BlueCross BlueShield of Tennessee Medical Policy Manual

Ipilimumab (Yervoy®)

NDC CODE(S)

00003-2327-XX YERVOY 50MG/10ML Solution (B-M SQUIBB U.S. (PRIMARY CARE)

00003-2328-XX YERVOY 200MG/40ML Solution (B-M SQUIBB U.S. (PRIMARY CARE)

DESCRIPTION

Ipilimumab (Yervoy®) is a recombinant human monoclonal antibody and an IgG1 kappa immunoglobulin.  It binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of T-cell activation, and blocks interaction with its ligands CD80/CD86.  Ipilimumab’s mechanism of action is likely through T-cell mediated anti-tumor immune responses.  Ipilimumab has been proven to be effective in crossing the blood brain barrier.

POLICY

MEDICAL APPROPRIATENESS

INITIAL APPROVAL CRITERIA

Cutaneous Melanoma

*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

Renal Cell Carcinoma (RCC)

Non-Small Cell Lung Cancer (NSCLC)

** Note: If there is insufficient tissue to allow testing for all the EGFR, ALK, ROS1, BRAF, NTRK1/2/3,

MET, and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes.

Malignant Pleural Mesothelioma

Central Nervous System (CNS) Cancer

Colorectal Cancer

* Single agent nivolumab should be used in patients who are not candidates for intensive therapy

Small Bowel Adenocarcinoma

Hepatocellular Carcinoma (HCC)

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

Genomic Aberration/Mutational Driver Targeted Therapies

(NOTE: not all inclusive, refer to guidelines for appropriate use

Sensitizing EGFR mutation-positive tumors

  • Afatinib

  • Dacomitinib

  • Erlotinib

  • Gefitinib

  • Osimertinib

ALK rearrangement-positive tumors

  • Alectinib

  • Brigatinib

  • Ceritinib

  • Crizotinib

  • Lorlatinib

ROS1 rearrangement-positive tumors

  • Ceritinib

  • Crizotinib

  • Entrectinib

BRAF V600E-mutation positive tumors

  • Dabrafenib ± Trametinib

  • Vemurafenib

 NTRK Gene Fusion positive tumors

  • Larotrectinib

  • Entrectinib

PD-1/PD-L1 expression-positive tumors (≥1%)

  • Pembrolizumab

  • Atezolizumab

  • Nivolumab ± ipilimumab

MET Exon-14 skipping mutations

  • Capmatinib

  • Crizotinib

RET rearrangement-positive tumors

  • Cabozantinib

  • Selpercatinib

  • Vandetanib

RENEWAL CRITERIA

Cutaneous Melanoma Re-induction

Cutaneous Melanoma Maintenance therapy (adjuvant treatment)

Non-Small Cell Lung Cancer (NSCLC)

MPM

DOSAGE/ADMINISTRATION

INDICATION

DOSE

Cutaneous Melanoma

(excluding adjuvant

therapy)

Single agent or in combination with nivolumab:

·         Administer 3 mg/kg intravenously every 3 weeks for a maximum of 4 doses

In combination with pembrolizumab as subsequent therapy:

·         Administer 1 mg/kg intravenously every 3 weeks for a maximum of 4 doses (given in combination with pembrolizumab, then follow with pembrolizumab monotherapy for up to 2 years)

Cutaneous Melanoma

(adjuvant therapy)

Administer 10 mg/kg intravenously every 3 weeks for 4 doses, followed by 10 mg/kg intravenously every 12 weeks for up to 3 years

Uveal Melanoma

Single agent:

·         Administer 3 mg/kg or 10mg/kg intravenously every 3 weeks for 4

doses

In combination with nivolumab:

·         Administer 3 mg/kg intravenously 3 weeks for 4 doses (given in combination with nivolumab, then follow with nivolumab monotherapy)

CNS metastases from

melanoma

Single agent:

