Medical Policy

 

Subject: Ipilimumab (Yervoy®)
Document #: DRUG.00046 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses ipilimumab (Yervoy, Bristol-Meyers Squibb, Princeton, NJ), a recombinant human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab has been shown to improve the overall survival of individuals with advanced melanoma.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Ipilimumab is considered medically necessary for the treatment of unresectable or metastatic melanoma when the following criteria are met:

  1. An individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and meets criteria under either “B” or “C”.
  2. Ipilimumab is used in combination with nivolumab as:
    1. First-line therapy; or
    2. Second-line or subsequent therapy for disease progression if nivolumab was not previously used; or
  3. Ipilimumab is used as a single agent for one of the following:
    1. First line therapy as a single course of 4 treatments; or
    2. Second-line or subsequent lines of therapy as a single course of 4 treatments; or
    3. Retreatment, consisting of a 4-dose limit, for an individual who had no significant systemic toxicity during prior ipilimumab therapy, and whose disease progressed after being stable for greater than 6 months following completion of a prior course of ipilimumab, and for whom no intervening therapy has been administered.

Ipilimumab is considered medically necessary for the adjuvant treatment of cutaneous melanoma in individuals with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including lymphadenectomy.

Investigational and Not Medically Necessary:

Ipilimumab is considered investigational and not medically necessary if the individual has an autoimmune disease which requires treatment with immunosuppressant drugs.

Ipilimumab is considered investigational and not medically necessary when the above criteria are not met and for all other indications including, but not limited to: lung cancer, prostate cancer, renal cell carcinoma, and pancreatic cancer.

Rationale

Unresectable or Metastatic Melanoma

The United States Food and Drug Administration (FDA) initially approved ipilimumab in March 2011 for treatment of unresectable or metastatic melanoma. This approval was based on a multicenter, randomized, double-blind phase III trial (Hodi, 2010) in which 676 subjects with previously treated metastatic melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 peptide vaccine (403 subjects), ipilimumab alone (137), or gp100 vaccine alone (136). Participants were treated every 3 weeks for a total of 4 treatments. Repeat treatment with ipilimumab (re-induction) was permitted in those with progressive disease who previously had stable disease or complete or partial remission. The primary endpoint was overall survival (OS). All study subjects had received a previous therapeutic regimen containing one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or interleukin-2. Other inclusion criteria were age at least 18 years, life expectancy of at least 4 months, ECOG performance status of 0 or 1, positive status for HLA-A*201, normal hematologic, hepatic, and renal function, and no systemic treatment in the previous 28 days. Exclusion criteria included primary ocular melanoma and untreated metastases in the central nervous system. Both ipilimumab groups showed statistically significant improved survival rates when compared with the gp100 vaccine alone. There was no statistically significant difference in OS between the two ipilimumab groups. The OS rates for ipilimumab plus gp100 vaccine, ipilimumab alone, and gp100 vaccine alone were 21.6%, 23.5%, and 13.7%, respectively at 24 months. Ipilimumab improved survival independent of age, sex, baseline serum lactate dehydrogenase levels, stage of metastasis, and use or non-use of interleukin-2 therapy. On July 21, 2017 the FDA expanded approval of ipilimumab in the treatment of unresectable or metastatic melanoma in adolescents (12 years of age or older) (Product Information Label, 2017).

At a 2 plus year follow-up of the Hodi trial, McDermott and colleagues (2013) analyzed 474 of the 676 originally randomized subjects. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among persons with survival of at least 2 years was comparable with the overall study population, with the onset of new ipilimumab-related toxic effects reported in 6 of 78 (8%) of cases. The authors reported that ipilimumab therapy was associated with survival of at least 2 years in approximately one-fifth of qualifying participants enrolled in the study.

In addition to the pivotal study above, there is an additional phase III randomized clinical trial (Robert, 2011) and multiple reports of phase II randomized clinical trials (Hersh, 2011; Thompson, 2012; Weber, 2009; Weber, 2011; Wolchok, 2010) which demonstrate the efficacy of ipilimumab in the treatment of unresectable or metastatic melanoma.

