Ipilimumab (Yervoy)

Number: 0815

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of ipilimumab is required of all Aetna participating providers and members in applicable plan designs.  For precertification of ipilimumab, call (866) 752-7021, or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies for ipilimumab (Yervoy). For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers ipilimumab (Yervoy) medically necessary for the treatment of the following indications:

• Colorectal cancer, small bowel adenocarcinoma, appendiceal carcinoma, and anal adenocarcinoma (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) for
   
  • In combination with nivolumab (for a maximum of 4 doses) as primary treatment for unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
  • In combination with nivolumab (for a maximum of 4 doses and if no previous treatment with a checkpoint inhibitor) as subsequent therapy for unresectable advanced or metastatic disease following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy.
     
• Central nervous system cancers - Used in persons with melanoma and brain metastases as a single agent or in combination with nivolumab.
   
• Cutaneous melanoma
   
  • As a single agent or in combination with nivolumab (for a maximum of 4 doses) for metastatic or unresectable disease; or
  • As a high-dose single agent (up to 3 years) as adjuvant treatment following complete lymph node resection or complete resection of metastatic disease.
    
    
• Small cell lung cancer (SCLC) as subsequent systemic therapy in combination with nivolumab for
   
  • Relapse within 6 months following complete or partial response or stable disease with initial treatment; or
  • Primary progressive disease.
     
• Malignant pleural mesothelioma as subsequent systemic therapy in combination with nivolumab
  
  
• Non-Small cell lung cancer (NSCLC) - in combination with nivolumab for tumor mutational burden (TMB)
  
  
• Kidney Cancer in combination with nivolumab for 4 cycles, followed by single-agent nivolumab, for relapsed, advanced, or stage IV disease as
   
  • First-line therapy for poor or intermediate risk
  • First-line therapy for clear cell histology and favorable risk
  • Subsequent therapy for predominant clear cell histology
    
    

• Uveal Melanoma - as a single agent or in combination with nivolumab for distant metastatic disease.

• Hepatocellular Carcinoma -  in combination with nivolumab (for a maximum of 4 doses) for subsequent treatment of hepatocellular carcinoma.

Aetna considers continued treatment with ipilimumab medically necessary (up to 3 years) in members requesting reauthorization for adjuvant melanoma when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers continued treatment with ipilimumab medically necessary (up to 4 doses maximum, if member has not already received 4 doses) in members requesting reauthorization for cutaneous melanoma, kidney cancer, colorectal cancer, and hepatocellular carcinoma when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers continued treatment with ipilimumab medically necessary in members requesting reauthorization for all other medically necessary indications when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers ipilimumab experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Astrocytoma
• Cholangiocarcinoma
• Esophageal cancer
• Gastric cancer
• Gliobastoma
• Merkel cell carcinoma
• Neuroendocrine tumor
• Non-Hodgkin's lymphoma
• Pancreatic cancer
• Prostate cancer
• Salivary tumor (adenocystic carcinoma)
• Sarcoma
• Use in combination with bevacizumab (Avastin) vemurafenib (Zelboraf), Tafinlar (dabrafenib) or Mekinist (trametinib) 
• Use in combination with nivolumab for the treatment of atypical pulmonary carcinoid

See also

Dosing Information

Ipilimumab is available as Yervoy in 50 mg and 200 mg vials. FDA-approved dosing for ipilimumab is:

Unresectable or metastatic melanoma: ipilimumab 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.

Adjuvant melanoma: ipilimumab 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity.

Advanced renal cell carcinoma: Nivolumab (Opdivo) 3 mg/kg administered intravenously over 30 minutes, followed by ipilimumab (Yervoy) 1 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for a maximum of 4 doses. After completing 4 doses of the combination,  administer nivolumab 240 mg as a single agent every 2 weeks or 480 mg every 4 weeks, administered intravenously over 30 minutes. The labeling recommends that ipilimuab be permanently discontinued for severe adverse reactions.

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer:  Nivolumab 3 mg/kg followed by ipilimumab (Yervoy)1 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. 

Hepatocellular carcinoma: 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.

Metastatic non-small cell lung cancer  Nivolumab 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. 

Source: Prescribing Information (BMS, 2020).

Background

Melanoma is a serious form of skin cancer that arises from melanocytes; however, in rare instances, it can originate in the eye or other non-skin organs.  Risk factors for melanoma entail freckling, genetic factors, history of sunburns, light skin or eye color, poor tanning ability, sun exposure, as well as tanning bed use.  About 80 % of melanomas are detected in a localized stage.  When detected early, the 5-year survival rate of melanoma is 98.5 %.  However, when melanoma is diagnosed after distant metastasis, the 5-year survival rate decreases to 15 % with a median survival between 8 and 9 months.  Tumor thickness, along with nodal involvement, is a prognostic factor for melanoma.  As tumor thickness increases to greater than 1.0 mm, the survival rate is reduced by 50 %.  The incidence of melanoma is rapidly increasing.  According to the National Cancer Institute (NCI), melanoma is the leading cause of death from skin disease.  Approximately 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease.  Treatments of melanoma include chemotherapy, immunotherapy, radiation therapy, surgery, as well as vaccine therapy (NCI, 2011).  According to the National Comprehensive Cancer Network, there are no optimal therapies for metastatic melanoma, and there is little consensus regarding standard therapy.  In community practice, the usual treatment is dacarbazine chemotherapy, which elicits a response of 3 or 4 months in duration in about 10 % to 20 % of patients.  Temozolomide has a similar rate of response (about 10 % to 20 % with a duration of 3 to 4 months).  Interleukin-2 (IL-2) can induce durable complete response (CR) in about 6 % and partial response (PR) in about 10 % of metastatic melanoma patients.  Evidence suggests that the combination of IL-2 therapy and a peptide vaccine such as the gp100 melanoma peptide vaccine (MDX-1379) may lead to higher response rates.

Agarwala and O'Day (2011) noted that the current treatment for melanoma with nodal involvement, but without distant metastasis, is surgical excision and lymph node dissection followed by adjuvant therapy.  A number of systemic regimens have been evaluated for melanoma patients with a medium or high risk of disease recurrence following surgery.  The only agent approved for the adjuvant therapy of melanoma is high-dose interferon (IFN)-alpha 2b, which prolongs relapse-free survival, but its effects on overall survival (OS) remain controversial.  Its use is also accompanied by significant toxicity.  Thus, despite its approval, high-dose IFN-alpha 2b is not always used for the adjuvant therapy of melanoma, particularly in countries other than the U.S.  Studies aimed at identifying subgroups of patients that have the greatest benefit-to-risk ratio with this regimen are ongoing.  Several vaccines have been studied in the adjuvant setting for melanoma, but none has shown superiority to IFN-containing regimens.  The GMK (ganglioside Memorial Kettering) vaccine, a GM2 ganglioside vaccine, for instance, has actually been shown to be inferior to high-dose IFN-alpha 2b.  Thus, a therapeutic regimen that improves OS with a favorable safety profile would be a major advance in the adjuvant therapy of melanoma.  One approach that is currently being investigated is the potentiation of anti-tumor immune responses through blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule on Helper T cells that is believed to play a critical role in regulating natural immune responses.  The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease.  Ipilimumab is a human monoclonal antibody that binds to cytotoxic CTLA-4.  It is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.

Ipilimumab for the Treatment of Melanoma

Yervoy (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4). Yervoy (Ipilimumab) binds to CTLA‐4 and blocks the interaction of CTLA‐4 with its ligands, CD80/CD86. Blockade of CTLA‐4 has been shown to augment T‐cell activation and proliferation. The mechanism of action of Yervoy (ipilimumab) as it relates to melanoma is indirect, possibly through T‐cell mediated anti‐tumor immune responses.

In March 2011, ipilimumab became the first immune checkpoint inhibitor approved by the US Food and Drug Administration (FDA).Yervoy (ipilimumab) was initially approved for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older). Currently, ipilimumab is also approved for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with nivolumab, and for the treatment of adult and pediatric patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. 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. 

