Ipilimumab, a recombinant, fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is an antineoplastic agent.1
Ipilimumab is used as monotherapy or in combination with nivolumab for the treatment of unresectable or metastatic melanoma in adults and pediatric patients who are ≥12 years of age.1 Ipilimumab is designated an orphan drug by the FDA for the treatment of this cancer.6
Ipilimumab is also used as adjuvant treatment in adults with cutaneous melanoma with pathologic involvement of regional lymph nodes of >1 mm who have undergone complete resection, including total lymphadenectomy.1
Unresectable or Metastatic Melanoma: Monotherapy
Efficacy of ipilimumab is based principally on observed survival benefits from a randomized, phase 3, double-blind, controlled study (MDX010-20) in 676 adults with previously treated (i.e., with one or more of the following: aldesleukin [23% of patients], dacarbazine, temozolomide, fotemustine [not commercially available in the US], carboplatin) unresectable or metastatic melanoma.1, 7 Eligible patients (59% male, median 57 years of age, 71% with TNM metastasis stage M1c, 98% with Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1, positive for human leukocyte antigen [HLA]-A2*0201 allele) were randomized (3:1:1) to receive ipilimumab with glycoprotein 100 (gp100) melanoma peptide vaccine (an investigational vaccine), ipilimumab monotherapy, or gp100 vaccine monotherapy.1, 7 Patients received induction regimens of ipilimumab (or placebo, as assigned) as a 90-minute IV infusion of 3 mg/kg followed by gp100 vaccine (or placebo, as assigned) as 2 separate 1-mg subcutaneous injections every 3 weeks for 4 doses.1, 7 This study excluded patients with autoimmune disease, primary ocular melanoma or untreated active CNS metastasis, and those receiving immunosuppressive agents (including long-term corticosteroids).1, 7 Assessment of tumor response occurred at 12 and 24 weeks and every 3 months thereafter.1 Median survival in patients receiving ipilimumab (with or without gp100 vaccine) was 10 months versus 6 months in patients receiving gp100 vaccine monotherapy.1 After a median follow-up of 28 months, rates of overall survival at 12, 18, and 24 months in patients receiving ipilimumab monotherapy were 45.6, 33.2, and 23.5%, respectively, compared with 25.3, 16.3, and 13.7%, respectively, in patients receiving gp100 vaccine monotherapy.7 Based on investigator assessment, best overall response rate was 10.9 and 1.5% in those receiving ipilimumab monotherapy and gp100 vaccine monotherapy, respectively.1, 7 In a long-term analysis, 2-year survival rates were 25% with ipilimumab alone compared with 19% with ipilimumab plus gp100; 3-year survival rates were 25% and 15%, respectively.17
Another phase 3 study evaluated ipilimumab as part of a combination chemotherapy regimen with dacarbazine in 502 adults with previously untreated, unresectable or metastatic melanoma.22 Patients were randomized to receive either ipilimumab and dacarbazine or dacarbazine and placebo.22 Treatment consisted of ipilimumab at higher than recommended doses (i.e., 10 mg/kg) and dacarbazine at doses of 850 mg/m2.22 Patients received induction regimens of ipilimumab and dacarbazine or dacarbazine and placebo IV at 1, 4, 7, and 10 weeks followed by dacarbazine alone every 3 weeks for 22 weeks.22 Patients with stable disease or an objective response during induction therapy were eligible to receive a maintenance regimen of ipilimumab or placebo every 12 weeks until disease progression, development of adverse effects, or study completion occurred.22 This study excluded patients receiving any prior treatment for metastatic disease or concomitant therapy with immunosuppressive agents (including long-term corticosteroids), or those with brain metastasis, primary ocular or mucosal melanoma, or autoimmune disease.22 Patients receiving ipilimumab and dacarbazine had increased median overall survival (11.2 months) compared with those receiving dacarbazine and placebo (9.1 months) with higher 1-year (47.3 versus 36.3%), 2-year (28.5 versus 17.9%), and 3-year (20.8 versus 12.2%) survival rates, respectively.22
In the CheckMate-067 study, 945 patients with previously untreated unresectable or metastatic melanoma were randomized (stratified by PD-L1 expression status, BRAF V600 mutation status, and stage of metastasis) to receive one of 3 regimens: nivolumab (1 mg/kg by IV infusion) in combination with ipilimumab (3 mg/kg by IV infusion) every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg by IV infusion every 2 weeks); nivolumab (3 mg/kg by IV infusion every 2 weeks) and placebo; or ipilimumab (3 mg/kg by IV infusion every 3 weeks for 4 doses) and placebo.1, 23 Treatment was continued until disease progression or unacceptable toxicity occurred; however, patients with disease progression could continue receiving treatment if they were considered to be deriving clinical benefit.23 The primary measures of efficacy were progression-free survival (as evaluated by an independent review committee according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1]) and overall survival; additional outcome measures were objective response rate and duration of response.1, 23 In this study, the median age of patients was 61 years; 97% were white, 65% were male, 46% had positive PD-L1 expression (defined as PD-L1 expression of any intensity on at least 5% of tumor cells as detected by immunohistochemistry assay), 36% had elevated LDH concentrations, 32% had BRAF V600 mutation-positive melanoma, 22% had received prior adjuvant therapy, and 4% had a history of brain metastasis.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (93%) had metastatic disease; 58% of patients had TNM metastasis stage M1c disease.1 Patients with autoimmune disease, conditions requiring therapy with immunosuppressive agents, ocular melanoma, or active brain metastasis were excluded from the study.1, 23
After a minimum follow-up of 28 months in the CheckMate-067 study, overall survival rate was higher in patients receiving nivolumab in combination with ipilimumab and in those receiving nivolumab compared with those receiving ipilimumab (59 and 55%, respectively, versus 37%).1 Progression-free survival also was prolonged in patients receiving nivolumab in combination with ipilimumab and in those receiving nivolumab compared with those receiving ipilimumab (11.5 and 6.9 months, respectively, versus 2.9 months).1, 23 In addition, patients receiving nivolumab in combination with ipilimumab and those receiving nivolumab had higher overall response rates compared with those receiving ipilimumab (50 and 40%, respectively, versus 14%); complete responses were achieved in 8.9, 8.5, or 1.9% of patients receiving combination therapy with nivolumab and ipilimumab, nivolumab, or ipilimumab, respectively.1, 23 After a minimum follow-up of 28 months, 55, 56, and 39% of patients receiving these respective treatments had durable responses of 24 months or more.1 After a minimum follow-up of 48 months, median overall survival was 36.9 and 19.9 months in patients receiving nivolumab and ipilimumab, respectively, but had not been reached in those receiving nivolumab in combination with ipilimumab.1, 41 At the final analysis conducted after a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab alone, and 19.9 months with ipilimumab alone.45 Progression-free survival remained similar to the initial interim results.45 Results of a subgroup analysis (including PD-L1 expression status and BRAF V600 mutation status, among others) suggested that the progression-free survival and overall survival benefit of nivolumab or nivolumab in combination with ipilimumab versus ipilimumab was consistent across all subgroups.45
The safety and effectiveness of ipilimumab have been established in pediatric patients 12 years of age and older for unresectable or metastatic melanoma as a single agent and in combination with nivolumab.1 Use of ipilimumab in these pediatric patients is supported by evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.1 Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults; in addition, the course of melanoma in pediatric patients 12 years of age and older is similar to that in adults to allow extrapolation of safety and efficacy.1
Resected Cutaneous Melanoma: Adjuvant Treatment