Robert and colleagues (2013) described the safety and efficacy data obtained from the subgroup of subjects retreated with ipilimumab in the pivotal phase III study previously described (Hodi, 2010). Of the 676 original participants, 32 had a partial or complete response or stable disease post-treatment and met eligibility criteria for retreatment. However, a total of 40 subjects actually received retreatment. A majority of those (34 of 40; 85%) who started a first retreatment cycle received the target number of 4 doses. A second retreatment cycle was started by 7 subjects, and of these 5 (71.4%) received all 4 doses. A third retreatment cycle was started and completed by only 1 subject. Best overall response rates (complete responses plus partial responses) for 31 subjects eligible for retreatment in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively. The disease control rate among those retreated with ipilimumab was 65.2% and 75.0% in the ipilimumab plus gp100 and ipilimumab plus placebo groups, respectively. Nineteen of 31 (61.3%) retreated subjects who received ipilimumab survived over 2 years from their initial randomization at study entry. No new types of toxicities occurred during retreatment and most events were mild-to-moderate.

Kelderman and colleagues (2014) evaluated baseline serum lactate dehydrogenase (LDH) as a predictive marker for overall metastatic melanoma survival rate. A total of 166 subjects with advanced cutaneous melanoma were treated in the Netherlands (NL) with ipilimumab. Best overall response and disease control rates were 17% and 35%, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8% and at 2 years was 22.9%. The findings were validated in an independent cohort of 64 subjects with advanced cutaneous melanoma in the UK. The authors concluded that their results show efficacy of ipilimumab comparable with that reported in the phase III studies and additionally stated:

In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

Larkin and colleagues (2015) conducted a multi-center, double-blind, phase III study (NCT01844505) of 945 previously untreated subjects with histologically confirmed unresectable stage III or IV melanoma randomized to nivolumab alone, nivolumab and ipilimumab, or ipilimumab alone. Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, age at least 18 years, measurable disease as assessed by computed tomography or magnetic resonance imaging, and a BRAF V600 mutation status. Of the individuals enrolled in the study, 316 were assigned to nivolumab, 314 to nivolumab and ipilimumab, and 315 to ipilimumab only. The coprimary end points of the study were progression-free survival (PFS) and overall survival (OS). In the nivolumab group, median PFS was 6.9 months as compared to 11.5 months in the nivolumab-plus-ipilimumab group, and 2.9 months in the ipilimumab group. Rates of objective responses as assessed by investigators were 43.7% for nivolumab only, 57.6% for nivolumab and ipilimumab, and 19% for the ipilimumab group. Time to an objective response was similar in all three groups and the median duration of response was not reached in any group. Treatment related adverse events of any grade were observed in 82.1% of subjects treated with nivolumab only, 95.5% of subjects treated with nivolumab and ipilimumab, and in 86.2% of those in the ipilimumab group. The authors concluded that longer PFS and higher rates of objective response occurred with nivolumab alone and the combination of nivolumab and ipilimumab versus ipilimumab alone. Additionally noted was that “the management of adverse events with combination therapy suggests that it can be used safely in a broad range of clinical settings.”

Postow and colleagues (2015) conducted a double blind study of 142 previously untreated subjects with metastatic melanoma. Inclusion criteria for the study included the presence of histologically confirmed, unresectable, previously untreated stage III or IV melanoma with measurable disease, a known BRAF V600 mutation status, an ECOG performance-status score of 0 or 1 (on a scale of 0 to 5, with 0 indicating no symptoms and higher scores indicating greater disability), and the availability of tumor tissue from a metastatic or unresectable site for immune histochemical assessment. Key exclusion criteria were active brain metastases, uveal melanoma, and serious autoimmune disease. Randomization occurred at a 2:1 ratio, and subjects were assigned to either ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for 4 doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among individuals with BRAF V600 wild-type tumors. Confirmed objective response occurred in 61% of subjects (44 of 72) with BRAF wild type tumors that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 subjects) in the group that received ipilimumab and placebo (ipilimumab monotherapy group). In the combination group, complete response occurred in 16 subjects (22%) and there were no complete responses achieved in the ipilimumab monotherapy group. Neither group reached the median duration of response. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy. Similar results for response rate and progression-free survival were observed in 33 subjects with BRAF mutation–positive tumors. Grade 3 or 4 drug related adverse events occurred in 54% of subjects who received the combination therapy as compared to 24% who received ipilimumab monotherapy.

