND
  • Member does NOT have any of the following:
    • Presence of active autoimmune disease
    • Prior treatment with anti-CTLA-4 antibody
  • Re-induction in select patients
• For the adjuvant treatment of cutaneous melanoma
  • Member has pathologic involvement of regional lymph nodes of more than 1 mm
  • Member has undergone complete resection, including total lymphadenectomy
• For the treatment of advanced renal cell carcinoma (RCC)
  • Member has intermediate or poor risk, previously untreated, disease
  • Member will use this in combination with nivolumab (Opdivo)
  • Member is > 18 years of age, AND
  • Karnofsky performance status of 70 or greater
• For the treatment of MSI-H or dMMR metastatic colorectal cancer
  • Member is over the age of 12 AND
  • Member has an ECOG performance score of 0-1 AND
  • Member experienced disease progression during or following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan AND
  • Member does NOT have any of the following:
    • Active brain metastases
    • Active autoimmune disease
    • Prior treatment with anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
  • Member will use this in combination with nivolumab (Opdivo)
• For the treatment of hepatocellular carcinoma
  • Member has histologically confirmed advanced hepatocellular carcinoma AND
  • Member is ≥18 years of age AND
  • Member has an ECOG performance score of 0-1 AND
  • Member has disease progression or intolerance following treatment with sorafenib AND
  • Member will use this in combination with nivolumab (Opdivo)
• For the treatment of non-small cell lung cancer (NSCLC)
  • Member has confirmed recurrent or metastatic non-small cell lung cancer expressing PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations AND
  • Member is ≥18 years of age AND
  • Member has an ECOG performance score of 0-1 AND
  • Member will use this as first line therapy in combination with nivolumab (Opdivo)
• For the treatment of non-small cell lung cancer (NSCLC)
  • Member has confirmed recurrent or metastatic non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations AND
  • Member is ≥18 years of age AND
  • Member has an ECOG performance score of 0-1 AND
  • Member will use this first line in combination with nivolumab (Opdivo) and 2 cycles of platinum-doublet chemotherapy

• Unresectable/Metastatic Melanoma
  • 3 mg/kg every 3 weeks for a total of 4 doses in a 16 weeks period.
• Adjuvant treatment of Melanoma:
  • 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks until documented disease recurrence or unacceptable toxicity for 6 months
• Advanced Renal Cell Carcinoma (RCC):
  • Combination of nivolumab (Opdivo) and ipilimumab (Yervoy):
    • nivolumab (Opdivo) 3 mg/kg IV, followed by ipilimumab (Yervoy) 1 mg/kg IV infusion on the same day, every 3 weeks for 4 doses.
    • after completing 4 doses of the combination, administer nivolumab (Opdivo), as single agent, either as 240mg every 2 weeks or 480mg every 4 weeks
    • ipilimumab (Yervoy) is considered investigational for more than 4 doses
• MSI-H or dMMR metastatic colorectal cancer (mCRC):
  • Combination of nivolumab (Opdivo) and ipilimumab (Yervoy):
    • nivolumab (Opdivo) 3 mg/kg IV, followed by ipilimumab (Yervoy) 1 mg/kg IV infusion on the same day, every 3 weeks for 4 doses.
    • after completing 4 doses of the combination, administer nivolumab (Opdivo), as single agent, 240mg every 2 weeks
    • ipilimumab (Yervoy) is considered investigational for more than 4 doses
• Hepatocellular carcinoma:
  • Combination of nivolumab (Opdivo) and ipilimumab (Yervoy):
    • nivolumab (Opdivo) 1 mg/kg IV, followed by ipilimumab (Yervoy) 3 mg/kg IV infusion on the same day, every 3 weeks for 4 doses
    • after completing 4 doses of the combination, administer nivolumab (Opdivo), as a single agent, 240 mg every 2 weeks or 480 mg every 4 weeks
    • ipilimumab (Yervoy) is considered investigational for more than 4 doses
• Metastatic non-small cell lung carcinoma (NSCLC):
  • Combination of nivolumab (Opdivo) and ipilimumab (Yervoy):
    • nivolumab (Opdivo) 3 mg/kg IV every 2 weeks, and ipilimumab (Yervoy) 1 mg/kg IV infusion every 6 weeks until disease progression or unacceptable toxicity for 6 months
    • nivolumab (Opdivo) 360 mg IV every 3 weeks, and ipilimumab (Yervoy) 1 mg/kg IV infusion every 6 weeks and histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles until disease progression or unacceptable toxicity for 6 months