Ku and colleagues (2010) reported on the findings of patients with advanced refractory melanoma who were treated in a compassionate use trial with ipilimumab 10 mg/kg of body weight every 3 weeks for 4 doses.  Those with evidence of clinical benefit at week 24 (CR, PR, or stable disease [SD]) then received ipilimumab every 12 weeks.  A total of 53 patients were enrolled, with 51 evaluable.  Grade 3/4 immune-related adverse events (AEs) were noted in 29 % of patients, with the most common immune-related AEs being pruritus (43 %), rash (37 %), and diarrhea (33 %).  On the basis of immune-related response criteria, the response rate (CR + PR) was 12 % (95 % confidence interval [CI]: 5 % to 25 %), whereas 29 % had SD (95 % CI: 18 % to 44 %).  The median progression-free survival (PFS) was 2.6 months (95 % CI: 2.3 to 5.2 months), whereas the median OS was 7.2 months (95 % CI: 4.0 to 13.3 months).  Patients with an absolute lymphocyte count (ALC) greater than 1000/microL after 2 ipilimumab treatments (week 7) had a significantly improved clinical benefit rate (51 % versus 0 %; p = 0.01) and median OS (11.9 versus 1.4 months; p < 0.001) compared with those with an ALC less than 1000/microL.  The authors concluded that these findings confirmed that ipilimumab is clinically active in patients with advanced refractory melanoma.  The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated.

In a multi-center, phase II clinical trial, Hersh and colleagues (2011) evaluated the safety and effectiveness of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma.  Chemotherapy-naïve patients were randomized to receive ipilimumab at 3 mg/kg every 4 weeks for 4 doses either alone or with up to 6 5-day courses of DTIC at 250 mg/m(2)/day.  The primary end point was objective response rate.  A total of 72 patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37).  The objective response rate was 14.3 % (95 % CI: 4.8 to 30.3) with ipilimumab plus DTIC and was 5.4 % (95 % CI: 0.7 to 18.2) with ipilimumab alone.  At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median OS was 14.3 months (95 % CI: 10.2 to 18.8) and 11.4 months (95 % CI: 6.1 to 15.6); 12-month, 24-month, and 36-month survival rates were 62 %, 24 % and 20 % for the ipilimumab plus DTIC group and were 45 %, 21 % and 9 % for the ipilimumab alone group, respectively.  Immune-related AEs were, in general, medically manageable and occurred in 65.7 % of patients in the combination group versus 53.8 % in the monotherapy group, with 17.1 % and 7.7 % greater than or equal to grade 3, respectively.  The authors concluded that ipilimumab resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

In a randomized, double-blind, phase II study, Wolchok et al (2010) examined the anti-tumor effectiveness of ipilimumab in patients with advanced melanoma.  A total of 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n = 73), 3 mg/kg (n = 72), or 0.3 mg/kg (n = 72) every 3 weeks for 4 cycles (induction) followed by maintenance therapy every 3 months.  Randomization was done with a permuted block procedure, stratified on the basis of type of previous treatment.  The primary end point was best overall response rate (BORR) (the proportion of patients with a CR or PR, according to modified World Health Organization [WHO] criteria).  Effectiveness analyses were done by intention-to-treat, whereas safety analyses included patients who received at least 1 dose of ipilimumab.  The best overall response rate was 11.1 % (95 % CI: 4.9 to 20.7) for 10 mg/kg, 4.2 % (CI: 0.9 to 11.7) for 3 mg/kg, and 0 % (CI: 0.0 to 4.9) for 0.3 mg/kg (p = 0.0015; trend test).  Immune-related AEs of any grade arose in 50 of 71 (70 %), 46 of 71 (65 %), and 19 of 72 (26 %) patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3 to 4 AEs were gastro-intestinal immune-related AEs (11 in the 10 mg/kg group, 2 in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhea (10 in the 10 mg/kg group, 1 in the 3 mg/kg group, none in the 0.3 mg/kg group).  The authors concluded that ipilimumab elicited a dose-dependent effect on safety and effectiveness measures in pre-treated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.

In a multi-center, single-arm, phase II study, O'Day et al (2010) examined the safety and effectiveness of ipilimumab monotherapy in patients with pre-treated advanced melanoma.  Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for 4 cycles (induction) followed by maintenance therapy every 3 months.  The primary end point was BORR using modified WHO criteria.  These investigators also performed an exploratory analysis of proposed immune-related response criteria (irRC).  Best overall response rate was 5.8 % with a disease control rate (DCR) of 27 % (n = 155); 1- and 2-year survival rates (95 % CI) were 47.2 % (39.5 % to 55.1 %) and 32.8 % (25.4 % to 40.5 %), respectively, with a median OS of 10.2 months (7.6 to 16.3).  Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8 % of all treated patients), resulting in a total DCR of 35 %.  Adverse events were largely immune-related, occurring mainly in the skin and gastrointestinal tract, with 19 % grade 3 and 3.2 % grade 4.  Immune-related AEs were manageable and generally reversible with corticosteroids.  The authors concluded that ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

In a phase III clinical trial, Hodi et al (2010) compared ipilimumab administered with or without a glycoprotein 100 (gp100) peptide vaccine with gp100 alone in patients with previously treated (one or more of the following: aldesleukin, carboplatin, dacarbazine, fotemustine, or temozolomide) metastatic melanoma.  A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (n = 403), ipilimumab alone (n = 137), or gp100 alone (n = 136).  Ipilimumab, at a dose of 3 mg/kg, was given with or without gp100 every 3 weeks for up to 4 treatments (induction).  Eligible patients could receive re-induction therapy.  The primary end point was OS.  The median OS was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio [HR] for death, 0.68; p < 0.001).  The median OS with ipilimumab alone was 10.1 months (HR for death in the comparison with gp100 alone, 0.66; p = 0.003).  No difference in OS was detected between the ipilimumab groups (HR with ipilimumab plus gp100, 1.04; p = 0.76).  Grade 3 or 4 immune-related AEs occurred in 10 to 15 % of patients treated with ipilimumab and in 3 % treated with gp100 alone.  There were 14 deaths related to the study drugs (2.1 %), and 7 were associated with immune-related AEs.  The authors concluded that ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved OS in patients with previously treated metastatic melanoma.  Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment

On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved ipilimumab (Yervoy) 3 mg/kg for the treatment of patients with unresectable or metastatic melanoma.  Yervoy 3 mg/kg is administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.  The manufacturer, Bristol-Myers Squibb, has agreed with the FDA to perform a post-marketing study comparing the safety and effectiveness of the 3 mg/kg dose versus an investigational 10 mg/kg dose in patients with unresectable or metastatic melanoma.

Common side effects associated with the use of ipilimumab include colitis, diarrhea, endocrine deficiencies, fatigue, and skin rash.  Severe to fatal autoimmune reactions were seen in 12.9 % of patients treated with ipilimumab.  When severe side effects occurred, ipilimumab was stopped and corticosteroid treatment was started.  Not all patients responded to this treatment.  Patients who did respond in some cases did not see any improvement for several weeks.  Due to the unusual and severe side effects associated with ipilimumab, the therapy is being approved with a risk evaluation and mitigation strategy (REMS) to inform health care professionals about these serious risks.  A medication guide will also be provided to patients to inform them about the therapy's potential side effects.

Black Box Warning:

Yervoy (ipilimumab) 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 (ipilimumab).

Permanently discontinue Yervoy (ipilimumab) and initiate systemic high‐dose corticosteroid therapy for severe immune‐mediated reactions.

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

Risk Evaluation and Mitigation Strategy:

In early development, severe and fatal immune-related adverse events emerged and were attributed to ipilimumab mechanism of action. At approval, the FDA required that a Risk Evaluation and Mitigation Strategy (REMS) communication plan directed at healthcare providers (HCPs) be developed to ensure that benefits with ipilimumab outweighed the risks from immune-related adverse events. Because the REMS met its goal and key activities were successfully completed with no required modifications at the 18-month and the 3-year assessments, the FDA released the REMS in March 2015.