The authors concluded that ipilimumab plus nivolumab combination therapy resulted in:

durable responses and a substantially higher objective response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy among patients with BRAF wild-type advanced melanoma and those with BRAF-mutant advanced melanoma.

The NCCN Drugs and Biologics Compendium (2017) indicates that for unresectable or metastatic disease, ipilimumab may be used with nivolumab as first-line therapy, or as a single drug or with nivolumab as second-line or subsequent treatment if the individual has disease progression and a performance status of 0-2, if not previously used. Additionally, NCCN indicates that ipilimumab may be used as a single-agent for re-induction therapy in certain individuals who did not have significant systemic toxicity during prior ipilimumab therapy and who relapse after initial clinical response or progress after stable disease greater than 3 months.

Adjuvant Treatment of Cutaneous Melanoma

On October 28, 2015 the FDA expanded their approval of ipilimumab to include the additional indication of adjuvant treatment of individuals with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. This approval was based on a randomized, double-blind, placebo-controlled phase 3 trial of individuals with resected Stage IIIA (> 1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma who had not received previous systemic therapy for melanoma (Eggermont, 2015). Between July of 2008 and August of 2011, a total of 951 individuals with a median age of 51 years from 91 hospitals located in 19 countries were randomly assigned to either ipilimumab (n=475) or placebo (n=476). Complete resection of melanoma with full lymphadenectomy within 12 weeks prior to randomization was required for enrollment. Those with prior therapy for melanoma, autoimmune disease, and prior or concomitant use of immunosuppressive agents were excluded. Of the enrollees, 94% had an ECOG performance status of 0. At a median follow-up of 2.74 years there were 528 recurrence-free survival events (234 in the ipilimumab group and 294 in the placebo group). Median recurrence-free survival was 26.1 months in the ipilimumab group and 17.1 months in the placebo group. At 3 years, the recurrence-free survival was 46.5% in the ipilimumab group versus 34.8% in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal, hepatic, and endocrine. Treatment was discontinued in 245 (52%) of 471 subjects who started ipilimumab during the initial treatment period due to adverse events. A total of 5 subjects died due to drug-related adverse events in the ipilimumab group. The authors concluded that adjuvant ipilimumab significantly improved recurrence-free survival for subjects with completely resected high-risk stage III melanoma and the adverse event profile was consistent with that observed in advanced melanoma.

Treatment of Melanoma with Brain Metastases

A phase II trial (Margolin, 2012) studied the safety and efficacy of ipilimumab in individuals with melanoma and brain metastases. A total of 72 subjects were enrolled in the study and divided into 2 parallel cohorts; 51 into cohort A and 21 into cohort B. Individuals in cohort A were neurologically asymptomatic and not receiving corticosteroid treatment at study entry, while those in cohort B were symptomatic and on a stable dose of corticosteroids. After 12 weeks, 9 subjects in cohort A demonstrated disease control as did 1 subject in cohort B. The assessment of the brain alone demonstrated that 12 subjects in cohort A (24%) and 2 in cohort B (10%) achieved disease control. Disease control outside of the brain was observed in 14 subjects (27%) in cohort A and in 1 subject (5%) in cohort B. Common adverse grade 3 events in cohort A were diarrhea and fatigue and in cohort B, were dehydration, hyperglycemia, and increased serum aspartate aminotransferase concentrations. One subject in each cohort had grade 4 confusion. The authors concluded that ipilimumab has activity without unexpected negative effects in some individuals with advanced melanoma and brain metastases, especially when metastases were small and asymptomatic.

The NCCN Drugs and Biologics Compendium (2017) indicates that ipilimumab may be considered as single-agent treatment for brain metastases if active against primary tumor (melanoma) for recurrent disease, and as single-agent treatment if active against primary tumor (melanoma) for brain metastases in persons with recurrent stable systemic disease.