The current indication for ipilimumab for the treatment of resected cutaneous melanoma is based principally on the results of a randomized, open-label, phase 3 study (E1609).1, 26 The E1609 study included adults with melanoma of cutaneous or unknown primary origin who were determined to be disease-free following surgical resection.1, 26 In this study, patients were randomized (stratified by cancer stage) to receive one of the following: ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by the same dose every 12 weeks for up to 4 additional doses; high-dose interferon alfa-2B (HDI) IV (5 days per week for 4 weeks, followed by subcutaneous administration every other day for 48 weeks); or ipilimumab 10 mg/kg IV every 3 weeks for 4 doses, followed by the same dose every 12 weeks for up to 4 additional doses.1, 26 Treatment was continued through a maximum of 60 weeks with ipilimumab or 52 weeks with HDI, or until disease progression, unacceptable toxicity, or withdrawal of consent occurred.1, 26 The primary measures of efficacy were recurrence-free survival (by imaging for CNS lesions or by imaging plus positive cytology or histology for non-CNS lesions) and overall survival;1, 26 these results were compared between the ipilimumab 3 mg/kg group and HDI group for approval.1 Among the 1051 patients randomized to the ipilimumab 3 mg/kg or HDI groups, the median age was 54 years, 97% were white, and 62% were male; 53% had stage IIIb disease, 40% had stage IIIc disease, and 7% had stage 4 disease.1 This study excluded patients with a history of previous treatment for melanoma or any autoimmune disease requiring steroid treatment.1, 26
At the time of analysis, 25% of patients in both the ipilimumab 3 mg/kg and the HDI groups had died; 5-year overall survival was 72% in the ipilimumab 3 mg/kg group versus 67% in the HDI group.1 Recurrence-free survival was a median of 4.5 years with ipilimumab 3 mg/kg versus 2.5 years with HDI.1
Ipilimumab is used in combination with nivolumab for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma in adults.1
The current indication for ipilimumab in combination with nivolumab for the treatment of intermediate- or poor-risk, previously untreated, advanced renal cell carcinoma is based principally on the results of a randomized, open-label phase 3 study (CheckMate-214) in adults with previously untreated advanced renal cell carcinoma.1, 37 In this study, 1082 patients were randomized (stratified by geographic region and International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk score) to receive either nivolumab (3 mg/kg by IV infusion) in combination with ipilimumab (1 mg/kg by IV infusion) every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg by IV infusion every 2 weeks), or sunitinib (50 mg orally once daily for 4 consecutive weeks of each 6-week cycle).1, 37 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary measures of efficacy were overall survival, progression-free survival (as evaluated by an independent review committee according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1]), and objective response rate (as evaluated by an independent review committee according to RECIST) in patients with intermediate- or poor-risk disease (defined as patients with at least one prognostic risk factor according to IMDC criteria).1, 37 The median age of patients enrolled in the study was 61 years (8% of patients were 75 years of age or older); 87% were white and 73% were male.1 All patients enrolled in the study had a baseline Karnofsky performance status of 70 or greater.1, 37 Patients were eligible for enrollment in the study regardless of tumor expression of PD-L1.1.1, 37 This study excluded patients with active autoimmune disease, any history of or active brain metastasis, or any condition requiring therapy with immunosuppressive agents.1, 37
At a median follow-up of 25.2 months, median overall survival for patients with intermediate- or poor-risk disease receiving nivolumab in combination with ipilimumab had not been reached versus 25.9 months with sunitinib; however, nivolumab in combination with ipilimumab reduced the risk of death by 37% compared with sunitinib.1, 37 Median progression-free survival was 11.6 months in patients receiving nivolumab in combination with ipilimumab and 8.4 months in those receiving sunitinib; however, the difference was not statistically significant.1, 37 Patients with intermediate- or poor-risk disease receiving nivolumab in combination with ipilimumab also had higher objective response rates (41.6 versus 26.5%); complete response was achieved in 9.4% of patients receiving nivolumab in combination with ipilimumab and 1.2% of those receiving sunitinib.1, 37 At the time of analysis, the median duration of response had not been reached in patients receiving nivolumab in combination with ipilimumab and was 18.2 months in those receiving sunitinib.1, 37 Results of a subgroup analysis (based on age, gender, geographic region, IMDC risk category, prior nephrectomy, baseline level of PD-L1 expression, and site of metastases) in patients with intermediate- or poor-risk disease suggested a survival benefit for nivolumab in combination with ipilimumab relative to sunitinib across subgroups.37 In an exploratory analysis, an overall survival benefit for the nivolumab-ipilimumab combination regimen compared with sunitinib was not apparent in a separate group of 249 patients who had favorable-risk disease (hazard ratio: 1.45).1, 37 At 5 years from randomization, mean overall survival was 40.7 months for patients treated with nivolumab plus ipilimumab versus 36.1 months for patients treated with sunitinib.57 At a median follow-up of 99.1 months (approximately 8 years), median overall survival was 52.7 months for patients treated with nivolumab plus ipilimumab versus 37.8 months with sunitinib.58
Ipilimumab is used in combination with nivolumab for the treatment of adults and pediatric patients ≥12 years of age with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) colorectal cancer.1
The current indication for ipilimumab in combination with nivolumab for the treatment of colorectal cancer is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-8HW) in adults with unresectable or metastatic MSI-H or dMMR colorectal cancer.1, 59, 60 Patients in the study were randomized (stratified by the number of previously received systemic treatments for colorectal cancer and tumor location) to receive one of the following: 1) ipilimumab 1 mg/kg every 3 weeks plus nivolumab 240 mg every 3 weeks for a maximum of 4 doses, then nivolumab 480 mg every 4 weeks; 2) nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks, or 3) investigator's choice chemotherapy, which was either mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil with or without bevacizumab or cetuximab) or FOLFIRI (irinotecan, leucovorin, and fluorouracil, with or without bevacizumab or cetuximab).1, 59, 60 Treatment was continued for up to 2 years for patients in the ipilimumab plus nivolumab or nivolumab groups, or until disease progression or unacceptable toxicity occurred.1, 59, 60 Patients randomized to chemotherapy could switch to receive ipilimumab plus nivolumab if disease progression occurred.1, 59 The primary measure of efficacy was progression-free survival (as evaluated by blinded independent central review per RECIST 1.1); objective response rate was also assessed.1, 59, 60 Ipilimumab plus nivolumab was evaluated in 2 different populations: it was compared to chemotherapy in the first-line setting and compared to nivolumab monotherapy, regardless of previous systemic treatment (all lines cohort).1 Patients with active autoimmune disease, symptomatic brain metastasis, any condition requiring therapy with systemic corticosteroids or immunosuppressive agents, or previous treatment with checkpoint inhibitors were excluded from the study.1 Across the entire population (N=839), patients had a median age of 63 years, 50% were male, and 87% were white; 56% of patients received ipilimumab plus nivolumab as first-line therapy, 24% had received 1 prior line of therapy, and 19% had received ≥2 prior lines of therapy.1
A total of 255 patients with unresectable metastatic MSI-H or dMMR colorectal cancer received treatment with ipilimumab plus nivolumab (n=171) or chemotherapy (n=84) in the first-line setting.1, 59 At a median follow-up of 31.5 months, progression-free survival was not reached in the ipilimumab plus nivolumab group and was 5.9 months with chemotherapy.59 In the all lines cohort, 296 patients were treated with ipilimumab plus nivolumab and 286 patients were treated with nivolumab monotherapy.1 After a minimum follow-up of 16.7 months, median progression-free survival was not reached in the ipilimumab plus nivolumab group and was 39.3 months in the nivolumab monotherapy group.1, 60 Objective response occurred in 71% of patients treated with ipilimumab plus nivolumab (30% complete response) compared with 58% who received nivolumab monotherapy (28% complete response).1, 60
The safety and effectiveness of ipilimumab have been established in pediatric patients 12 years of age and older when used in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1 Use of ipilimumab in these pediatric patients is supported by evidence from adequate and well-controlled studies in adults with MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients.1 Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults; in addition, the course of MSI-H or dMMR mCRC in pediatric patients 12 years of age and older is similar to that in adults to allow extrapolation of safety and efficacy.1
Ipilimumab is used in combination with nivolumab for the treatment of adults with unresectable or metastatic hepatocellular carcinoma, both as first-line therapy and in those previously treated with sorafenib.1
Previously Untreated Unresectable or Metastatic Hepatocellular Carcinoma.