Recommended Dose Adjustments:

Withhold scheduled dose of Yervoy (ipilimumab) for any moderate immune‐mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–), and who are receiving less than 7.5 mg prednisone or equivalent per day, resume Yervoy (ipilimumab) 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 Yervoy (ipilimumab) 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: 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.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal.
• Stevens‐Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.
• Severe motor or sensory neuropathy, Guillain‐Barré syndrome, or myasthenia gravis.
• Severe immune‐mediated reactions involving any organ system (e.g., nephritis, pneumonitis, pancreatitis, non‐infectious myocarditis).
• Immune‐mediated ocular disease that is unresponsive to topical immunosuppressive therapy

Yervoy (ipilimumab) should not be used in the following:

• Hypersensitivity to Yervoy (ipilimumab) or any of its components
• Women who are pregnant or lactating and have not been apprised of the potential hazard to the fetus
• Patients < 18 years of age (safety and effectiveness have not been established)
• Members with an active auto‐immune disease
• Members receiving systemic immunosuppressive therapy
• Members with primary ocular melanoma
• Members with unstable and/or symptomatic brain metastasis

A randomized controlled clinical study found that ipilimumab in combination with dacarbazine, as compared with dacarbazine plus placebo, improved OS in patients with previously untreated metastatic melanoma.  Robert et al (2011) randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (at a dose of 10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22.  Patients with SD or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy.  The primary end-point was OS.  The investigators found that OS was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months versus 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3 % versus 36.3 %), 2 years (28.5 % versus 17.9 %), and 3 years (20.8 % versus 12.2 %) (HR for death, 0.72; p < 0.001).  Grade 3 or 4 adverse events occurred in 56.3 % of patients treated with ipilimumab plus dacarbazine, as compared with 27.5 % treated with dacarbazine and placebo (p < 0.001).  The investigators reported that no drug-related deaths or gastro-intestinal perforations occurred in the ipilimumab-dacarbazine group.  The investigators stated that the types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastro-intestinal events were lower than expected on the basis of prior studies.

Danielli et al (2012) evaluated the activity and safety of ipilimumab in patients with uveal melanoma (UM) in a setting similar to daily clinical practice.  Patients participating in a multi-center expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg.  Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion.  Tumor assessment was assessed per modified World Health Organization criteria at baseline, week 12, week 24, and week 36.  Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0.  A total of 13 pre-treated patients with metastatic UM were treated at 6 European institutions.  All patients received at least 1 dose of ipilimumab.  Overall, no objective responses were observed; however, 2 patients had stable disease (SD), with a 3rd patient achieving SD after initial progressive disease.  Median OS as of July 1, 2011, was 36 weeks (range of 2 to 172+ weeks).  No grade 3/4 AEs of non-immune origin were reported.  Three patients (23 %) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy.  The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.

Piulats et al (ongoing clinical trial) stated uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for metastatic uveal melanoma (MUM). Combination nivolumab (NIVO) and ipilimumab (IPI) has shown efficacy in metastatic cutaneous melanoma. However, MUM patients were excluded in these trials. GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult patients with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible patients had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes patients with PD at first radiological evaluation. Safety population includes all patients receiving at least one dose of study treatment. Nineteen patients enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% patients and extra-liver M1 42% patients, 31% elevated baseline LDH. 11 patients completed cycle 2 and 8 patients stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 patients and lead to end of treatment in 2 patients. Grade ≥3 toxicities were seen in 7 patients (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. The authors concluded combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing and final results will be updated.

The FDA approved ipilimumab 10 mg/kg for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection including total lymphadenectomy. The approval was based on clinical data from a pivotal Phase 3 trial, CA184-029 (EORTC 18071), which demonstrated ipilimumab significantly improved recurrence-free survival (RFS) versus placebo in this setting, with a 25 percent reduction in the risk of recurrence or death. The median RFS was 26 months (95% CI: 19, 39) for Yervoy vs. 17 months (95% CI: 13, 22) for placebo (hazard ratio [HR]=0.75; 95% CI: 0.64, 0.90; p<0.002).

The randomized, double-blind Phase 3 trial, CA184-029 (EORTC 18071), demonstrated that ipilimumab 10 mg/kg (n=475) significantly improved RFS vs. placebo (n=476) in patients with resected Stage IIIa (lymph node >1 mm), IIIb and IIIc (with no in-transit metastases) histologically confirmed cutaneous melanoma. The median RFS was 26 months (95% CI: 19, 39) for ipilimumab vs. 17 months (95% CI: 13, 22) for placebo (HR=0.75; 95% CI: 0.64, 0.90; p<0.002). In the trial, patients were randomized to receive ipilimumab 10 mg/kg (n=475) or placebo (n=476) as an intravenous infusion every 3 weeks for 4 doses, followed by ipilimumab 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3 years), or until documented disease recurrence or unacceptable toxicity. Ipilimumab was studied across a broad range of patient characteristics, including patients with Stage IIIa with lymph node >1 mm (20%), IIIb (44%) or IIIc with no in-transit metastases (36%); 42% had ulcerated primary lesions and 58% had macroscopic lymph node involvement. The primary endpoint was RFS, defined as the time between the date of randomization and the date of first recurrence or death, as assessed by the Independent Review Committee.

In patients who received ipilimumab 10 mg/kg (n=471), severe to fatal immune-mediated adverse reactions were reported, and included enterocolitis (16%), hepatitis (11%), endocrinopathy (8%), hypopituitarism (7%), dermatitis (4%), neuropathy (1.7%), hyperthyroidism (0.6%), meningitis (0.4%), primary hypothyroidism (0.2%), myocarditis (0.2%), pericarditis (0.2%), pneumonitis (0.2%), and uveitis (0.2%). The most common adverse reactions were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%). Ipilimumab was discontinued for adverse reactions in 52% of patients.

Ipilimumab for Small Cell Lung Cancer

Spigel et al (2013) stated that SCLC is an aggressive malignancy that although initially sensitive to chemo- and radio-therapy, inevitably relapses resulting in poor survival.  Increasing evidence suggested that immune responses against SCLC cells make immunotherapy a viable therapeutic approach.  Furthermore, pre-clinical data have shown that certain chemotherapeutic regimens may augment the immunotherapeutic response in SCLC.  This review discussed current evidence supporting immunotherapy for SCLC, progress made, and ongoing clinical trials.  These investigators searched PubMed and abstracts presented at recent oncology congresses for publications on the clinical benefit of immunotherapy/checkpoint blockade for treatment of SCLC.  Preliminary data from ongoing clinical trials in SCLC have shown that some anti-angiogenic agents, vaccines, and immunomodulators, including interferon-alpha, and immune check-point blockers (i.e., anti-cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4] antibodies) may be effective as single agents and in combination with standard-of-care regimens.  Notably, in a phase II trial, ipilimumab demonstrated encouraging results when used as part of a chemoimmunotherapeutic regimen in patients with SCLC.

Antonia, et al. (2016) assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with small cell lung cancer (SCLC) who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicenter, multi-arm, open-label trial was conducted at 23 sites (academic centers and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. The investigators stated that these data support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomized controlled trials in SCLC.

Ipilimumab for Pleural Mesothelioma

Scherpereel, et al. (2017) reported on a multicenter randomized non comparative phase 2 trial of nivolumab and ipilimumab for malignant pleural mesothelioma. Eligible patients were over 18 years of age, performance status (PS) 0-1, histologically proven malignant pleural mesothelioma (MPM) relapsing after 1 or 2 prior lines including pemetrexed/platinum doublet, measurable disease. Randomized patients (1:1) received nivolumab 3 mg/kg every two weeks, or nivolumab 3 mg/kg every two weeks plus ipilimumab 1 mg/kg every 6 weeks, until progression or unacceptable toxicity. Primary endpoint was disease control rate (DCR) at 12 weeks with a blinded independent central review (BICR). 114 patients were to be randomized (with 108 eligible), with one-step Fleming procedure, H0 P<20% versus H1 P>40%, with 95% power, 5% one-sided a-risk: greater than or equal to 17 failure-free patients had to be observed at 12 weeks in either arm, to conclude to the activity of the corresponding regimen. From March to August 2016, 125 patients were enrolled in 21 centers. Eighty percent of study subjects were males, median age of subjects was  71.8 years (range 32.5-88.1). 62.4% were performance status 1, 83.2% had epithelioid cancers, 69.6% had one previous line of therapy, 70% of patients received 3 or more cycles of either treatment. Twelve weeks-DCR assessed by BICR in the first 108 eligible patients was 42.6% [95% CI: 29.4-55.8%] with nivolumab (n=23/54), and 51.9% [95% CI: 38.5%-65.2%] with nivolumab plus ipilimumab (n=28/54). Overall response rate (ORR) was 16.7% [95% CI: 6.7%-26.6%] with nivolumab (n=9/54), and 25.9% [95% CI: 14.2%-37.6%] with nivolumab plus ipilimumab (n=14/54). All grade/G3-4 toxicities were slightly increased in the combination nivolumab plus ipilimumab arm (86.9%/16.4%) versus nivolumab alone (77.8%/9.5%). Three treatment-related deaths were observed in the combination nivolumab/ipilimumab arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). The investigators concluded that both nivolumab and nivolumab plus ipilimumab arms reached their endpoint in 2nd/3rd-line MPM patients, suggesting that immunotherapy may provide new options for these patients.