Small-Cell Lung Cancer (SCLC)

The NCCN Drug and Biologics and Compendium and the NCCN SCLC Clinical Practice Guideline (2017) offer off-label recommendations (category 2A) for use of nivolumab and nivolumab plus ipilimumab as treatment options for SCLC as second-line or subsequent therapy after disease relapse (6 months or less) after primary therapy. Antonia and colleagues (2016) reported interim results from the CheckMate 032 trial, a phase I/II multi-center, open-label trial that evaluated nivolumab with or without ipilimumab in participants with advanced or metastatic SCLC after disease progression with one or more platinum-containing regimens. Objective response rates were 10% (10/98) for nivolumab 3 mg/kg, 23% (14/61) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (10/54) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The NCCN panel recommendations were based on the interim results from the SCLC cohort in the CheckMate 032 trial; however, phase III trial outcomes are pending at the time of this writing.

Uveal Melanoma

Recently, there has been increasing interest in the use of ipilimumab for another form of metastatic melanoma, uveal melanoma metastatic to the liver. Several small case series (Danielli, 2012; Khattak, 2013) indicate that ipilimumab may demonstrate clinical activity in persons with metastatic uveal melanoma.

Other Potential Uses

Ipilimumab in combination with nivolumab (immunotherapy) is currently being studied (NCT02716272) for use in the treatment of malignant pleural mesothelioma (MPM). The NCCN CPG for mesothelioma (2017) added combination of nivolumab and ipilimumab as a treatment option for subsequent systemic therapy. In the ongoing study, preliminary results reported by Scherpereel and colleagues (2017) reported more grade 3 & 4 toxicities in the combination arm (86.9%/ 16.4%) versus the nivolumab arm (77.8%/ 9.5%); there were 3 treatment related deaths reported in the combination arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). The authors concluded that immunotherapy may provide new options for these individuals.

Ipilimumab has also been studied in clinical trials for other uses including, but not limited to, prostate cancer (Kwon, 2014), non-small-cell lung cancer (Lynch, 2012), renal cell (Yang, 2007) and pancreatic cancer (Le, 2013). However, the published evidence is currently insufficient to support the use of ipilimumab for these conditions.

Background/Overview

Melanoma

Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). In men, melanoma is often found on the trunk or the head and neck. In women, it often develops on the lower legs. Melanoma is rare in individuals with very dark skin. When it does develop in dark-skinned people, it tends to occur under the fingernails or toenails, or on the palms or soles. Occasionally, melanoma may arise in the lining of the brain (meninges), the digestive tract, lymph nodes, or other areas where melanocytes are found. People at high risk for developing melanoma, include those with a personal or family history of the disease, fair complexions, and weakened immune systems. Individuals with familial dysplastic nevus syndrome or with several dysplastic or atypical nevi have more than a fivefold greater risk of developing melanoma.

Primary treatment of melanoma includes surgical excision and usually involves additional testing to appropriately identify the severity of the disease, also called clinical staging. Melanoma often begins as a single lesion or tumor. If the cancer cells spread from one part of the body to another it is called advanced or metastatic melanoma. Treatment is based on the extent of the disease and may include single agent or combination chemotherapy, radiation therapy, as well as FDA approved biologic agents such as interleukin-2 (IL-2) and interferon alpha.

Lung Cancer

The two main types of lung cancer are non-small cell lung cancer (NSCLC) and SCLC (sometimes called oat cell cancer). Lung cancer is the leading cause of death from cancer worldwide, with SCLC representing approximately 10-15% of the total cases. According to the National Cancer Institute (NCI), in 2017, an estimated 222,500 new cases of lung cancer (NSCLC and SCLC) will be diagnosed in the United States, and of these, approximately 155,870 deaths (70%) will occur as a result of the disease. Over the past few decades there has been a decline in the overall incidence of mortality in SCLC in the United States. It has been estimated that only 14% of all individuals with lung cancer will survive 5 years or more following diagnosis (NCI, 2017).