The current indication for ipilimumab for the treatment of unresectable or metastatic hepatocellular carcinoma is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-9DW).1, 61 To be enrolled in the study, patients had to have hepatocellular carcinoma, Child Pugh Class A, and not have received previous systemic treatment for advanced disease.1, 61 Patients were randomized (stratified by cancer etiology, presence or absence of macrovascular invasion and/or extrahepatic spread, and alpha-fetoprotein levels) to receive ipilimumab plus nivolumab (ipilimumab 3 mg/kg IV plus nivolumab 1 mg/kg IV every 3 weeks, for up to 4 doses, followed by nivolumab 480 mg as monotherapy given every 4 weeks) or investigator's choice of oral lenvatinib or sorafenib.1, 61 Treatment was continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 61 The primary measure of efficacy was overall survival; objective response rate and duration of response (both evaluated by blinded independent central review per RECIST 1.1) were also assessed.1, 61 The CheckMate-9DW study included 668 patients who had a median age of 66 years; 82% were male, 53% were white, and 44% were Asian.1 Thirty-four percent of patients had hepatitis B virus (HBV) infection, 28% had hepatitis C virus (HCV) infection, and 36% had neither HBV or HCV.1 Most patients (73%) had stage C disease at baseline.1 Among the 333 patients randomized to investigator's choice of treatment, 85% received lenvatinib and 15% received sorafenib.1 The study excluded patients with autoimmune disease, brain or leptomeningeal metastasis, a history of hepatic encephalopathy, current or prior episodes of clinically important ascites, a platelet count <60,000, HIV infection, active HBV and HCV coinfection, or active HBV and hepatitis D virus (HDV) coinfection.1, 61
At a minimum follow-up of 26.8 months, overall survival was a median of 23.7 months in patients treated with ipilimumab plus nivolumab versus 20.6 months with lenvatinib or sorafenib.1, 61 The objective response rate was 36% with ipilimumab plus nivolumab (7% complete response) and 13% with lenvatinib or sorafenib (2% complete response).61 The median duration of response was 30.4 and 12.9 months, respectively.1, 61
Previously Treated Hepatocellular Carcinoma
The current indication for ipilimumab for the treatment of previously treated hepatocellular carcinoma is based principally on the results for a cohort of patients with hepatocellular carcinoma in an open-label, multicenter, noncomparative, phase 1/2 study (CheckMate-040); the cohort included 49 adults with advanced hepatocellular carcinoma who had experienced disease progression during sorafenib therapy or who had not tolerated such therapy and were treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, followed by monotherapy with nivolumab 240 mg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred (cohort 4).1, 25 The primary measure of efficacy was objective response rate as assessed by a blinded independent review committee according to RECIST 1.1 and modified RECIST for hepatocellular carcinoma.1 The median age of patients in the nivolumab plus ipilimumab cohort was 60 years; 82% had Child-Pugh class A5 hepatic impairment, 88% were male, 80% had extrahepatic spread, 74% were Asian, 57% had active HBV infection, 51% had α-fetoprotein concentrations of 0.4 mg/L or more, 35% had vascular invasion, 8% had active HCV infection, and 29% had received at least 2 prior systemic therapies.1 All patients enrolled in cohort 4 had an ECOG performance status of 0 or 1 and previously had received sorafenib therapy; sorafenib was discontinued because of intolerable toxicity in 10% of patients.1 Alcohol consumption and nonalcoholic liver disease was the cause of hepatocellular carcinoma in 16 and 6% of patients, respectively.1 Prior therapies included surgical resection, locoregional therapy, and radiation therapy in 74, 59, and 29% of patients, respectively.1, 1, 25 The study excluded patients with autoimmune disease, brain metastasis, a history of hepatic encephalopathy, current or prior episodes of clinically important ascites, HIV infection, active HBV and HCV coinfection, or active HBV and hepatitis D virus (HDV) coinfection.1
The objective response rate according to RECIST 1.1 and modified RECIST for patients in cohort 4 of this study was 33 and 35%, respectively; according to these response criteria, complete response was achieved in 8 and 12%, respectively, of patients.1 The duration of response ranged from 4.6 to ≥30.5 months; 88% of patients who responded to the drug had durable responses of 6 months or more, 56% had durable responses of 12 months or more, and 31% had durable responses of 24 months or more.1
Ipilimumab is used in combination with nivolumab for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) expressing programmed-death ligand-1 (PD-L1; i.e., tumor proportion score ≥1%), with no EGFR or ALK genomic aberrations.1 An FDA-approved diagnostic test is required to confirm the presence of high PD-L1 expression prior to initiation of therapy.1
Ipilimumab is used in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy for the first-line treatment of adults with metastatic or recurrent NSCLC with no EGFR or ALK genomic aberrations.1
The current indication for ipilimumab used in combination with nivolumab for the first-line treatment of metastatic or recurrent NSCLC is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-227).1, 50 In part 1a of the CheckMate-227 trial, patients with previously untreated recurrent or stage IV NSCLC were randomized (stratified by tumor histology) to receive either nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks or platinum-doublet chemotherapy every 3 weeks.1, 50 Choice of agents for platinum-doublet chemotherapy was based on histology: pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin (AUC 5 or 6 mg/mL per minute) for non-squamous histology; and either gemcitabine 1000 mg/m2 or 1250 mg/m2 plus cisplatin 75 mg/m2 or gemcitabine 1000 mg/m2 plus carboplatin (AUC 5 mg/mL per minute) for squamous histology.1 Treatment was continued through 2 years of follow up or until disease progression or unacceptable toxicity occurred.1, 50 The primary measure of efficacy in part 1a of the trial, which evaluated 793 patients with PD-L1 expression >1%, was overall survival.1, 50 Progression-free survival, objective response rate, and duration of response (all evaluated by blinded independent central review) were also assessed.1
The median age of patients enrolled in the study was 64 years; 76% were white, 65% were male, 85% were former or current smokers, and 50% had tumors with PD-L1 expression ≥50% at baseline.1 Almost all patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (71%) had non-squamous histology, and 10% had brain metastases.1 This study excluded patients with known EGFR mutations or ALK translocations, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.1
At a minimum follow-up of 29.3 months, median overall survival was 17.1 months in the nivolumab plus ipilimumab group and 14.9 months with chemotherapy.1, 50 Median progression-free survival was 5.1 months with nivolumab plus ipilimumab and 5.6 months with platinum-doublet chemotherapy1 ; the objective response rates were 35.9 and 30%, respectively.50 At the time of analysis, the median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy.1, 50 At a minimum follow-up of 61.3 months, 5-year overall survival rates were 24% for nivolumab plus ipilimumab and 14% for chemotherapy; median duration of response was 24.5 or 6.7 months, respectively.51 At a minimum follow-up of 73.5 months, estimated overall survival rates were 20% for nivolumab plus ipilimumab and 11% for chemotherapy.54
The current indication for ipilimumab used in combination with nivolumab and platinum-doublet chemotherapy for the first-line treatment of metastatic or recurrent NSCLC is based principally on the results of a randomized, open-label, phase 3 study (CheckMate-9LA).1, 52 In CheckMate-9LA, 719 patients with recurrent or stage IV NSCLC not previously treated in the metastatic setting were randomized (stratified by tumor PD-L1 expression level, tumor histology, and sex) to receive either nivolumab 360 mg IV every 3 weeks plus ipilimumab 1 mg/kg IV every 6 weeks and platinum doublet chemotherapy IV every 3 weeks for 2 cycles, or platinum-doublet chemotherapy alone every 3 weeks for up to 4 cycles.1, 52 Choice of agents for platinum-doublet chemotherapy was based on histology: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (AUC 5 or 6 mg/mL per minute) for non-squamous histology; and paclitaxel 200 mg/m2 plus carboplatin (AUC 6 mg/mL per minute) for squamous histology.1, 52 Patients with non-squamous histology could also receive optional maintenance therapy with pemetrexed.1, 52 Treatment was continued through 2 years of follow up or until disease progression or unacceptable toxicity occurred.1, 52 The primary measure of efficacy was overall survival.1 Progression-free survival, objective response rate, and duration of response (all evaluated by blinded independent central review) were also assessed.1 The median age of patients enrolled in the study was 65 years; 89% were white, 70% were male, 86% were former or current smokers, and 57% had tumors with PD-L1 expression ≥1% at baseline.1 Almost all patients enrolled in the study had an ECOG performance status of 0 or 1.1 Most patients (68%) had non-squamous histology, and 17% had metastases to the CNS.1 This study excluded patients with known EGFR mutations or ALK translocations, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.1
At a prespecified interim analysis conducted after a minimum follow-up of 8.1 months, median overall survival was 14.1 months in the nivolumab/ipilimumab/chemotherapy group and 10.7 months with chemotherapy alone.1, 52 Median progression-free survival was 6.8 months with nivolumab/ipilimumab/chemotherapy and 5 months with chemotherapy alone.1, 52 The objective response rate was 37.7% with nivolumab/ipilimumab/chemotherapy and 25.1% with chemotherapy alone.52 After an additional 4.6 months of follow-up, median overall survival was 15.6 months with nivolumab/ipilimumab/chemotherapy and 10.9 months with chemotherapy alone.1 The median duration of response was 10 and 5.1 months, respectively.1 At a minimum follow-up of 57.3 months, 5-year overall survival rates were 18% for nivolumab/ipilimumab/chemotherapy and 11% for chemotherapy alone; median 5-year duration of response rates were 19% or 8%, respectively.53 At the final analysis (minimum follow-up of 68.6 months), overall survival rates continued to be higher with nivolumab/ipilimumab/chemotherapy versus chemotherapy alone (16 versus 10%, respectively).62