Ipilimumab for Renal Cell Carcinoma

In a phase III trial (CheckMate 214), the combination of ipilimumab plus nivolumab (N + I) resulted in significantly improved overall survival and response rates compared with sunitinib (S) in previously untreated intermediate- and poor-risk patients with advanced clear cell RCC. Escudier, et al.(2017) randomized adults with clear-cell mRCC to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg daily orally for 4 weeks (6-week cycles). Co-primary endpoints were overall response rate (ORR), progression-free survival (PFS) per independent committee (IRRC) and overall survival (OS) all in intermediate/poor risk patients. The investigators randomized 1096 patients. With approximately 17.5 month minimum follow-up, confirmed ORR in intermediate/poor risk patients was 41.6% (9.4% complete response [CR]) versus 26.5% (1.2% CR) for N+I versus S (P<0.0001); median duration of response was not reached (NR; 95% CI 21.82-NR) versus 18.2 months (95% CI 14.82-NR), respectively; median PFS was 11.6 versus 8.4 months (HR 0.82, P=0.0331), respectively. In all treated patients, drug-related adverse events occurred in 509/547 (93% any grade, 46% grade 3-4) with N+I versus 521/535 (97% any grade, 63% grade 3-5) with S, including 22% versus 12% with adverse events leading to discontinuation. Death occurred in 159 N+I patients (7 [1%] drug-related) and 202 S patients (4 [1%] drug-related). The authors concluded that this study showed higher ORR and longer PFS for N+I compared with S in intermediate/poor risk mRCC, particularly in patients with tumor PD-L1 expression ≥1%, with a manageable safety profile. These results support the use of N+I as a potential first-line treatment for these patients. Based upon the results of Checkmate 214, the European Association of Urology revised its guidelines to recommend this combination as first-line treatment.

In a phase II study, Yang et al (2007) examined the effects of ipilimumab in patients with metastatic renal cell cancer with a primary end point of response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.  Two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing cohort response rates).  Major toxicities were enteritis and endocrine deficiencies of presumed autoimmune origin.  One of 21 patients receiving the lower dose had a PR.  Five of 40 patients at the higher dose had PR (95 % CI for cohort response rate 4 % to 27 %) and responses were seen in patients who had previously not responded to IL-2.  Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity.  There was a highly significant association between autoimmune events and tumor regression (response rate = 30 % with autoimmune events, 0 % without autoimmune events).  The authors concluded that ipilimumab induced cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies.  These regressions are highly associated with other immune-mediated AEs of presumed autoimmune origin by mechanisms as yet undefined.

Ipilimumab for the Treatment Hepatocellular Carcinoma

On March 10, 2020, the Food and Drug Administration granted accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (CHECKMATE-040; NCT01658878). The CHECKMATE-40 trial was a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible. The efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in Cohort 4 of CHECKMATE-040. A total of 49 patients received the combination regimen, which was administered every 3 weeks for four doses, followed by single-agent nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80); 88% were male; 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven percent (57%) of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had alfa-fetoprotein (AFP) levels ≥400 µg/L. Prior treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies. The main efficacy outcome measures were overall response rate  and duration of response as determined by blinded independent central review (BICR) using RECIST v1.1. 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.

Most common adverse reactions (≥20%) with ipilimumab in combination with nivolumab are fatigue, rash, pruritus, diarrhea, musculoskeletal pain, cough, pyrexia, decreased appetite, nausea, abdominal pain, arthralgia, headache, vomiting, dyspnea, dizziness, hypothyroidism, and decreased weight.

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. 

Ipilimumab for the Treatment of Other Tumors / Malignancies

The therapeutic responses seen in melanoma has led many researchers to examine the potential of ipilimumab in a variety of advanced solid tumors and malignancies.  Early results with anti-CTLA-4 monoclonal antibodies have revealed the feasibility, safety, and activity of these agents, thus suggesting a promising therapeutic role to be further investigated in phase II/III trials in a wide range of tumors (Calabrò et al, 2010).  The principal limitations for applicability of this mode of treatment are better definition of the mechanism that leads to tumor rejection as well as the validation of favorable observations in single-arm studies into prospectively randomized clinical trials (Agarwala and Ribas, 2010).  Ipilimumab is undergoing clinical trials for the treatment of metastatic hormone-refractory prostate cancer, and non-small cell lung cancer (NSCLC).  Albiges et al (2010) stated that despite that greater knowledge of prostate cancer biology has led to the isolation of many new and promising targets, treatment of metastatic prostate cancer is still challenging.  New agents targeting these molecules are currently under development in large randomized phase III trials to improve OS and the quality of life of patients with metastatic castrate-resistant prostatic cancer (CRPC).  Cytotoxic chemotherapy (docetaxel-based chemotherapy) demonstrated clinical benefit on OS, but could be improved.  Drugs targeting directly or not the androgen receptor such as abiraterone or new specific peripheral anti-androgens (MDV3100) are very promising.  Bone targeted therapies (e.g., endothelin1 receptor A inhibitor, RANK ligand, and metabolic irradiation) are also very promising and are in development in large phase III trials.  Anti-angiogenic therapies could also be effective in CRPC.  Autologous vaccine against prostatic acid phosphatase has been reported to prolong OS (on April 29, 2010, sipuleucel-T [Provenge] was approved by the FDA for the treatment of asymptomatic or minimally symptomatic prostate cancer that has metastasized and is resistant to standard hormone treatment).  Other vaccines and immunotherapy strategies are in development (e.g., ipilimumab).

In a pilot study, Small et al (2007) attempted to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of ipilimumab and assessed if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with ipilimumab.  Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg intravenous dose of ipilimumab.  Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry.  Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken.  A total of 14 patients were treated: 12 patients received a single dose of ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression.  Two patients showed PSA declines of greater than or equal to 50 %.  Treatment was well-tolerated with clinical autoimmunity limited to 1 patient who developed grade 3 rash/pruritus requiring systemic corticosteroids.  The mean +/- SD ipilimumab terminal elimination half-life was 12.5 +/- 5.3 days.  The authors concluded that a single dose of 3 mg/kg ipilimumab given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity.  They stated that the observed PSA-modulating effects of ipilimumab warrant further investigation.

In a pilot study, O'Mahony et al (2007) examined the effects of ipilimumab after cancer vaccine failure in patients with advanced malignancy.  The primary end point was drug toxicity.  Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.  A total of 11 patients (3 with colon cancer, 4 with non-Hodgkin's lymphoma, and 4 with prostate cancer) were treated.  The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of 4 cycles.  Tumor regression was observed in 2 patients with lymphoma; 1 of which obtained a PR of 14-month duration.  Ipilimumab was well-tolerated with predominantly grade 1/2 toxicities.  One drug-related grade 3 toxicity was observed.  One patient died within 30 days of treatment due to progressive colon cancer.  No increase in vaccine-specific T-cell responses was observed after therapy.  Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.  The authors concluded that ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anti-cancer vaccines.  A PR was seen in 1 patient with follicular lymphoma.  They noted that a phase I/II clinical trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

In a phase I clinical trial, Ansell et al (2010) evaluated the safety, immunologic activity, and potential clinical effectiveness of ipilimumab in patients with relapsed/refractory B-cell lymphoma.  Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg x 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly x 4 months (dose level 2).  A total of 18 patients were treated, 12 at the lower dose level and 6 at the higher dose level.  Ipilimumab was generally well-tolerated, with common AEs attributed to it, including abdominal pain, anorexia, diarrhea, fatigue, headache, neutropenia, and thrombocytopenia.  Two patients had clinical responses; 1 patient with diffuse large B-cell lymphoma had an ongoing CR (greater than 31 months), and 1 with follicular lymphoma had a PR lasting 19 months.  In 5 of 16 cases tested (31 %), T-cell proliferation to recall antigens was significantly increased (greater than 2-fold) after ipilimumab therapy.  The authors concluded that blockade of CTLA-4 signaling with the use of ipilimumab is well-tolerated at the doses used and has anti-tumor activity in patients with B-cell lymphoma.  They stated that further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.