Warnings and Precautions

The 2017 FDA Product Information label includes the following warnings and precautions:

Warning: Immune-Mediated Adverse Reactions

Yervoy can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of Yervoy.

Permanently discontinue Yervoy and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Assess patients for signs and symptoms of enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose.

Additional precautions include:

Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions.

Information for use in specific populations includes:

Pregnancy Category C
There are no adequate and well-controlled studies of Yervoy in pregnant women. Use Yervoy during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers
It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Yervoy, a decision should be made whether to discontinue nursing or to discontinue Yervoy, taking into account the importance of Yervoy to the mother.

Pediatric Use
Safety and effectiveness of Yervoy have not been established in pediatric patients.

Geriatric Use
Of the 511 patients treated with Yervoy at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment
No formal studies of Yervoy in patients with renal impairment have been conducted.

Hepatic Impairment
No formal studies of Yervoy in patients with hepatic impairment have been conducted.

Definitions

ECOG Performance Status: A scale used to determine the individual’s level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

0    Fully active, able to carry on all pre-disease performance without restriction
1    Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2    Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3    Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4    Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5    Dead

Immunosuppressant: Drugs used to control or reduce the immune system response. Such drugs may include prednisone, azathioprine, cyclophosphamide, and tacrolimus.

Line of therapy:

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread. 

Phase II trial: A study to test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results) and whether it works against a certain type of cancer.

Phase III trial: A study to compare the results of people taking a new treatment with the results of those taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II; may include hundreds of people.

Unresectable: Unable to be removed with surgery.

Uveal melanoma: A type of cancer that can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract of the eye.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J9228

Injection, ipilimumab, 1 mg [Yervoy]

 

 

ICD-10 Diagnosis

 

C43.0-C43.9

Malignant melanoma of skin

C69.30-C69.32

Malignant neoplasm of choroid

C69.40-C69.42

Malignant neoplasm of ciliary body

C79.2

Secondary malignant neoplasm of skin

C79.31

Secondary malignant neoplasm of brain

Z85.820

Personal history of malignant melanoma of skin

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. 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; 17(7):883-895.
  2. 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; 61(1):41-48.
  3. 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; 16(5):522-530.
  4. Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522-30. 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; 16(6):e262.
  5. Hersh EM, O'Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011; 29(3):489-498.
  6. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-723.
  7. Kelderman S, Heemskerk B, van Tinteren H, et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother. 2014; 63(5):449-458.
  8. Khattak MA, Fisher R, Hughes P, et al. Ipilimumab activity in advanced uveal melanoma. Melanoma Res. 2013; 23(1):79-81.
  9. Kwon ED, Drake CG, Scher HI, et al.; CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014; 15(7):700-712.
  10. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373(1):23-34.
  11. Le DT, Lutz E, Uram JN, Sugar EA, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013; 36(7):382-389.
  12. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012; 30(17):2046-2054.
  13. Margolin KA, Di Giacomo AM, Maio M. Brain metastasis in melanoma: clinical activity of CTLA-4 antibody therapy. Semin Oncol. 2010; 37(5):468-472.
  14. Margolin K, Ernstoff MS, Hamid O. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012; 13(5):459-465.
  15. McDermott D, Haanen J, Chen TT, et al.; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013; 24(10):2694-2698.
  16. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015; 372(21):2006-2017.
  17. Robert C, Schadendorf D, Messina M, et al.; MDX010-20 investigators. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013; 19(8):2232-2239.
  18. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364(26):2517-2526.
  19. Scherpereel A, Mazleres J, Greillier L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus iplilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. 2017; 35(18) [Epub Ahead of Print].
  20. Thompson JA, Hamid O, Minor D, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial. J Immunother. 2012; 35(1):73-77.
  21. Weber JS, Amin A, Minor D, et al. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res. 2011; 21(6):530-534.
  22. Weber J, Thompson JA, Hamid O. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009; 15(17):5591-5598.
  23. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010; 11(2):155-164.
  24. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007; 30(8):825-830.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bristol-Myers Squibb. Phase 3 study of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in previously untreated advanced melanoma (CheckMate 067). NLM Identifier: NCT01844505. Last updated September 26, 2017. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01844505. Accessed on September 28, 2017.
  2. Ipilimumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised April 6, 2016. Accessed on September 5, 2017.
  3. Ipilimumab (systemic). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 31, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 5, 2017.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 27, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 28, 2017.
  1. Yervoy® [Product Information]. Princeton, NJ. Bristol-Myers Squibb Company. July 21, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125377s087lbl.pdf. Accessed on September 28, 2017.
Websites for Additional Information
  1. American Cancer Society. Melanoma. Revised May 20, 2016. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed on September 5, 2017.
  2. American Cancer Society. Lung cancer (small cell). Revised May 16, 2016. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003116-pdf.pdf. Accessed on September 5, 2017.
  3. National Cancer Institute. Available at: https://www.cancer.gov/types. Accessed on September 28, 2017.
Index