Malignant Pleural Mesothelioma
Ipilimumab is used in combination with nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma (MPM) in adults;1 Ipilimumab is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.6
The current indication for ipilimumab in combination with nivolumab as first-line treatment of unresectable MPM is based principally on the results of an open-label, randomized, phase 3 study (CheckMate-743).1, 55 Adults with unresectable MPM, with no prior treatment and no palliative radiotherapy within the past 14 days, were enrolled.1, 55 In this study, 605 patients were randomized (stratified by tumor histology and sex) in a 1:1 ratio to receive nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to 2 years or chemotherapy with either pemetrexed 500 mg/m2 and either cisplatin 75 mg/m2or carboplatin (AUC 5 mg/mL per minute) given every 3 weeks for 6 cycles.1, 55 Treatment was continued for up to 2 years or until disease progression or unacceptable toxicity occurred.1, 55 The primary measure of efficacy was overall survival; additional efficacy measures included progression-free survival, overall response rate, and duration of response, as assessed by a blinded independent central review committee according to Response Evaluation Criteria in Solid Tumors (RECIST).1, 55 The median age of patients enrolled was 69 years; 85% were white, 11% were Asian, and 77% were male.1 Most patients (75%) had epithelioid histology; 75% had PD-L1 expression ≥1%, 35% had stage III disease, and 51% had stage IV disease.1 All patients enrolled had an ECOG performance status of 0 or 1.1 This study excluded patients with active autoimmune disease, conditions requiring therapy with immunosuppressive agents, active brain metastases, or interstitial lung disease.1, 55
At a minimum of 22.1 months of follow-up, median overall survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months for chemotherapy; median progression-free survival was 6.8 and 7.2 months, respectively.1, 55 Patients treated with nivolumab plus ipilimumab had an overall response rate of 40% versus 43% for patients treated with chemotherapy.1, 55 The duration of response was 11 and 6.7 months for nivolumab plus ipilimumab and chemotherapy, respectively.1, 55 At a median follow-up of 43.1 months, overall survival benefits of nivolumab plus ipilimumab were sustained.56
Ipilimumab is used in combination with nivolumab for first-line treatment of adults with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (i.e., tumor proportion score ≥1%).1
The current indication for ipilimumab as first-line treatment of unresectable advanced or metastatic ESCC is based principally on the results of a randomized, active-controlled, open-label, phase 3 trial (CheckMate-648).1, 66 CheckMate-648 included patients with untreated, unresectable advanced, recurrent, or metastatic ESCC that was not amenable to chemoradiation or surgery with curative intent (although prior treatment with curative intent was allowed if completed >6 months before enrollment); patients were also required to have tumors that were evaluable for PD-L1 expression.1, 66 Patients were randomized (stratified by tumor PD-L1 expression, geographic region, ECOG performance status, and number of organs with metastases) to receive one of the following IV treatment regimens: 1) nivolumab 240 mg every 2 weeks plus chemotherapy (4-week cycles consisting of fluorouracil 800 mg/m2 per day on days 1-5 and cisplatin 80 mg/m2 on day 1); 2) nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; or 3) chemotherapy (4-week cycles consisting of fluorouracil 800 mg/m2 per day on days 1-5 and cisplatin 80 mg/m2 on day 1).1, 66 Treatment was continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 66 The primary measures of efficacy were overall survival and progression-free survival as assessed by a blinded independent review committee; these outcomes were tested in a hierarchical fashion, first in patients with PD-L1 expression ≥1% and then in the entire population.1, 66 Objective response rate (assessed by blinded independent central review) was also assessed in both populations.1, 66 To assess the efficacy of ipilimumab, these results were compared between patients who received ipilimumab plus nivolumab and those who received chemotherapy with cisplatin and fluorouracil and evaluated in patients with tumor cell PD-L1 expression ≥1% and in the larger population of patients with a PD-L1 combined positive score (CPS) of ≥1.1 Among 546 patients with a PD-L1 CPS of ≥1, the median age of patients enrolled in the study was 63 years; all patients had an ECOG performance status of 0 or 1, 84% were male, 71% were Asian, 99% had histological confirmation of squamous cell carcinoma, and 1.3% had histological confirmation of adenosquamous cell carcinoma.1 This study excluded patients with symptomatic brain metastases, conditions requiring therapy with corticosteroids or immunosuppressive agents, or a high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor.1
Data were evaluated after a minimum follow-up of 13 months.66 When comparing ipilimumab plus nivolumab to chemotherapy alone, median overall survival was substantially longer with nivolumab plus ipilimumab compared to chemotherapy alone, both among patients with PD-L1 expression ≥1% (13.7 versus 9.1 months) and among the larger population of patients with PD-L1 CPS ≥1 (12.7 versus 9.8 months).1 Median progression-free survival was similar between patients treated with ipilimumab plus nivolumab and patients treated with chemotherapy alone among the subgroup of patients with PD-L1 expression ≥1% (4 versus 4.4 months); however, median progression-free survival was reduced with ipilimumab plus nivolumab versus chemotherapy in the population with PD-L1 CPS ≥1 (2.8 versus 5.6 months).1 Ipilimumab plus nivolumab was also associated with higher objective response rates compared to chemotherapy alone among patients with PD-L1 expression ≥1% (35.4 versus 19.7%), but not in the population with PD-L1 CPS ≥1 (28 versus 27%); duration of response was longer with nivolumab plus ipilimumab compared to chemotherapy alone in patients with PD-L1 expression ≥1% (11.8 versus 5.7 months) and in the population with PD-L1 CPS ≥1 (11.8 versus 6.9 months).1
At a minimum follow-up of 29 months, ipilimumab plus nivolumab continued to demonstrate improvements in median overall survival compared to chemotherapy alone (PD-L1 ≥1%, 13.1 versus 9.1 months; entire population, 12.7 versus 10.7 months).67 Progression-free survival was not substantially different between patients treated with ipilimumab plus nivolumab and those treated with chemotherapy alone among patients with PD-L1 expression ≥1% (4 versus 4.4 months).67
Dispensing and Administration Precautions
Ipilimumab is available as a 5-mg/mL, preservative-free, injection concentrate in single-use vials containing 50 or 200 mg of the drug.1
Ipilimumab is administered by IV infusion.1 Dilution of the concentrate is required prior to administration.1 Administer diluted ipilimumab through an IV line containing an inline, sterile, nonpyrogenic, low-protein-binding filter.1 Flush the IV line with 0.9% sodium chloride or 5% dextrose injection after each dose.1
When administered in combination with nivolumab, infuse nivolumab first followed by ipilimumab on the same day.1
When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by ipilimumab, and then platinum-doublet chemotherapy on the same day.1 Use separate infusion bags and filters for each infusion.1 Do not co-administer other drugs through the same IV line.1
Store ipilimumab injection concentrate at 2-8°C.1 Do not shake or freeze; protect from light by storing in the original carton until time of use.1
The diluted solution may be refrigerated (2-8°C) or stored at controlled room temperature (20-25°C) for no more than 24 hours from the time of preparation to the time of infusion.1 Discard any partially used vials, including unused diluted solution.1
Ipilimumab injection concentrate must be diluted prior to administration .1 Prior to dilution, allow the appropriate number of vials containing ipilimumab injection concentrate to stand at room temperature for approximately 5 minutes.1 For IV infusion, withdraw the appropriate dose from the vial(s) and inject into an IV bag.1 Dilute the injection concentrate with 0.9% sodium chloride or 5% dextrose injection to achieve a final ipilimumab concentration of 1-2 mg/mL.1 Mix the diluted solution by gentle inversion.1 Do not shake vials containing ipilimumab injection concentrate or diluted solutions of the drug.1
Infuse final diluted ipilimumab solutions IV over 30 minutes1 Flush the IV line with 0.9% sodium chloride or 5% dextrose injection after each dose.1
Monotherapy for Unresectable or Metastatic Melanoma : When used as monotherapy for the treatment of unresectable or metastatic melanoma, the recommended dosage of ipilimumab in adults is 3 mg/kg administered every 3 weeks as a 30-minute IV infusion for a maximum of 4 doses.1
Adjuvant Treatment of Melanoma : When used as adjuvant treatment for adults with cutaneous melanoma with pathologic involvement of regional lymph nodes (greater than 1 mm) who have undergone complete resection, including total lymphadenectomy, the recommended dosage of ipilimumab is 3 mg/kg every 3 weeks as a 30-minute IV infusion for a maximum of 4 doses, followed by 3 mg/kg every 12 weeks for up to 4 additional doses.1
Combination Therapy for Unresectable or Metastatic Melanoma : When used in combination with nivolumab for the treatment of unresectable or metastatic melanoma in adults, the recommended dosage of ipilimumab is 3 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 1 mg/kg for up to 4 doses or until unacceptable toxicity occurs.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.1
Combination Therapy for Intermediate or Poor Risk Advanced Renal Cell Carcinoma : When used in combination with nivolumab for advanced renal cell carcinoma in adults, the recommended dosage of ipilimumab is 1 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 3 mg/kg for up to 4 doses.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.1
Combination Therapy for Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer : When used in combination with nivolumab for the treatment of microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer in adults, the recommended dosage of ipilimumab is 1 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 240 mg for a maximum of 4 doses.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression, unacceptable toxicity, or up to 2 years.1