Mori et al (2011) stated that ipilimumab is intended to be used as a drug to activate the immune system by binding to CTLA-4.

Lowery and O'Reilly (2011) noted that the development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies.  More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from pre-malignant precursor lesion to malignant cells with metastatic potential.  FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as peri-operative therapy.  The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors.  Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike.

George and Moul (2012) performed a review of literature to identify ongoing and planned phase III studies of novel agents to treat castration-resistant prostate cancer (CRPC).  Multiple studies were identified, including novel androgen biosynthesis inhibitors (abiraterone, TAK-700), androgen-receptor inhibitors (MDV3100), angiogenesis inhibitors (aflibercept, tasquinimod), endothelin antagonists (zibotentan, atrasentan), a Src tyrosine kinase inhibitor (dasatinib), a novel radiotherapy (radium-223), and new immunotherapies (ipilimumab and ProstVac).  In addition, both sipuleucel-T (an immunotherapy) and cabazitaxel (3rd-generation taxane) and the RANK-L inhibitor, denosumab, have recently been approved by the FDA.  The authors concluded that various combinations of these agents could theoretically be used to treat future patients with CRPC by targeting multiple signaling pathways as well as aspects of the tumor and bone microenvironments.  They stated that additional research is needed to understand how to best use these agents and individualize care to optimize CRPC patient outcomes.

Hall et al (2013) discussed recent clinical trials using immunotherapy techniques to treat both NSCLC and SCLC and highlighted ongoing immunotherapy research efforts.  For NSCLC, phase II clinical trials have examined allogeneic vaccines that target mucin 1, epidermal growth factor or melanoma-associated antigen 3.  These vaccines are now undergoing larger phase III trials.  An autologous cellular therapy directed against transforming growth factor beta-2 and a recombinant protein with anti-tumor properties have also shown promise in prolonging survival in NSCLC in phase II trials.  The monoclonal antibodies ipilimumab, lambrolizumab (anti-PD-1), and BMS936559 (anti-PD-L1) lead to enhanced T-cell-mediated anti-tumor effects and have produced objective responses in early-phase clinical trials.  Studies for SCLC also exist, such as a novel vaccine therapy targeting p53.  The authors concluded that recent clinical trials in lung cancer demonstrated the potential of immuno-therapeutics to increase OS in patients with lung cancer compared with the current standard of care.

Sarcoma (cancer of the connective tissues) frequently strikes young people, comprising a large percentage of cancer in children and young adults, but may occur at any age.  Goldberg (2013) described the current advances in immunotherapy and how they can be applied to sarcoma.  The author noted that although molecularly targeted inhibitors are of great interest in treating sarcoma patients, immunotherapy is emerging as a plausible therapeutic modality because of the recent advances in other cancer types that may be translated to sarcoma.  The licensing of ipilimumab and sipuleucel-T for cancer, and the remarkable success of immunotherapy for some childhood cancers, suggest a role for immunotherapy in the treatment of tumors like sarcoma.  The author concluded that recent advances in sarcoma biology and cancer immunotherapy suggested that the understanding of the immune system has reached the point where it can be used to augment both targeted and multi-modality therapy for sarcoma.

In a pilot study, Maki et al (2013) examined the clinical activity of ipilimumab in patients with advanced or metastatic synovial sarcoma.  A Simon 2-stage phase II design was used to determine if there was sufficient activity to pursue further.  The primary end-point was tumor response rate by RECIST 1.0.  Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for 3 cycles and then re-staged.  Re-treatment was possible for patients receiving an extra 3-week break from therapy.  Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity.  A total of 6 patients were enrolled and received 1 to 3 cycles of ipilimumab.  All patients showed clinical or radiological evidence of disease progression after no more than 3 cycles of therapy, for a RECIST response rate of 0 %.  The study was stopped for slow accrual, lack of activity, and lack of immune response.  There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy.  The authors concluded that despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. 

UpToDate reviews on “Adjuvant chemotherapy for malignant gliomas” (Batchelor, 2013), “Management of malignant gliomas in elderly patients” (Batchelor and Shih, 2013), and “Management of recurrent malignant gliomas” (Batchelor et al, 2013) do not mention the use of ipilimumab as a therapeutic option.  Furthermore, NCCN’s Drugs & Biologics Compendium (2013) does not list glioblastoma as a recommended indication of ipilimumab.

In a multi-center, randomized, double-blind, phase III clinical trial, Kwon and colleagues (2014) evaluated the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.  Men with at least 1 bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to 4 doses.  Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death.  Patients were randomly assigned to either treatment group via a minimization algorithm, and stratified by Eastern Cooperative Oncology Group (ECOG) performance status, alkaline phosphatase concentration, hemoglobin concentration, and investigator site.  Patients and investigators were masked to treatment allocation.  The primary end-point was overall survival (OS), assessed in the intention-to-treat population.   From May 26, 2009, to Feb 15, 2012, a total of 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis.  Median OS was 11·2 months (95 % CI: 9.5 to 12.7) with ipilimumab and 10.0 months (8.3 to 11.0) with placebo (hazard ratio [HR] 0.85, 0.72 to 1.00; p = 0.053).  However, the assessment of the proportional hazards assumption showed that it was violated (p = 0.0031).  A piece-wise hazard model showed that the HR changed over time: the HR for 0 to 5 months was 1.46 (95 % CI: 1.10 to 1.95), for 5 to 12 months was 0.65 (0.50 to 0.85), and beyond 12 months was 0.60 (0.43 to 0.86).  The most common grade 3 to 4 adverse events were immune-related, occurring in 101 (26 %) patients in the ipilimumab group and 11 (3 %) of patients in the placebo group.  The most frequent grade 3 to 4 adverse events included diarrhea (64 [16 %] of 393 patients in the ipilimumab group versus 7 [2 %] of 396 in the placebo group), fatigue (40 [11 %] versus 35 [9 %]), anemia (40 [10 %] versus 43 [11 %]), and colitis (18 [5 %] versus 0).  Four (1 %) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.  The authors concluded that although there was no significant difference between the ipilimumab group and the placebo group in terms of OS in the primary analysis, there were signs of activity with the drug that warrant further investigation.

Hodi and colleagues (2014) stated that ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy.  Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking.  These researchers investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab.  Patients with metastatic melanoma were treated in 4 dosing cohorts of ipilimumab (3 or 10 mg/kg) with 4 doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks.  A total of 46 patients were treated.  Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2).  On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration.  Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies.  Best overall response included 8 PR, 22 instances of SD, and a disease-control rate of 67.4 %.  Median survival was 25.1 months.  Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration.  The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation.  The authors concluded that these findings provided a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of anti-angiogenesis agents and immune check-point blockade.

Salivary Tumor (Adenocystic Carcinoma)

An UpToDate review on “Salivary gland tumors: Treatment of locoregional disease” (Lydiatt and Quivey, 2015) does not mention ipilimumab as a therapeutic option. National Comprehensive Cancer network (NCCN)’s clinical practice guideline on “Head and neck cancers” (Version 1.2015) does not list ipilimumab as a therapeutic option. Furthermore, NCCN’s Drugs & Biologics Compendium (2015) does not list salivary tumor (adenocystic carcinoma) as a recommended indication of ipilimumab.

Combinational Use of Ipilimumab and Nivolumab for Melanoma

Postow and colleagues (2015) noted that in a phase I dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including CRs, among patients with advanced melanoma. In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, these researchers randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg/kg of body weight) combined with either nivolumab (1 mg/kg) or placebo once every 3 weeks for 4 doses, followed by nivolumab (3 mg/kg) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end-point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61 % (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11 % (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (p < 0.001), with CRs reported in 16 patients (22 %) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median PFS was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (HR associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95 % CI: 0.23 to 0.68; p < 0.001). Similar results for response rate and PFS were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54 % of the patients who received the combination therapy as compared with 24 % of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase I study, and most of these events resolved with immune-modulating medication. The authors concluded that the objective-response rate and the PFS among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy; combination therapy had an acceptable safety profile.