·         Initial: Administer 10 mg/kg intravenously every 3 weeks for 4 doses

·         Subsequent (starting at week 24): Administer 10 mg/kg intravenously every 12 weeks until disease progression or unacceptable toxicity

In combination with nivolumab:

·         Administer 3 mg/kg intravenously every 3 weeks for 4 doses (given in combination with nivolumab, then follow with nivolumab monotherapy)

Hepatocellular

Carcinoma (HCC)

Administer 3 mg/kg intravenously every 3 weeks for a total of 4 doses (given in

combination with nivolumab, then follow with nivolumab monotherapy)

Non-Small Cell Lung

Cancer (NSCLC)

In combination with nivolumab:

·         Administer 1 mg/kg intravenously every 6 weeks (given in combination with nivolumab 3 mg/kg every 2 weeks), until disease progression or unacceptable toxicity for up to 2 years

In combination with nivolumab and platinum-doublet chemotherapy:

·         Administer 1 mg/kg intravenously every 6 weeks (given in combination with nivolumab 360 mg every 3 weeks and histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles), until disease progression or unacceptable toxicity for up to 2 years

Renal Cell Carcinoma

(RCC), Colorectal Cancer (CRC), Small Bowel Adenocarcinoma (SBA)

Administer 1 mg/kg intravenously every 3 weeks for a total of 4 doses (given in

combination with nivolumab, then follow with nivolumab monotherapy)

Malignant Pleural

Mesothelioma

Initial Therapy:

·         Administer 1 mg/kg intravenously every 6 weeks (given in combination with nivolumab) until disease progression or unacceptable toxicity until disease progression or unacceptable toxicity for up to 2 years

Subsequent Therapy:

Administer 1 mg/kg intravenously every 6 weeks (given in combination with nivolumab) until disease progression or unacceptable toxicity for up to 2 years

* All treatments given for a maximum of 4 doses must be administered within 16 weeks of the first dose.

LENGTH OF AUTHORIZATION

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

Renal Cell Carcinoma (RCC)/Cutaneous Melanoma (excluding adjuvant therapy)/Colorectal

Cancer (CRC)/Small Bowel Adenocarcinoma/Hepatocellular Carcinoma (HCC)/Uveal

Melanoma/CNS metastases from Melanoma (combination therapy with nivolumab)

Requests for Cutaneous Melanoma may be renewed if the patient meets the provisions for reinduction therapy.

Non-Small Cell Lung Cancer (NSCLC)/ Malignant Pleural Mesothelioma (excluding subsequent therapy)

Cutaneous Melanoma (adjuvant therapy)

CNS metastases from Melanoma (single agent therapy)

DOSING LIMITS

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

Indication

Billable Units (BU)

Per unit time (days)

Cutaneous Melanoma (excluding adjuvant therapy)

350 BU

21 days x 4 doses

Cutaneous Melanoma (adjuvant therapy), CNS metastases from melanoma

Initial: 1150 BU

Initial: 21 days x 4 doses

Followed by: 1150 BU

Followed by: 84 days

Uveal Melanoma

1150 BU

21 days x 4 doses

CRC, RCC, SBA

115 BU

21 days x 4 doses

MPM, NSCLC

115 BU

42 days

HCC

350 BU

21 days x 4 doses

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

APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS

BlueCross BlueShield of Tennessee’s Medical Policy complies with Tennessee Code Annotated Section 56-7-2352 regarding coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is recognized in one of the statutorily recognized standard reference compendia or in the published peer-reviewed medical literature.

IMPORTANT REMINDER

We develop Medical Policies to provide guidance to Members and Providers.  This Medical Policy relates only to the services or supplies described in it.  The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy.  For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed.  If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.

ADDITIONAL INFORMATION 

For appropriate chemotherapy regimens, dosage information, contraindications, precautions, warnings, and monitoring information, please refer to one of the standard reference compendia (e.g., the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) published by the National Comprehensive Cancer Network®, Drugdex Evaluations of Micromedex Solutions at Truven Health, or The American Hospital Formulary Service Drug Information).