Combination Therapy for Unresectable or Metastatic Hepatocellular Carcinoma : When used in combination with nivolumab for first-line treatment of adults with unresectable or metastatic hepatocellular carcinoma (HCC), or in adults with unresectable or metastatic HCC previously treated with sorafenib, the recommended dosage of ipilimumab is 3 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 1 mg/kg for up to 4 doses or until unacceptable toxicity occurs.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.1
Combination Therapy for Metastatic Non-Small Cell Lung Cancer Expressing PD-L1 : When used in combination with nivolumab for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumors express PD-L1 with no EGFR or ALK genomic tumor aberrations, the recommended dosage of ipilimumab is 1 mg/kg administered every 6 weeks as a 30-minute IV infusion in combination with nivolumab 360 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.1
Combination Therapy for Metastatic or Recurrent Non-Small Cell Lung Cancer : When used in combination with nivolumab and platinum-doublet chemotherapy for the first-line treatment of metastatic non-small cell lung cancer in adults with no EGFR or ALK genomic tumor aberrations, the recommended dosage of ipilimumab is 1 mg/kg administered every 6 weeks as a 30-minute IV infusion in combination with nivolumab 360 mg every 3 weeks and histology-based platinum-doublet chemotherapy every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.1 Platinum-doublet chemotherapy is given for 2 cycles.1
Malignant Pleural Mesothelioma
Combination Therapy for Unresectable Malignant Pleural Mesothelioma : When used in combination with nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma in adults, the recommended dosage of ipilimumab is 1 mg/kg administered every 6 weeks as a 30-minute IV infusion in combination with nivolumab 360 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.1
Combination Therapy for Unresectable Advanced or Metastatic Esophageal Squamous Cell Carcinoma : When used in combination with nivolumab for the first-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma in adults whose tumors express PD-L1, the recommended dosage of ipilimumab is 1 mg/kg every 6 weeks as a 30-minute IV infusion in combination with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years.1
Monotherapy for Unresectable or Metastatic Melanoma : When used as monotherapy for the treatment of unresectable or metastatic melanoma in pediatric patients ≥12 years of age, the recommended dosage of ipilimumab is 3 mg/kg administered every 3 weeks as a 30-minute IV infusion for a maximum of 4 doses.1
Combination Therapy for Unresectable or Metastatic Melanoma : When used in combination with nivolumab for the treatment of unresectable or metastatic melanoma in pediatric patients ≥12 years of age, the recommended dosage of ipilimumab is 3 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 1 mg/kg for up to 4 doses or until unacceptable toxicity occurs.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.1
Combination Therapy for Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer : When used in combination with nivolumab for the treatment of microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer in pediatric patients ≥12 years of age weighing ≥40 kg, the recommended dosage of ipilimumab is 1 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 240 mg for a maximum of 4 doses.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression, unacceptable toxicity, or up to 2 years.1
When used in combination with nivolumab for the treatment of microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer in pediatric patients ≥12 years of age weighing <40 kg, the recommended dosage of ipilimumab is 1 mg/kg administered every 3 weeks as a 30-minute IV infusion in combination with nivolumab 3 mg/kg for a maximum of 4 doses.1 After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression, unacceptable toxicity, or up to 2 years.1
Dosage Modification for Toxicity
Dosage reduction is not recommended for adverse reactions.1 In general, withhold ipilimumab for severe (grade 3) immune-mediated adverse reactions.1
Permanently discontinue ipilimumab therapy in patients experiencing life-threatening (grade 4) immune-mediated adverse reactions; recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment; persistent moderate (grade 2) or severe (grade 3) reactions (excluding endocrinopathy) lasting 12 weeks or longer after the last ipilimumab dose; or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.1
When ipilimumab is administered in combination with nivolumab, withhold or permanently discontinue both ipilimumab and nivolumab for toxicity.1
Withhold ipilimumab for grade 2 colitis and resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for grade 3 or 4 colitis.1
Patients without tumor involvement of the liver, or with tumor involvement of the liver/non-hepatocellular carcinoma : Withhold ipilimumab for AST or ALT >3 to ≤5 times the upper limit of normal (ULN), or total bilirubin >1.5 to ≤3 times ULN.1 Resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for AST or ALT >5 times ULN or total bilirubin >3 times ULN.1
Patients with tumor involvement of the liver and receiving ipilimumab/nivolumab combination therapy for hepatocellular carcinoma : Withhold ipilimumab for patients with a baseline AST or ALT less than or equal to ULN who have increases in AST or ALT to >3 to ≤5 times ULN or total bilirubin to >1.5 to ≤3 times ULN.1 Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for patients with a baseline AST or ALT less than or equal to ULN who have increases in AST or ALT to >5 times ULN or total bilirubin increases to >3 times ULN.1
Withhold ipilimumab for patients with baseline AST or ALT >1 to ≤3 times ULN who have increases in AST or ALT to >5 to ≤10 times ULN, or for patients with a baseline AST or ALT >3 to ≤5 times ULN who have increases in AST or ALT to >8 to ≤10 times ULN.1 Resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for AST or ALT >10 times ULN or total bilirubin >3 times ULN.1
Exfoliative Dermatologic Conditions
Withhold ipilimumab for suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS).1
Permanently discontinue ipilimumab for confirmed SJS, TEN, or DRESS.1
Depending on severity, consider withholding ipilimumab until symptom improvement with hormone replacement for grade 2 endocrinopathy.1 Resume once acute symptoms have resolved.1
Withhold ipilimumab until clinically stable or permanently discontinue ipilimumab depending on severity for patients with grade 3 or 4 endocrinopathies.1
Withhold ipilimumab for grade 2 pneumonitis and resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for grade 3 or 4 pneumonitis.1
Nephritis with Renal Dysfunction
Withhold ipilimumab for grade 2 or 3 increased blood creatinine and resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce prednisone or equivalent to 10 mg or less per day within 12 weeks of initiating corticosteroid.1
Permanently discontinue ipilimumab for grade 4 increased blood creatinine.1
Withhold ipilimumab for grade 2 neurologic toxicities and resume in patients with complete or partial resolution (grade 0 or 1) after corticosteroid taper.1 Permanently discontinue if there is no complete or partial resolution within 12 weeks of last ipilimumab dose or there is an inability to reduce the corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating the corticosteroid.1
Permanently discontinue ipilimumab for grade 3 or 4 neurologic toxicities.1
Permanently discontinue ipilimumab for grade 2, 3, or 4 myocarditis.1
Permanently discontinue ipilimumab for grade 2, 3, or 4 ophthalmologic reactions that do not improve to grade 1 within 2 weeks of treatment with topical therapy or that require systemic treatment.1
Ipilimumab has not been studied in patients with underlying moderate or severe hepatic impairment.1 Mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST >ULN) did not demonstrate a clinical impact on the clearance of ipilimumab.1
The manufacturer makes no specific dosage recommendations for patients with underlying hepatic impairment.1 Dosage modifications are recommended in patients who develop hepatic enzyme increases during ipilimumab treatment.1
Renal impairment (glomerular filtration rate [GFR] ≥15 mL/minute per 1.73 m2) did not demonstrate a clinical impact on the clearance of ipilimumab.1
The manufacturer makes no specific dosage recommendations for patients with underlying renal impairment.1 Dosage modifications are recommended in patients who develop creatinine increases during ipilimumab treatment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.1 The reactions can occur at any time after starting ipilimumab.1 While immune-mediated adverse reactions usually manifest during treatment, they can also manifest after discontinuation of ipilimumab.1
Early identification and management are essential to ensure safe use of ipilimumab.1 Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions.1 Evaluate clinical chemistries including liver enzymes, serum creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose.1 Institute medical management promptly, including specialty consultation as appropriate.1
Withhold or permanently discontinue ipilimumab depending on severity.1 In general, if ipilimumab requires interruption or discontinuation, administer systemic corticosteroid therapy (1—2 mg/kg per day prednisone or equivalent) until improvement to grade 1 or less.1 Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.1 Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.1
Ipilimumab can cause immune-mediated colitis, which may be fatal.1 Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis.1 In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.1
Monitor patients for manifestations of colitis.1 Withhold or permanently discontinue treatment depending on severity.1
Ipilimumab Monotherapy (3 mg/kg) : In one clinical study, immune-mediated colitis occurred in 12% (62/511) of patients, including grade 3-5 (7%) and grade 2 (5%) reactions.1 Colitis led to permanent discontinuation of ipilimumab in 4.3% and withholding of at least one dose of ipilimumab in 0.2% of patients.1