In a randomized, double-blind, phase III clinical trial, Larkin and associates (2015) compared nivolumab alone or nivolumab plus ipilimumab with ipilimumab alone in patients with metastatic melanoma. These investigators assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone; PFS and OS were co-primary end-points. Results regarding PFS were presented here. The median PFS was 11.5 months (95 % CI: 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95 % CI: 2.8 to 3.4) with ipilimumab (HR for death or disease progression, 0.42; 99.5 % CI: 0.31 to 0.57; p < 0.001), and 6.9 months (95 % CI: 4.3 to 9.5) with nivolumab (HR for the comparison with ipilimumab, 0.57; 99.5 % CI: 0.43 to 0.76; p < 0.001). In patients with tumors positive for the PD-L1, the median PFS was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, PFS was longer with the combination therapy than with nivolumab alone (11.2 months [95 % CI: 8.0 to not reached] versus 5.3 months [95 % CI: 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3 % of the patients in the nivolumab group, 55.0 % of those in the nivolumab-plus-ipilimumab group, and 27.3 % of those in the ipilimumab group. The authors concluded that among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer PFS than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.

Furthermore, an UpToDate review on “Overview of the management of advanced cutaneous melanoma” (Sosman, 2015) recommends immunotherapy with ipilimumab and nivolumab for advanced melanoma for the following indications:

• For patients without a V600 BRAF mutation, we recommend immunotherapy with nivolumab in combination with ipilimumab rather than with an anti-PD-1 antibody (nivolumab, pembrolizumab) alone (Grade 1A). Targeted therapy is not indicated in patients without a characteristic V600 mutation.

• For patients with a V600 BRAF mutation and a good performance status, we suggest immunotherapy rather than targeted therapy as the initial systemic therapy (Grade 2C). The preference for immunotherapy rather than targeted therapy is based upon the prolonged disease control achieved with immunotherapy in some patients, whereas those treated with targeted therapy almost always relapse relatively rapidly. In addition, BRAF inhibition in patients who have progressed after immunotherapy appears to have similar efficacy compared with BRAF inhibition prior to immunotherapy.

  When immunotherapy is indicated in this situation, checkpoint inhibition with nivolumab plus ipilimumab rather than an anti-PD-1 antibody alone is the preferred option.

  For patients with a V600 BRAF mutation who were initially treated with an anti-PD1 antibody and whose disease can no longer be controlled with immunotherapy, we recommend targeted therapy against the MAP kinase pathway with a combination of BRAF plus MEK inhibition (e.g., dabrafenib plus trametinib) rather than chemotherapy (Grade 1B).

• For patients with a V600 BRAF mutation and a poor performance status, we suggest MAP kinase pathway targeted therapy (e.g., dabrafenib plus trametinib) rather than immunotherapy (Grade 2C). Targeted therapy is associated with more rapid responses in this situation. Immunotherapy with a checkpoint inhibitor is an alternative. Immunotherapy may be an option for second line therapy when patients progress after targeted therapy.

Combinational Use of Ipilimumab and Nivolumab for Colorectal Cancer (dMMR/MSI-H)

On July 11, 2018, Bristol-Meyers Squibb announced the U.S. Food and Drug Administartion (FDA) approval of Opdivo (nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) for the treatment of patients 12 years 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 (BMS, 2018).

Approval for this indication has been granted under the FDA’s accelerated approval which was based on overall response rate (ORR) and duration of response (DOR) from the ongoing Phase 2, multicenter, non-randomized, multiple-parallel cohort, open-label CheckMate -142 trial, which demonstrated an ORR of 46% (95% CI: 35-58; n = 38/82). The CheckMate -142 trial enrolled MSI-H/dMMR mCRC patients who had received at least one prior line of therapy for metastatic disease, and efficacy was analyzed for both patients who had received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119 patients) as well as for all enrolled patients.

Among all enrolled patients, 49% (95% CI: 39-58; n = 58/119) responded to treatment with Opdivo + Yervoy; 4.2% (n = 5/119) experienced a complete response, while 45% (n = 53/119) experienced a partial response. Among the 58 responders, the median DOR was not reached (range: 1.9-23.2+ months); 83% of those patients had responses of six months or longer, and 19% had responses of 12 months or longer. In the combination cohort, 51 of 58 responders were ongoing at the time of database lock; 78% of these ongoing responders had not reached 12 months of follow-up from the date of onset of response. The application was granted Priority Review and Breakthrough Therapy Designation by the FDA. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials (BMS, 2018).

Overman et al. (2018) state nivolumab plus ipilimumab may provide clinical benefit in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). In the CheckMate-142 trial, 119 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Out of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% and disease control rate for ≥ 12 weeks was achieved in 80% of patients. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life.  The authors concluded that nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC. Evaluation of nivolumab plus ipilimumab as a firstline therapy (phase II) in patients with dMMR/MSI-H mCRC is ongoing.

The most frequent serious adverse reactions (greater than 2% of patients) were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (greater than 20% of patients) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%) (BMS, 2018).

Investigational Indications

De Mello and associates (2019) stated that esophago-gastric (EG) cancer has a poor prognosis despite the use of standard therapies, such as chemotherapy and biologic agents.  Recently, immune checkpoint inhibitors (ICIs) have been introduced as treatments for EG malignancies (e.g., esophageal and gastric cancers); nivolumab and pembrolizumab have been approved in the U.S. and Europe to treat advanced EG cancer.  Other ICIs, such as avelumab, durvalumab, ipilimumab, and tremelimumab, have been evaluated in several trials, although their roles are still not established in clinical practice.  In addition, pre-clinical evidence suggested that combining an ICI with a tumor-targeting antibody can result in greater anti-tumor effects in metastatic EG cancer.  There are not yet validated predictive biomarkers to identify which patients will respond best to ICI treatment.  PD-L1 expression may predict intensity of response, although PD-L1-negative patients can still respond to ICIs.  Despite differences in PD-L1 expression between Asian and non-Asian populations, no geographic differences in rates of treatment-related or immune-mediated/infusion-related AEs have been reported.  Also, several trials are currently evaluating combinations of ICIs, standard chemotherapy, and biologic agents as well as novel biomarkers to improve treatments and outcomes.

Glutsch and colleagues (2019) noted that immune-checkpoint blockade (ICB) shows significant activity in metastatic Merkel cell carcinoma (MCC); however, primary resistance remains a major clinical challenge.  These investigators reported a complete response to combined ipilimumab and nivolumab in a patient with metastatic MCC and primary resistance to the PD-L1 inhibitor avelumab.  A 60-year old man with a known history of stage III MCC (UICC 2017, Merkel cell poliomavirus positive) relapsed with limited retroperitoneal lymph node metastases and was treated with avelumab (10 mg/kg, q2w).  The patient, however, experienced progressive disease (PD, RECIST 1.1) after 3 months of treatment; 4 months after salvage surgery of the retroperitoneal tumor mass, a CT scan showed a relapse again.  A new adrenal metastasis was then treated with palliative radiation therapy (RT).  The patient was hospitalized 4 months later with a painful new lymph node metastasis in the left axilla.  A CT scan of chest and abdomen revealed new soft tissue, peritoneal, peri-hepatic, inter-enteric and retro-sternal metastases.  A grand round recommended off-label  combined immunotherapy with ipilimumab and nivolumab according to the ongoing CheckMate-358 study (NCT02488759).  The patient received 4 applications of a combined immunotherapy (ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, q3w).  Apart from grade 1 fatigue (CTCAE 4.03) the patient did not experience any toxicity.  A CT scan of chest and abdomen 4 weeks after the last dose of ipilimumab and nivolumab showed a complete remission (CR, RECIST 1.1) without any signs of residual disease.  Due to the complete response and the lack of clinical data for the treatment of MCC with combined immunotherapy, these researchers refrained from a maintenance monotherapy with nivolumab recommended in metastatic melanoma.  In patients with disseminated MCC refractory to PDL-1 blockade with avelumab, systemic therapeutic options are limited to chemotherapy known to induce only short-lived responses.  Although these researchers could not provide data on the durability of the response observed, combined ipilimumab/nivolumab might be considered as a treatment for metastatic MCC showing primary resistance to avelumab.  These researchers stated that this initial observation warrants further investigations to unravel the underlying mechanisms and its clinical significance in the treatment of metastatic MCC.

Furthermore, National Comprehensive Cancer Network’s Drugs and Biologics Compendium (2019) does not list astrocytoma, cholangiocarcinoma, esophageal cancer, gastric cancer, Merkel cell carcinoma and neuroendocrine tumor as recommended indications of ipilimumab.