SOURCES 

1.     Yervoy [package insert]. Princeton, NJ; Bristol Meyers Squib; November 2020. Accessed February 2021.

2.     Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) ipilimumab. National Comprehensive Cancer Network, 20210. 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 February 2021.

3.     Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Small Cell Lung Cancer. Version 12.2021. National Comprehensive Cancer Network, 20201. 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 February 2021.

4.     Referenced with permission from the NCCN Clinical Practice Guidelines (NCCNcGuidelines®) Central Nervous System Cancers. Version 3.2020. National ComprehensivecCancer Network, 20201. 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 February 2021.

5.     Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Malignant Pleural Mesothelioma. Version 1.20210. National Comprehensive Cancer Network, 20201. 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 February 2021.

6.     Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19; 363(8):711-23.

7.     Wilgenhof S, Du Four S, Vandenbroucke F, et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J Immunother. 2013 Apr; 36(3):215-22.

8.     Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May; 13(5):459-65.

9.     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.

10.  Tawbi HA, 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. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 9507-9507.

11.  Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 9508-9508.

12.  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.

13.  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.

14.  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

15.  Bach PB, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016 Feb 29;352:i788.

16.  Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Non-Small Cell Lung Cancer. Version 82.20210. National Comprehensive Cancer Network, 2021. 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 February 2021.

17.  Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31.

18.  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.

19.  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.

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). Annals of Oncology, Volume 29, Issue suppl_8, October 2018, mdy289.003, https://doi.org/10.1093/annonc/mdy289.003.

21.  Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma. PLoS One. 2015 Mar 11;10(3):e0118564. doi: 10.1371/journal.pone.0118564. eCollection 2015.

22.  Danielli R, Ridolfi R, Chiarion-Sileni V, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother. 2012 Jan;61(1):41-8. doi: 10.1007/s00262-011-1089-0. Epub 2011 Aug 11.

23.  Luke JJ, Callahan MK, Postow MA, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013 Oct 15;119(20):3687-95. doi: 10.1002/cncr.28282. Epub 2013 Aug 2.

24.  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 Nov 21;381(21):2020-2031. doi: 10.1056/NEJMoa1910231. Epub 2019 Sep 28.

25.  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.

26.  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.

27.  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.

28.  Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. doi: 10.1016/S1470-2045(12)70090-6. Epub 2012 Mar 27.

29.  Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Small Bowel Adenocarcinoma. Version 2.2020. National Comprehensive Cancer Network, 20201. 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 February 2021.

30.  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.

31.  Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Colon Cancer. Version 42.20201. National Comprehensive Cancer Network, 20201. 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 February 2021.

32.  Referenced with permission from the NCCN Clinical Practice Guidelines (NCCN Guidelines®) Uveal Melanoma. Version 2.20202021. National Comprehensive Cancer Network, 20201. 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 February 2021.

33.  Hellmann M, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. J Clin Oncol 2017; 35 Abstract 8503.

34.  Zalcman G, Mazieres J, Greillier L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Updated results of the IFCT-1501 MAPS2 randomized phase 2 trial [abstract]. Ann Oncol 2017; 28:Abstract LBA58_PR.

35.  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.

36.  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.

37.  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.

38.  Olson D, Luke J, Poklepovic A, et al. Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial. Journal of Clinical Oncology 2020 38:15_suppl, 10004-10004

39.  Lexi-Comp Online. (2021, February). AHFS DI. Ipilimumab. Retrieved March from Lexi-Comp Online with AHFS.

40.  MICROMEDEX Healthcare Series. Drugdex Evaluations. (2021, February). Ipilimumab. Retrieved March 16, 2021 from MICROMEDEX Healthcare Series.  

ORIGINAL EFFECTIVE DATE:  9/11/2011

MOST RECENT REVIEW DATE:    7/31/2021

ID_MRx

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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