• Adjuvant treatment of Melanoma:
  • 10 mg/kg every 12 weeks until documented disease recurrence or unacceptable toxicity for 6 months
  • For subsequent renewals, approve for 6 months for up to 3 years since the start of 10mg/kg every 12 weeks dosing
• Unresectable/Metastatic Melanoma
  • Use of re-induction if the member relapsed and had no unacceptable toxicity, the therapy will be approved for an additional 16 week period at the recommended dose of 3 mg/kg every 3 weeks for a total of 4 doses.
• Metastatic non-small cell lung carcinoma (NSCLC):
  • Combination of nivolumab (Opdivo) and ipilimumab (Yervoy):
    • nivolumab (Opdivo) 3 mg/kg IV every 2 weeks, and ipilimumab (Yervoy) 1 mg/kg IV infusion every 6 weeks for 6 months
    • nivolumab (Opdivo) 360 mg IV every 3 weeks, and ipilimumab (Yervoy)1 mg/kg IV infusion every 6 weeks or 6 months
    • For subsequent renewals, approve for additional 6 months for up to 2 years total since the start of therapy
[INFORMATIONAL NOTE: Based on FDA approved package insert and National Comprehensive Cancer Network (NCCN) guidelines, a total administration of 8 doses of Ipilimumab (Yervoy) or 32 weeks of therapy is permitted if re-induction criteria are met. The NCCN guideline for metastatic melanoma recommends the use of ipilimumab for re-induction of patients who relapsed after at least 3 months past their initial induction and had no unacceptable toxicity.]

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Ipilimumab (Yervoy)
Yervoy (Ipilimumab)

References:
1. Bristol Myers Squibb. Yervoy Package Insert. Princeton, NJ 08543. May 2020.

2. Ipilimumab. Clinicaltrial.gov. Accessed on 3/30/11. Available at: http://clinicaltrials.gov/ct2/results?term=Ipilimumab

3. O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10.

4. Hodi SF, O’Day S, McDermott D, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. The New England Journal of Medicine. 2010 Aug; 363(8): 711-723.

5. Schartz N, Farges C, Madelaine I, et al. Complete regression of a previously untreated melanoma brain metastasis with ipilimumab. Melanoma Res. 2010;20(3):247-50.

6. Hodi FS, Oble D, Drappatz J, et al. CTLA-4 blockade with ipilimumab induced significant clinical benefit in a female with melanoma metastases to the CNS. Nat Clin Pract Oncol. 2008;5(9):557-61.

7. Lawrence D, Hamid O, McDermott D et al. Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastasis [Poster]. Presented at: The 46th Annual Meeting of American Society of Clinical Oncology (ASCO). June 4-8, 2010; Chicago, Illinois.

8. Margolin K, Lawrence D, Hamid O et al. Phase II multi-institution trial of ipilimumab for patients with melanoma and brain metastasis [Poster]. Presented at: The joint ECCO 15th-34th Multidisciplinary Congress. September 20-24, 2009; Berlin, Germany.

9. Amin A, DePril V, Hamid O, et al. Systemic corticosteroids for the treatment of immune-related adverse events (irAEs) do not impact the development or maintenance of ipilimumab clinical activity. [Poster] Presented at: The 45th Annual Meeting of the American Society of Clinical Oncology (ASCO). May 29-June 2, 2009. Orlando, FL.

10. Danielli R, Queirolo P, Testori A, et al. Ipilimumab in pretreated metastatic uveal melanoma patients: safety and clinical efficacy [Poster]. Presented at: The 34th Annual Meeting of European Society for Medical Oncology Multidisciplinary Congress. September 20-24, 2009; Berlin, Germany.

11. Ipilimumab. NCCN Drugs & Biologics Compendium. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=370. Accessed May 2020.

12. Combinbed Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. NJEM. [Online] July 2015. Available at: http://www.nejm.org/doi/full/10.1056/nejmoa1504030

13. Robert C, et al. KEYNOTE-006; Phase III Study of pembrolizumab versus ipilimumab in advanced melanoma. New England Journal of Medicine (2015). 372(26):2521-2532.

14. Motzer RJ, Tannir NM, Mcdermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018.

15. ClinicalTrials.gov. Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214). Available at: https://clinicaltrials.gov/ct2/show/NCT02231749

16. ClinicalTrials.gov. An Investigational Immuno-therapy Study of Nivolumab, and Nivolumab in Combination with other Anti-cancer Drugs, in Colon Cancer That Has Come Back or Has Spread (CheckMate142). Available at: https://clinicaltrials.gov/ct2/show/NCT02060188

17. FDA grants accelerated approval to nivolumab and ipilmumab combination for hepatocellular carcinoma. U.S. Food & Drug Administration. FDA approved drugs. March 11, 2020. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma

18. ClinicalTrials.gov. An Immuno-therapy Study to Evaluate the Effectiveness, Safety, and Tolerability of Nivolumab or Nivolumab in Combination With Other Agent in Patients With Advanced Liver Cancer (CheckMate040). NCT01658878. Available at: https://clinicaltrials.gov/ct2/show/NCT01658878

19. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. U.S. Food & Drug Administration. FDA approved drugs. May 26, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc

20. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). U.S. Food & Drug Administration. FDA approved drugs. May 15, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1

21. ClinicalTrials.gov. A Study of Nivolumab and Ipilimumab Combined With Chemotherapy Compared to Chemotherapy Alone in First Line NSCLC (CheckMate 9LA). NCT03215706. Available at: https://clinicaltrials.gov/ct2/show/NCT03215706

22. ClinicalTrials.gov. An Investigational Immuno-therapy Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227). NCT02477826. Available at: https://clinicaltrials.gov/ct2/show/NCT02477826

Codes:

(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

J9228