Ipilimumab for the Treatment of Malignancies in Solid Organ Transplant Recipients

Fisher and colleagues (2019) stated that the use of immunotherapies in the treatment of metastatic cancers has significantly advanced oncology.  However, due to safety concerns, solid organ transplant recipients (SOTRs) are routinely excluded from immunotherapy trials; thus, there is limited data for these agents in this population.  These researchers carried out a systematic review to examine the safety and efficacy of immunotherapies in SOTRs with metastatic cancers.  Fisher's exact test and Kruskal-Wallis test were used for analysis.  In total, 37 % of patients experienced organ rejection, and 14 % died as a result of graft rejection.  Nivolumab was associated with the highest rejection rate (52.2 %), followed by pembrolizumab (26.7 %) and ipilimumab (25 %; p = 0.1774).  The highest rejection rate was observed in patients with kidney transplants (40.1 %), then liver (35 %) and heart (20 %) transplants (p = 0.775), and 64 % of patients succumbed to the progression of malignancy.  For all cases, rates of progression or death secondary to disease were highest for ipilimumab (75 %), followed by nivolumab (43 %) and pembrolizumab (40 %; p = 0.1892).  The ORR was highest for pembrolizumab (40 %), followed by nivolumab (30 %) and ipilimumab (25 %; p = 0.7929).  The authors concluded that physicians must be cautious when administering immunotherapy to SOTRs.  However, rejection was not the most common cause for death in this population.  The main drawback of this review was its small sample size.

Combined Ipilimumab and Nivolumab for the Treatment of Atypical Pulmonary Carcinoid

Nestor and colleagues (2019) stated that atypical pulmonary carcinoid (APC) is a lung neuroendocrine neoplasm (NEN), whose treatment draws from management of gastro-intestinal (GI) NENs and SCLC.  These investigators presented the case of a patient with recurrent metastatic APC and persistent mediastinal lymphadenopathy refractory to cisplatin and etoposide.  After pursuing alternative treatments, he returned with significant progression, including diffuse subcutaneous nodules, weight loss and worsening cough.  New biopsy analysis demonstrated APC with low mutational burden, low Ki-67 and PD-L1, and without microsatellite instability.  These researchers pursued combination ipilimumab and nivolumab therapy based on success of CheckMate 032 in SCLC.  The patient's symptoms dramatically responded within 1 month, with almost complete resolution of lymphadenopathy following 4 cycles.  He had been successfully maintained on nivolumab for the last 18 months.  The authors concluded that the findings of this single-case study suggested that combination immunotherapy may be beneficial in the treatment of metastatic APC, and that PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors may be valuable in treating tumors lacking traditional biomarkers.  These preliminary findings need to be validated by well-designed studies.

Combined Ipilimumab and Radiofrequency Ablation for the Treatment of Uveal Melanoma

Rozeman and colleagues (2019) noted that approximately 50 % of patients with uveal melanoma develop distant metastasis for which no standard therapy is established.  In contrast to cutaneous melanoma, the anti-CTLA-4 antibody ipilimumab showed no clinical activity in uveal melanoma.  Liver directed therapies improve local control, but fail to show OS benefit.  Pre-clinical experiments demonstrated that radiofrequency ablation (RFA) induced durable responses in combination with anti-CTLA-4.  In a phase-Ib/II clinical trial, these researchers examined safety and efficacy of RFA plus ipilimumab in uveal melanoma.  Patients underwent RFA of 1liver lesion and subsequently received 4 courses ipilimumab 0.3, 3 or 10 mg/kg every 3 weeks in a 3 + 3 design.  Primary end-points were safety in terms of dose limiting toxicities (DLTs) per cohort to define the recommended phase-II dose (RP2D) in the phase-Ib part and confirmed the ORR and DCR of non-RFA lesions in the phase-II part.  Secondary end-points were PFS and OS.  Ipilimumab 10 mg/kg + RFA was initially defined as the RP2D.  However, after 19 patients, the study was amended to adjust the RP2D to ipilimumab 3 mg/kg + RFA, because 47 % of patients treated with 10 mg/kg had developed grade-3 colitis.  In the 3 mg/kg cohort, also 19 patients had been treated.  Immunotherapy-related grade greater than or equal to 3 AEs were observed in 53 % of patients in the 10 mg/kg cohort versus 32 % in the 3 mg/kg cohort.  No confirmed objective responses were observed; the confirmed DCR was 5 % in the 10 mg/kg cohort and 11 % in the 3 mg/kg cohort.  Median PFS was 3 months and comparable for both cohorts, median OS was 14.2 months for the 10 mg/kg cohort versus 9.7 months for the 3 mg/kg cohort.  The authors concluded that combined RFA with ipilimumab 3 mg/kg was well-tolerated, however, this approach showed very limited clinical activity in uveal melanoma.

Combined Ipilimumab and Stereotactic Radiotherapy for the Treatment of Metastatic Cancers (e.g., in the Liver or Lung)

Welsh and colleagues (2019) noted that ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors.  These investigators reported a phase-II clinical trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung.  Ipilimumab (every 3 weeks for 4 doses) was administered with radiotherapy begun during the 1st dose (concurrent) or 1 week after the 2nd dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions.  A total of 106 patients received greater than or equal to 1 cycle of ipilimumab with radiation.  Median follow-up was 10.5 months.  Median PFS time was 2.9 months (95 % DI: 2.45 to 3.40), and median OS time was not reached.  Rates of clinical benefit of non-irradiated tumor volume were 26 % overall, 28 % for sequential versus 20 % for concurrent therapy (p = 0.250), and 31 % for lung versus 14 % for liver metastases (p = 0.061).  The sequential lung group had the highest rate of clinical benefit at 42 %.  There were no differences in treatment-related AEs between groups.  Exploratory analysis of non-targeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31 % versus 5 %, p = 0.0091).  The authors concluded that the findings of this phase-II clinical trial of ipilimumab with stereotactic radiotherapy described satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

National Comprehensive Cancer Network (NCCN) Recommendations

NCCN Drugs and Biologics Compendium (NCCN, 2019) recommends ipilimumab for the following:

Central Nervous System Cancers

Limited Brain Metastases

• Used in combination with nivolumab (preferred) or as a single-agent treatment for limited brain metastases in patients with melanoma [2A]

  • may be considered as initial treatment in select patients (eg, patients with small asymptomatic brain metastases) and
  • consider as treatment for recurrent brain metastases
  • treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options

Extensive Brain Metastases

• Treatment in combination with nivolumab (preferred) or as a single agent for extensive brain metastases in patients with melanoma [2A]

  • may be considered as primary treatment in select patients (eg, patients with small asymptomatic brain metastases)
  • as treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options

Colon Cancer 

• Primary treatment in combination with nivolumab for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
• Subsequent therapy in combination with nivolumab (if no previous treatment with a checkpoint inhibitor) for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy [2A]
  
• Therapy in combination with nivolumab in patients (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2B]
  
  
  • as adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in patients who have received previous chemotherapy
  • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment
    
    

• Therapy in combination with nivolumab (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2B]

  • as primary treatment for locally unresectable or medically inoperable disease
  • for unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy
  • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction
  • for synchronous unresectable metastases of other sites
  • as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy
  • for unresectable metachronous metastases that remain unresectable after primary treatment

Cutaneous Melanoma

• Preferred first-line systemic therapy option in combination with nivolumab for metastatic or unresectable disease [1]
• Useful in certain circumstances as a single-agent adjuvant systemic therapy option (if prior exposure to anti-PD-1 therapy) [2A for all others; 2B if NED after initial treatment with local or regional therapy]
  
  
  • for local satellite/in-transit recurrence if no evidence of disease (NED) after complete excision to clear margins or consider if NED after initial treatment with local or regional therapy
  • following therapeutic lymph node dissection and/or complete resection of nodal recurrence
  • following complete resection of distant metastatic disease 
    
    

• Second-line or subsequent systemic therapyfootnotes1* option for metastatic or unresectable diseaseFootnotes2** after disease progression or maximum clinical benefit from BRAF targeted therapy [2A for all others; 2B for combination with talimogene laherparepvec]

  • as a single agent if anti-PD-1 checkpoint inhibitor immunotherapy was not previously used
  • in combination with nivolumab (preferred) or as a single agent if checkpoint inhibitor immunotherapy was not previously used or for patients who progress on single agent anti-PD-1 checkpoint inhibitor immunotherapy
  • useful in certain circumstances in combination with intralesional injection of talimogene laherparepvec (for low burden of disease and injectable lesions)
  • may be considered as re-induction therapy (as a single agent or in combination with nivolumab) if prior anti-PD-1 checkpoint inhibitor immunotherapy resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression/relapse occurred >3 months after treatment discontinuation
    
    

  footnotes1* Systemic therapy is preferred for unresectable metastatic disease.

  footnotes2** 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.