Ipilimumab
Metastatic Melanoma
Small Cell Lung Cancer
Unresectable Melanoma
Yervoy

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. 

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date”. Updated Rationale, Background, References and Websites sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Medically necessary criteria for the treatment of unresectable or metastatic melanoma updated from stating “meets criteria under either 2 or 3” to “meets criteria under either B or C.” Formatting updated in position statement. Description, Rationale, Background, References, Websites and Index sections updated.

Reviewed

05/05/2016

MPTAC review.

Reviewed

05/04/2016

Hematology/Oncology Subcommittee review. Rationale section updated.

Revised

03/21/2016

MPTAC review.

Revised

03/09/2016

Hematology/Oncology Subcommittee review. Added “second-line or subsequent lines of therapy as a single course of 4 treatments” to medically necessary statement for single agent use. Rationale and Definition sections updated.

Revised

02/04/2016

MPTAC review.

Revised

01/11/2016

Hematology/Oncology Subcommittee review. Clarified medically necessary statement for unresectable or metastatic melanoma. Rationale, Background and Reference sections updated.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Trademark symbol in title of document replaced with registered sign. Clarified medically necessary statement for retreatment of an individual who had no significant systemic toxicity during prior ipilimumab therapy. Updated ECOG performance statuses to 0-2. Added a medically necessary statement addressing the use of ipilimumab as a single agent in combination with nivolumab for treatment of metastatic or unresectable disease as second-line or subsequent therapy. Added a medically necessary statement addressing the adjuvant treatment of cutaneous melanoma. Rationale, Coding, Reference and Background sections were updated. Removed ICD-9 codes from Coding section.

Revised

08/06/2015

MPTAC review.

Revised

07/25/2015

Hematology/Oncology Subcommittee review. Added nivolumab and ipilimumab combined therapy for untreated melanoma as medically necessary with criteria. The Rationale and Reference sections were also updated.

Revised

11/13/2014

MPTAC review.

Revised

11/12/2014

Hematology/Oncology Subcommittee review. Investigational and Not Medically Necessary statement updated with specific cancer types. Description, Rationale and Reference sections updated.

Revised

05/15/2014

MPTAC review.

Revised

05/14/2014

Hematology/Oncology Subcommittee review. Position statement updated to allow for retreatment under specific circumstances. Rationale, Background and Reference sections updated.

Reviewed

05/09/2013

MPTAC review.

Reviewed

05/08/2013

Hematology/Oncology Subcommittee review. Rationale, Definition, Coding and Reference sections updated.

Revised

02/14/2013

MPTAC review. Approved document revisions as recommended by Hematology/Oncology Subcommittee.

Revised

01/29/2013

Hematology/Oncology Subcommittee approved a recommendation to remove the criteria requiring no systemic treatment in the previous 28 days. Rationale and Reference sections updated.

Reviewed

11/08/2012

MPTAC review.

Reviewed

11/07/2012

Hematology/Oncology Subcommittee review. Rationale and Reference sections updated.

New

11/17/2011

MPTAC review.

New

11/16/2011

Hematology/Oncology Subcommittee review. Initial document development.