Systemic corticosteroids were required in 74% (46/62) of patients with immune-mediated colitis1 Five patients required coadministration of another immunosuppressant with corticosteroids.1 Colitis resolved in 76% of the 62 patients.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg : In clinical studies, immune-mediated colitis occurred in 9% (60/666) of patients for the treatment of renal cell carcinoma (RCC) or metastatic colorectal cancer (mCRC), including grade 3 (4.4%), and grade 2 (3.7%) reactions.1 Colitis led to permanent discontinuation of ipilimumab and nivolumab in 3.2% and withholding of ipilimumab and nivolumab in 2.7% of patients.1
Use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated colitis.1 Systemic corticosteroids were required in 100% (60/60) of patients with immune-mediated colitis.1 Approximately 23% of patients required coadministration of another immunosuppressant with corticosteroids.1 Colitis resolved in 95% of the 60 patients.1 Of the 18 patients in whom ipilimumab or nivolumab was withheld for colitis, 16 received additional treatment after symptom improvement; of these, 10 had recurrence of colitis.1
Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg : In clinical studies, immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or hepatocellular carcinoma (HCC), including grade 4 (0.4%), grade 3 (14%), and grade 2 (8%) adverse reactions.1 Colitis led to permanent discontinuation of ipilimumab with nivolumab in 14% and withholding of treatment in 4.4% of patients.1
Systemic corticosteroids were required in 100% (115/115) of patients with colitis.1 Approximately 23% of patients required addition of infliximab to high-dose corticosteroids.1 Colitis resolved in 93% of 115 patients.1 Of the 20 patients in whom ipilimumab with nivolumab was withheld for colitis, 16 reinitiated treatment after symptom improvement, and 9 had recurrence of colitis.1
Severe, life-threatening, and sometimes fatal immune-mediated hepatitis has been reported.1
Evaluate liver function tests at baseline and prior to each dose; assess patients for manifestations of hepatotoxicity prior to each dose of drug.1 Withhold or permanently discontinue treatment depending on severity.1
Ipilimumab Monotherapy (3 mg/kg) : In one clinical study, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including grade 3-5 (1.6%) and grade 2 (2.5%) reactions.1 Hepatitis led to permanent discontinuation of ipilimumab in 0.4% of patients.1 No patients required withholding of ipilimumab.1
Systemic corticosteroids were required in 29% (6/21) of patients with immune-mediated hepatitis.1 No patients required the coadministration of another immunosuppressant with corticosteroids.1 Hepatitis resolved in 86% of the 21 patients.1
Ipilimumab 3 mg/kg + Vemurafenib : In a dose-finding trial, grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg : In clinical studies, immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or mCRC, including grade 4 (1.2%), grade 3 (4.9%), and grade 2 (0.4%) reactions.1 Hepatitis led to permanent discontinuation of ipilimumab and nivolumab in 3.6% of patients, and withholding of ipilimumab and nivolumab in 2.6% of patients.1
Use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated hepatitis.1 Systemic corticosteroids were required in 100% (48/48) of patients with immune-mediated hepatitis.1 Approximately 19% of patients required coadministration of another immunosuppressant with corticosteroids.1 Hepatitis resolved in 88% of the 48 patients.1 Of the 17 patients in whom ipilimumab or nivolumab was withheld for hepatitis, 14 received additional treatment after symptom improvement; of these, 10 had recurrence of hepatitis.1
Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg : In clinical studies, immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC, including grade 4 (2.4%), grade 3 (11%), and grade 2 (1.8%) adverse reactions.1 Immune-mediated hepatitis led to permanent discontinuation of ipilimumab with nivolumab in 8% of patients, and withholding of treatment in 3.5% of patients.1
Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis.1 Approximately 9% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids.1 Hepatitis resolved in 91% of the 70 patients.1 Of the 16 patients in whom ipilimumab with nivolumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement, and 8 had recurrence of hepatitis.1
Immune-mediated Dermatologic Adverse Reactions
Ipilimumab can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS).1 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.1
Withhold or permanently discontinue ipilimumab depending on severity.1
Ipilimumab Monotherapy (3 mg/kg) : In one clinical study, immune-mediated rash occurred in 15% (76/511) of patients, including grade 3-5 (2.5%) and grade 2 (12%) reactions.1 Rash led to permanent discontinuation of ipilimumab in 0.2% of patients, and withholding of at least one dose of ipilimumab in 1.4% of patients.1
Systemic corticosteroids were required in 43% (33/76) of patients with an immune-mediated rash.1 Rash resolved in 71% of the 76 patients.1 Of the 7 patients in whom ipilimumab was withheld for rash, 3 received additional treatment after symptom improvement; of these, 1 had recurrence of rash.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg : In clinical studies, immune-mediated rash occurred in 16% (108/666) of patients who received the drugs for the treatment of RCC or mCRC, including grade 3 (3.5%) and grade 2 (4.2%) reactions.1 Rash led to permanent discontinuation of ipilimumab and nivolumab in 0.5% of patients, and withholding of ipilimumab and nivolumab in 2.0% of patients.1
Use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated rash.1 Systemic corticosteroids were required in 100% (108/108) of patients.1 Rash resolved in 75% of 108 patients.1 Of the 13 patients in whom ipilimumab or nivolumab was withheld for rash, 11 received additional treatment after symptom improvement; of these, 5 had recurrence of rash.1
Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg : In clinical studies, immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including grade 3 (4.8%) and grade 2 (10%) adverse reactions.1 Immune-mediated rash led to permanent discontinuation of ipilimumab with nivolumab in 0.4% of patients, and withholding of treatment in 3.9% of patients.1
Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash.1 Rash resolved in 84% of the 127 patients.1 Of the 18 patients in whom ipilimumab with nivolumab was withheld for rash, 15 reinitiated treatment after symptom improvement, and 8 had recurrence of rash.1
Immune-mediated Endocrinopathies
Severe or life-threatening immune-mediated endocrinopathies, including hypophysitis, adrenal insufficiency, hyperthyroidism, hypothyroidism, thyroiditis, and type 1 diabetes mellitus, can occur.1
Monitor patients for manifestations of these conditions.1 Perform laboratory testing (e.g., thyroid function tests) prior to each dose of ipilimumab and as clinically indicated throughout treatment.1
Withhold or permanently discontinue treatment depending on severity.1
Ipilimumab Monotherapy (3 mg/kg) : In one clinical study, grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients.1
Severe to life-threatening (grade 3-4) endocrinopathies occurred in 9 patients (1.8%).1 All 9 of these patients had hypopituitarism with some patients having additional concomitant endocrinopathies, such as adrenal insufficiency, hypogonadism, and hypothyroidism.1 Six of the 9 patients were hospitalized for severe endocrinopathies.1
Moderate (grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushing syndrome.1
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 required long term hormone replacement therapy, including adrenal hormones and thyroid hormones.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg :
Hypophysitis: Ipilimumab can cause immune-mediated hypophysitis, which can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts.1 Hypophysitis can cause hypopituitarism.1 Initiate hormone replacement as clinically indicated.1 Withhold or permanently discontinue ipilimumab depending on severity.1
In clinical studies, hypophysitis occurred in 4.4% (29/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 4 (0.3%), grade 3 (2.4%), and grade 2 (0.9%) reactions.1 Hypophysitis led to permanent discontinuation of ipilimumab and nivolumab in 1.2% of patients, and withholding of ipilimumab with nivolumab in 2.1% of patients.1 Approximately 72% of patients with hypophysitis received hormone replacement therapy.1
Systemic corticosteroids were required in 72% (21/29) of patients with immune-mediated hypophysitis.1 Hypophysitis resolved in 59% of the 29 patients.1 Of the 14 patients in whom ipilimumab or nivolumab was withheld for hypophysitis, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of hypophysitis.1
Adrenal Insufficiency: In clinical studies, adrenal insufficiency occurred in 7% (48/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 4 (0.3%), grade 3 (2.5%), and grade 2 (4.1%) reactions.1 Adrenal insufficiency led to permanent discontinuation of ipilimumab with nivolumab in 1.2% and withholding of ipilimumab with nivolumab in 2.1% of patients.1 Approximately 94% of patients with adrenal insufficiency received hormone replacement therapy.1
Systemic corticosteroids were required in 94% (45/48) of patients with adrenal insufficiency.1 Adrenal insufficiency resolved in 29% of the 48 patients.1 Of the 14 patients in whom ipilimumab or nivolumab was withheld for adrenal insufficiency, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of adrenal insufficiency.1
Hyperthyroidism: In clinical studies, hyperthyroidism occurred in 12% (80/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 3 (0.6%) and grade 2 (4.5%) reactions.1 No patients discontinued ipilimumab for hyperthyroidism.1 Hyperthyroidism led to withholding of ipilimumab with nivolumab in 2.3% of patients.1 Approximately 19% received a thyroid hormone synthesis inhibitor.1
Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism.1 Hyperthyroidism resolved in 85% of the 80 patients.1 Of the 15 patients in whom ipilimumab or nivolumab was withheld for hyperthyroidism, 11 received additional treatment; of these, 3 had recurrence of hyperthyroidism.1
Hypothyroidism: In clinical studies, hypothyroidism occurred in 18% (122/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 3 (0.6%) and grade 2 (11%) reactions.1 Hypothyroidism led to permanent discontinuation of ipilimumab with nivolumab in 0.2% and withholding of ipilimumab with nivolumab in 1.4% of patients.1 Approximately 82% received thyroid hormone replacement.1
Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism.1 Hypothyroidism resolved in 27% of the 122 patients.1 Of the 9 patients in whom ipilimumab or nivolumab was withheld for hypothyroidism, 5 received additional treatment after symptom improvement; of these, one patient had recurrence of hypothyroidism.1
Thyroiditis: In clinical studies, thyroiditis occurred in 2.7% (22/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 3 (4.5%) and grade 2 (2.2%) reactions.1 Thyroiditis led to permanent discontinuation of ipilimumab with nivolumab in 0.2% of patients, and withholding of ipilimumab with nivolumab in 0.8% of patients.1
Systemic corticosteroids were required in 18% (4/22) of patients with thyroiditis.1 Thyroiditis resolved in 64% of the 22 patients.1 Of the 5 patients in whom ipilimumab or nivolumab was withheld for thyroiditis, 5 received additional treatment after symptom improvement; of these, no patients had recurrence of thyroiditis.1
Type 1 Diabetes Mellitus: In clinical studies, diabetes occurred in 2.7% (15/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 4 (0.6%), grade 3 (0.3%), and grade 2 (0.9%) reactions.1 Diabetes led to the permanent discontinuation of ipilimumab with nivolumab in 0.5% of patients, and withholding of ipilimumab with nivolumab in 0.5% of patients.1
Systemic corticosteroids were required in 7% (1/15) of patients with diabetes.1 Diabetes resolved in 27% of the 15 patients.1 Of the 3 patients in whom ipilimumab or nivolumab was withheld for diabetes, 2 received additional treatment after symptom improvement; of these, none had recurrence of diabetes.1
Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
Hypophysitis:In clinical studies, hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including grade 3 (2.4%) and grade 2 (6%) adverse reactions.1 Hypophysitis led to permanent discontinuation of ipilimumab with nivolumab in 0.9%, and withholding of treatment in 4.2% of patients.1
Approximately 86% of patients with hypophysitis received hormone replacement therapy.1 Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis.1 Hypophysitis resolved in 38% of the 42 patients.1 Of the 19 patients in whom ipilimumab with nivolumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement, and 1 had recurrence of hypophysitis.1
.1
Adrenal Insufficiency: In clinical studies, adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including grade 4 (0.2%), grade 3 (2.4%), and grade 2 (4.2%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation of ipilimumab with nivolumab in 0.4% of patients, and withholding of treatment in 2.0% of patients.1
Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids.1 Adrenal insufficiency resolved in 37% of the 35 patients.1 Of the 9 patients in whom ipilimumab with nivolumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement, and all required hormone replacement therapy for their ongoing adrenal insufficiency.1
Hyperthyroidism: In clinical studies, hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC receiving ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including grade 3 (0.9%) and grade 2 (4.2%) adverse reactions.1 Hyperthyroidism led to permanent discontinuation of ipilimumab with nivolumab in no patients, and withholding of treatment in 2.4% of patients.1
Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole.1 Systemic corticosteroids were required in 17% (7/42) of patients.1 Hyperthyroidism resolved in 91% of the 42 patients.1 Of the 11 patients in whom ipilimumab with nivolumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement, and 1 had recurrence of hyperthyroidism.1
Hypothyroidism: In clinical studies, hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including grade 3 (0.4%) and grade 2 (11%) adverse reactions.1 Hypothyroidism led to permanent discontinuation of ipilimumab with nivolumab in 0.9% of patients, and withholding of treatment in 0.9% of patients.1
Approximately 89% of patients with hypothyroidism received levothyroxine.1 Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism.1 Hypothyroidism resolved in 41% of the 91 patients.1 Of the 4 patients in whom ipilimumab with nivolumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement, and none had recurrence of hypothyroidism.1
Withhold or permanently discontinue treatment depending on severity.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg : In clinical studies, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 3 (1.4%) and grade 2 (2.6%) adverse reactions.1 Pneumonitis led to permanent discontinuation of ipilimumab and nivolumab in 1.8% of patients, and withholding of ipilimumab and nivolumab in 1.5% of patients.1
In patients who received ipilimumab 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated pneumonitis.1 Systemic corticosteroids were required in 100% (26/26) of patients with immune-mediated pneumonitis.1 Approximately 8% required coadministration of another immunosuppressant with corticosteroids.1 Pneumonitis resolved in 92% of the 26 patients.1 Of the 10 patients in whom ipilimumab or nivolumab was withheld for pneumonitis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of pneumonitis.1
In a study in patients with non-small cell lung cancer (NSCLC), immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving ipilimumab 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks, including grade 4 (0.5%), grade 3 (3.5%), and grade 2 (4.0%) immune-mediated pneumonitis.1 Four patients (0.7%) died due to pneumonitis.1 The median duration was 1.5 months (range, 5 days to 25+ months).1 Immune-mediated pneumonitis led to permanent discontinuation of ipilimumab with nivolumab in 5% of patients, and withholding of ipilimumab with nivolumab in 3.6% of patients.1
Systemic corticosteroids were required in 100% of patients with pneumonitis followed by a corticosteroid taper.1 Pneumonitis resolved in 72% of the patients.1 Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of ipilimumab with nivolumab.1
Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg : In clinical studies, immune-mediated pneumonitis occurred in 7% (31/456) of patients who received ipilimumab, including grade 4 (0.2%), grade 3 (2.0%), and grade 2 (4.4%) reactions.1 Immune-mediated pneumonitis led to permanent discontinuation or withholding of treatment in 2.9 and 3.9% of patients, respectively.1
Systemic corticosteroids were required in 100% of patients with pneumonitis.1 Pneumonitis resolved in 94% of the patients.1 Of the 13 patients in whom ipilimumab or nivolumab was withheld for pneumonitis, 13 received additional treatment after symptom improvement, and 4 had recurrence of pneumonitis.1
Immune-mediated Nephritis with Renal Dysfunction
Monitor serum creatinine at baseline and before each dose.1 Withhold or permanently discontinue treatment based on severity.1
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg : In clinical studies, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including grade 4 (0.6%), grade 3 (1.1%), and grade 2 (2.2%) reactions.1 Nephritis with renal dysfunction led to permanent discontinuation of ipilimumab and nivolumab in 1.2% of patients, and withholding of nivolumab and ipilimumab in 1.8% of patients.1
In patients who received ipilimumab 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated nephritis with renal dysfunction.1 Systemic corticosteroids were required in 100% (27/27) of patients with immune-mediated nephritis with renal dysfunction.1 Nephritis with renal dysfunction resolved in 67% of the 27 patients.1 Of the 12 patients in whom ipilimumab or nivolumab was withheld for nephritis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of nephritis.1
Other immune-mediated adverse reactions have occurred with ipilimumab monotherapy or in combination with nivolumab.1 Reactions occurring in 1-2.5% of patients include autoimmune neuropathy, pancreatitis, cytopenias, and eosinophilia.1 Other immune-mediated reactions occurring in <1% of patients include nervous system, cardiovascular, ocular, gastrointestinal, musculoskeletal and connective tissue, and hematologic/immune effects.1
Severe infusion-related reactions can occur with ipilimumab.1
In one clinical study, infusion-related reactions occurred in 0.6% (3/511) of patients who received single-agent ipilimumab 3 mg/kg for the unresectable or metastatic treatment of melanoma.1 In clinical studies, infusion-related reactions occurred in 5% (33/666) of patients who received ipilimumab 1 mg/kg with nivolumab for the treatment of RCC or CRC.1 Infusion-related reactions occurred in 8% (4/49) of patients who received ipilimumab 3 mg/kg with nivolumab for the treatment of HCC.1 Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received ipilimumab 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks.1
Discontinue ipilimumab in patients with severe or life-threatening infusion reactions (grade 3 or 4).1 Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions (grade 1 or 2).1
Complications of Allogeneic Hematopoietic and Stem Cell Transplant
Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive ipilimumab either before or after allogeneic hematopoietic stem cell transplantation (HSCT).1 These complications may occur despite intervening therapy between cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blocking antibody and allogeneic HSCT.1
Follow patients closely for evidence of GVHD and intervene promptly.1 Consider the benefits versus risks of treatment with ipilimumab after allogeneic HSCT.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and findings from animal studies, ipilimumab can cause fetal harm when administered to a pregnant woman.1 The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.1 Higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality were observed in animal reproduction studies.1
Advise pregnant women of the potential risk to a fetus.1 Verify pregnancy status in females of reproductive potential prior to initiating ipilimumab.1 Advise females of reproductive potential to use effective contraception during treatment with ipilimumab and for 3 months after the last dose.1
Risks when Administered in Combination with Nivolumab
When used in combination with nivolumab, refer to the full nivolumab prescribing information for additional risk information that applies to the combination use treatment.1
There is a potential for immunogenicity with ipilimumab therapy.1 Development of binding antibodies to ipilimumab or anti-drug antibodies (ADAs) was detected by electrochemiluminescence in 1.1—13.7% of patients treated with ipilimumab with or without nivolumab for its varied labeled indications.1 Development of ADAs did not increase the incidence of infusion-related reactions nor was an impact on ipilimumab pharmacokinetics observed.1
Based on findings from animal studies and its mechanism of action, ipilimumab can cause fetal harm when administered to a pregnant woman.1 There is insufficient human data for ipilimumab exposure in pregnant women.1 In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner.1 The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.1
Human IgG1is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.1
Verify pregnancy status in females of reproductive potential prior to initiating ipilimumab.1 Advise pregnant women of the potential risk to a fetus.1 Report pregnancies to the manufacturer (Bristol-Myers Squibb) at 1-844-593-7869.1
There are no data on the presence of ipilimumab in human milk or its effects on the breast-fed child or milk production.1 In monkeys, ipilimumab was present in milk.1
Because of the potential for serious adverse reactions in breastfed children, advise women not to breast-feed during treatment with ipilimumab and for 3 months following the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ipilimumab.1
Ipilimumab can cause fetal harm when administered to a pregnant woman.1 Advise females of reproductive potential to use effective contraception during treatment with ipilimumab and for 3 months following the last dose.1
The safety and effectiveness of ipilimumab have been established in pediatric patients 12 years of age and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma; in combination with nivolumab for the treatment of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR ) unresectable and metastatic CRC; and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1
The safety and effectiveness of ipilimumab have not been established in pediatric patients <12 years of age with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.1
The safety and effectiveness of ipilimumab have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma, or esophageal cancer.1
No overall differences in safety were observed between younger patients and patients ≥65 years of age with ipilimumab as monotherapy for unresectable or metastatic melanoma or in combination with nivolumab for renal cell carcinoma.1
Although no overall differences in safety were observed between younger patients and patients ≥65 years of age, discontinuation rates due to adverse reactions were higher in patients ≥75 years of age who received combination treatment with ipilimumab and nivolumab for NSCLC, malignant pleural mesothelioma, metastatic CRC (in patients ≥65 years of age), esophageal squamous cell carcinoma, and in patients who received ipilimumab in combination with nivolumab plus platinum-doublet chemotherapy.1
Increase in hepatic enzymes and hepatitis can occur.1 Dosage modification is recommended based on severity of the adverse reaction.1
Mild hepatic impairment (total bilirubin >1 to 1.5 times the upper limit of normal [ULN] or AST >ULN) had no clinically important effect on the clearance of ipilimumab.1 Ipilimumab has not been studied in patients with moderate or severe hepatic impairment.1
Increase in creatinine and nephritis can occur.1 Dosage modification is recommended based on severity of the adverse reaction.1
Renal impairment (glomerular filtration rate ≥15 mL/min per 1.73 m2) had no clinically important effect on the clearance of ipilimumab.1
The most common adverse reactions (≥20%) with ipilimumab as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache.1
The most common adverse reactions (≥20%) with ipilimumab in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness.1
The most common adverse reactions (≥20%) with ipilimumab in combination with nivolumab and platinum doublet chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.1
Other than use in combination with nivolumab and antineoplastic chemotherapy, no formal drug interaction studies have been performed to date.1
When ipilimumab was used in combination with nivolumab, the clearance of ipilimumab and nivolumab either remained unchanged or slightly increased depending on the dose of each agent.1
When ipilimumab 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and chemotherapy, the clearance of ipilimumab increased and the clearance of nivolumab was unchanged.1
Ipilimumab, a recombinant, fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is an antineoplastic agent.1, 8, 10 The drug is an IgG1 kappa immunoglobulin that is produced in mammalian (Chinese hamster ovary) cell culture.1, 8, 10
Ipilimumab has high affinity and specificity for CTLA-4, an inducible receptor expressed on the surface of T-cells after activation.1, 8, 10 CTLA-4 competes with CD28, a costimulatory T-cell receptor, for the ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells.1, 8, 10 The interaction between CTLA-4 and CD80 or CD86 results in inhibition of T-cell activation and proliferation.1, 8, 10 Anti-CTLA-4 antibodies block the interaction with CD80 and CD86, and allow for prolonged T-cell activation and enhanced immune response.1, 8, 10 The antineoplastic effects of the drug are indirect and appear to result from augmented T-cell-mediated antitumor immune response.1, 12 An initial increase in total tumor burden (e.g., enlargement of baseline lesions, development of new lesions) observed in the absence of substantial clinical deterioration during ipilimumab therapy may not indicate treatment failure,11, 16 but may be a result of lymphocytic infiltration of the lesions or tumor growth prior to complete immune system activation.11
The pharmacokinetics of ipilimumab following IV administration is characterized by a 2-compartment model with first-order elimination and dose-dependent clinical effects.15 Plasma concentrations and AUC reportedly are dose proportional in the ipilimumab dosage range of 0.3-10 mg/kg with minimal systemic accumulation when administered every 3 weeks.1 Steady-state concentrations are reached by the third infusion dose and terminal half-life is approximately 15.4 days.1
Systemic clearance of ipilimumab increases with increasing body weight, but this is not considered clinically important when the drug is dosed based on body weight.1, 15 Clearance of the drug is not affected by age, sex, anti-ipilimumab antibody status, previous antineoplastic therapy, baseline lactate dehydrogenase concentrations, or performance status.1 Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults at recommended dosages.1 Renal impairment (i.e., baseline glomerular filtration rate of 15 mL/minute per 1.73 m2 or greater) did not have a clinically important effect on the pharmacokinetics of ipilimumab.1 Mild hepatic impairment (AST greater than upper limit of normal [ULN] or total bilirubin >1 to 1.5 times ULN) did not have a clinically important effect on the pharmacokinetics of the drug.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Ipilimumab is available through specialty pharmacy distributors.2000
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV infusion only | 5 mg/mL (50 or 200 mg) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Bristol-Myers Squibb. Yervoy® (ipilimumab) injection prescribing information. Princeton, NJ. 2025 May.
6. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
7. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med . 2010; 363:711-23. [PubMed 20525992]
8. Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol . 2010; 37:473-84. [PubMed 21074063]
10. Morse MA. Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb. Curr Opin Mol Ther . 2005; 7:588-97. [PubMed 16370382]
11. Wolchok JD, Hoos A, O'Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res . 2009; 15:7412-20. [PubMed 19934295]
12. Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun . 2008; 8:1. [PubMed 18198818]
15. Wolchok JD, Neyns B, Linette G et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol . 2010; 11:155-64. [PubMed 20004617]
16. Pennock GK, Waterfield W, Wolchok JD. Patient Responses to Ipilimumab, a Novel Immunopotentiator for Metastatic Melanoma: How Different are these From Conventional Treatment Responses?. Am J Clin Oncol . 2011; :.
17. McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013;24(10):2694-2698.
22. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med . 2011; 364:2517-26. [PubMed 21639810]
23. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373:23-34
24. Overman MJ, McDermott R, Leach JL et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017; 18:1182-1191
25. Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020;6(11):e204564.
26. Tarhini AA, Lee SJ, Hodi FS, et al. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020;38(6):567-575.
37. Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378:1277-1290
38. Overman MJ, Lonardi S, Wong KYM et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018; 36:773-779
41. Hodi FS, Chiarion-Sileni V, Gonzalez R et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018; 19:1480-1492
45. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2025;392(1):11-22.
50. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019;381(21):2020-2031.
51. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023;41(6):1200-1212.
52. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211.
53. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. 2024;211:114296.
54. Peters S, Regan MM, Paz-Ares LG, et al. Treatment-Free Survival Over 6 Years of Follow-up in Patients With Metastatic NSCLC Treated With First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in CheckMate 227 Part 1. J Thorac Oncol. 2025;20(10):1505-1516.
55. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):375-386.
56. Peters S, Scherpereel A, Cornelissen R, et al. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022;33(5):488-499.
57. Mantia CM, Jegede OA, Plimack ER, et al. Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214. J Immunother Cancer. 2024;12(7):e009495.
58. Tannir NM, Albigès L, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2024;35(11):1026-1038.
59. Andre T, Elez E, Van Cutsem E, et al. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024;391(21):2014-2026.
60. André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395.
61. Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405(10492):1851-1864.
62. Carbone DP, Ciuleanu TE, Cobo M, et al. Nivolumab plus ipilimumab with chemotherapy as first-line treatment of patients with metastatic non-small-cell lung cancer: final, 6-year outcomes from CheckMate 9LA. ESMO Open. 2025;10(6):105123.
66. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462.
67. Kato K, Doki Y, Chau I, et al. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024;13(9):e7235.
1169. Institute for Safe Medication Practices (ISMP). ISMP list of high-alert medications in acute care settings. ISMP; 2018.
2000. Bristol Myers Squibb Access Support. Yervoy: Codes and Coverage. BMS websited. Accessed Nov 17, 2025. [Web]