Hepatocellular Carcinoma

• Subsequent treatment in combination with nivolumab (Child-Pugh Class A only) for progressive disease in patients who have not been previously treated with a checkpoint inhibitor and [2A]

  • have unresectable disease and are not a transplant candidate
  • are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only
  • have metastatic disease or extensive liver tumor burden

Kidney Cancer

• Used in combination with nivolumab for 4 cycles followed by single-agent nivolumab for relapse or stage IV disease [1 for first-line therapy for poor/intermediate risk; 2A for first-line therapy for favorable risk or for subsequent therapy]

  • as first-line therapy for clear cell histology and favorable risk
  • as preferred first-line therapy for clear cell histology and poor/intermediate risk
  • as preferred subsequent therapy for clear cell histology

Malignant Pleural Mesothelioma 

• Subsequent systemic therapy in combination with nivolumab [2A] 

Non-Small Cell Lung Cancer

• Activity against tumor mutational burden (TMB) in combination with nivolumab [2A]

  Tumor mutational burden (TMB) is an evolving biomarker that may be helpful in selecting patients for immunotherapy. There is no consensus on how to measure TMB.

• Treatment for recurrent, advanced or metastatic disease in combination with nivolumab for patients with performance status (PS) 0-1 and no contraindications to PD-1 or PD-L1 inhibitors as [2A for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease]

  • initial systemic therapy for EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negativefootnotes3*** and PD-L1 <1%
  • first-line (useful in certain circumstances) or subsequent therapy for BRAF V600E-mutation positive tumors
  • first-line (useful in certain circumstances) or subsequent therapy for NTRK gene fusion positive tumors
  • first-line (useful in certain circumstances) or subsequent therapy for MET exon 14 skipping mutation positive tumors
  • first-line or subsequent therapy for RET rearrangement positive tumors
  • subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib therapy
  • subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
  • subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib, entrectinib, or ceritinib therapy
    
    

  footnotes3*** If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, 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

• Treatment in combination with nivolumab (useful in certain circumstances) for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negativefootnotes4**** and no contraindications to PD-1 or PD-L1 inhibitors and performance status 0-2 [2A for all others; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease]

  footnotes4**** If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, 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

Rectal Cancer

• Subsequent therapy in combination with nivolumab (if no previous treatment with a checkpoint inhibitor) for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy [2A]
• Primary treatment in combination with nivolumab for unresectable metachronous metastases (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
• Therapy in combination with nivolumab for patients with advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2B]
  
  
  • as adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy
  • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy.
    
    

• Therapy in combination with nivolumab in patients (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) who are not appropriate for intensive therapy [2B]

  • as primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant therapy
  • for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy
  • following palliative radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy
  • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction
  • as primary treatment for synchronous unresectable metastases of other sites
  • as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy
  • for unresectable metachronous metastases that remain unresectable after primary treatment

Small Bowel Adenocarcinoma

• Subsequent therapy in combination with nivolumab for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) [2A]
• Initial therapy in combination with nivolumab for advanced or metastatic disease (deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] only) in patients with prior oxaliplatin exposure in the adjuvant setting or contraindication [2A]

Small Cell Lung Cancer

• Subsequent systemic therapy for patients with performance status 0-2 in combination with nivolumab for [2A]
  
  
  • relapse within 6 months following complete or partial response or stable disease with initial treatment (not recommended for relapse disease in patients on maintenance atezolizumab or durvalumab at time of relapse)
  • primary progressive disease

Uveal Melanoma

• Consider for distant metastatic disease [2A]
  
  
  • as single-agent therapy
  • in combination with nivolumab

Appendix

Unresectable Melanoma

The compassionate use trial for unresectable melanoma with ipilimumab (Bristol-Myers Squibb, 2010) provided the following inclusion as well as exclusion criteria.  Compassionate Use Trial for Unresectable Melanoma With Ipilimumab.

Inclusion Criteria

• Histologically confirmed stage III (unresectable) or stage IV melanoma.
• Must have failed at least 1 systemic therapy for malignant melanoma or be intolerant to at least 1 prior systemic treatment.
• Subjects with asymptomatic brain metastases are eligible.
• Primary ocular and mucosal melanomas are allowed.
• Must be at least 28 days since treatment with chemotherapy, biochemotherapy, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment.  Must have recovered from prior surgery or radiation.  Systemic corticosteroids should be eliminated or weaned to the minimum dose before starting ipilimumab treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
• Life expectancy greater than or equal to 16 weeks.
• Subjects must have the complete set of baseline (screening/baseline) radiographical images, including but not limited to abdomen, bone, brain, chest, and pelvis scans.
• Required values for initial laboratory tests:
  WBC: greater than or equal to 2000/uL (greater than or equal to 2 x 10*9*/L); ANC: greater than or equal to 1000/uL (greater than or equal to 1 x 10*9*/L); platelets: greater than or equal to 75 x 103/uL (greater than or equal to 75 x 10*9*/L); hemoglobin: greater than or equal to 9 g/dL (greater than or equal to 80 g/L; may be transfused); creatinine: less than or equal to 2.0 x ULN; AST/ALT: less than or equal to 2.5 x ULN for subjects without liver metastasis less than or equal to 5 times for liver metastases; bilirubin: less than or equal to 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must have a total bilirubin of less than 3.0 mg/dL).
• Men and women, at least 16 years of age.
• Prior treatment with an anti-CTLA-4 drug is allowed provided therapy was not discontinued due to drug-related toxicity.

Exclusion Criteria

• Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire duration of treatment and for up to 8 weeks after the last dose of ipilimumab. 
• WOCBP using a prohibited contraceptive method.
• Women who are pregnant or breast-feeding.
• Women with a positive pregnancy test before administration of ipilimumab.
• Subjects on any other systemic therapy for cancer, including any other experimental treatment.
• Prior treatment with an anti-CTLA-4 antibody if treatment failure was due to immune-related AEs or discontinuation was due to an AE/serious AE.
• Presence of active autoimmune disease.
• Presence of known hepatitis B or hepatitis C (active) infection, regardless of control on anti-viral therapy.
• Any subject who has a life-threatening condition that requires high-dose immuno-suppressants.
• Subjects with melanoma who have another active, concurrent, malignant disease, with the exception of adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
81210	BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
81301	Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
96413	Chemotherapy administration, IV infusion technique; up to 1 hour, single or initial substance/drug
96415	each additional hour (list in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9228	Injection, ipilimumab, 1 mg
Other HCPCS codes related to the CPB:
J9035	Injection, bevacizumab,10 mg [considered experimental and investigational when use in combination with ipilimumab]
J9206	Injection, irinotecan, 20 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg
Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
ICD-10 codes covered if selection criteria are met:
C17.0 - C17.9	Malignant neoplasm of small intestine, including duodenum [small bowel adenocarcinoma]
C18.0 - C18.9	Malignant neoplasm of colon
C21.0 - C21.1	Malignant neoplasm of anal canal and anus [anal adenocarcinoma]
C22.0	Liver cell carcinoma
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [small cell lung cancer]
C43.0 - C43.9	Malignant melanoma of skin
C64.1 - C64.9	Malignant neoplasm of kidney, except renal pelvis
C69.30 - C69.32	Malignant neoplasm of choroid
C69.40 - C69.42	Malignant neoplasm of ciliary body
C79.31	Secondary malignant neoplasm of brain
D03.0 - D03.9	Melanoma in situ
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C07.0 - C08.9	Malignant neoplasm of parotid gland and other and unspecified major salivary glands
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C22.1	Intrahepatic bile duct carcinoma
C25.0 - C25.9	Malignant neoplasm of pancreas
C45.0	Mesothelioma of pleura
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue
C4A. 0 - C4A.9	Merkel cell carcinoma
C61	Malignant neoplasm of prostate
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C7A.00 - C7A.8	Malignant neuroendocrine tumor
C82.00 - C84.09 C84.A0 - C86.6 C88.4, C96.A	Non-hodgkin's lymphoma

The above policy is based on the following references: