YERVOY

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YERVOY

Classes

Antineoplastic Monoclonal Antibodies Targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)

Administration

Emetic Risk
Minimal

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the vial if the solution is cloudy, there is pronounced discoloration, or there is foreign particulate matter other than translucent-to white, amorphous particles.

Intravenous Administration

Do not shake undiluted product.
When using combination therapy, administer nivolumab prior to ipilimumab (followed by platinum-based chemotherapy, if applicable); use separate infusion bags and filters for each drug.
Preparation:
Allow the ipilimumab vials to stand at room temperature for approximately 5 minutes before infusion preparation.
Withdraw the required volume of ipilimumab and transfer into an intravenous bag. Discard partially used vials or empty vials of ipilimumab.
Dilute with 0.9% Sodium Chloride injection or 5% Dextrose injection to prepare a solution with a final concentration ranging from 1 to 2 mg/mL. Mix diluted solution by gentle inversion.
Do not mix ipilimumab with other medicinal products.
Storage: Once diluted, store under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or at room temperature (20 to 25 degrees C or 68 to 77 degrees F) for no more than 24 hours from the time for preparation to the time of infusion.
Intravenous (IV) Infusion:
Administer the diluted solution through an IV line containing a sterile, non-pyrogenic, low-protein-binding, in-line filter.
The administration time is as follows:
Infuse IV over 90 minutes when administered as a 10 mg/kg dose for adjuvant therapy in melanoma patients
Infuse IV over 30 minutes for all other doses (1 mg/kg or 3 mg/kg) and indications
Do not administer with other drugs through the same IV line.
After each infusion, flush the intravenous line with 0.9% Sodium Chloride injection or 0.5% Dextrose injection.

Adverse Reactions
Severe

elevated hepatic enzymes / Delayed / 3.5-40.0
hyponatremia / Delayed / 0-32.0
colitis / Delayed / 0-15.7
hyperamylasemia / Delayed / 2.0-15.0
hepatitis B exacerbation / Delayed / 0-14.0
hepatitis / Delayed / 0-13.4
lymphopenia / Delayed / 5.0-13.0
hyperbilirubinemia / Delayed / 0-11.0
diarrhea / Early / 1.9-11.0
GI perforation / Delayed / 0-10.0
neutropenia / Delayed / 0-9.0
anemia / Delayed / 0-9.0
hypopituitarism / Delayed / 0-8.6
infection / Delayed / 0-8.0
rash / Early / 2.0-8.0
fatigue / Early / 2.0-8.0
hyperglycemia / Delayed / 0-7.0
abdominal pain / Early / 0-6.0
hypokalemia / Delayed / 0-5.0
dysphagia / Delayed / 0-5.0
pneumonitis / Delayed / 0-4.8
dyspnea / Early / 0-4.7
hyperkalemia / Delayed / 0-4.3
thrombocytopenia / Delayed / 0-4.3
pruritus / Rapid / 0-4.0
musculoskeletal pain / Early / 0-4.0
anorexia / Delayed / 0.2-4.0
vomiting / Early / 0-3.8
nausea / Early / 0-2.8
adrenocortical insufficiency / Delayed / 0-2.8
hypophysitis / Delayed / 0-2.7
hypertension / Early / 0-2.2
leukopenia / Delayed / 0-2.1
influenza / Delayed / 0-2.0
hypercalcemia / Delayed / 0-2.0
dyspepsia / Early / 0-2.0
edema / Delayed / 0-2.0
weight loss / Delayed / 0-1.9
interstitial nephritis / Delayed / 1.7-1.7
headache / Early / 0.8-1.7
hypocalcemia / Delayed / 0-1.4
pancreatitis / Delayed / 1.3-1.3
arthralgia / Delayed / 0-1.3
hypomagnesemia / Delayed / 0-1.2
hypoglycemia / Early / 0-1.2
acute respiratory distress syndrome (ARDS) / Early / 0-1.0
erythema multiforme / Delayed / 0-1.0
myasthenia gravis / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
pericarditis / Delayed / 0-1.0
myocarditis / Delayed / 0-1.0
vasculitis / Delayed / 0-1.0
renal failure (unspecified) / Delayed / 0-1.0
uveitis / Delayed / 0-1.0
Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
hearing loss / Delayed / 0-1.0
rhabdomyolysis / Delayed / 0-1.0
peptic ulcer / Delayed / 0-1.0
organ transplant rejection / Delayed / 0-1.0
hyperthyroidism / Delayed / 0-0.9
diabetes mellitus / Delayed / 0-0.9
cough / Delayed / 0-0.8
insomnia / Early / 0-0.8
alopecia / Delayed / 0-0.8
hypothyroidism / Delayed / 0-0.6
hepatic failure / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
retinal detachment / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known
hemophagocytic lymphohistiocytosis / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known

Moderate

antibody formation / Delayed / 1.1-13.7
infusion-related reactions / Rapid / 0-12.0
neuritis / Delayed / 0-10.0
hypotension / Rapid / 0-10.0
stomatitis / Delayed / 0-10.0
dehydration / Delayed / 0-2.5
eosinophilia / Delayed / 2.1-2.1
psoriasis / Delayed / 0-1.0
meningitis / Delayed / 0-1.0
paresis / Delayed / 0-1.0
conjunctivitis / Delayed / 0-1.0
ocular inflammation / Early / 0-1.0
blepharitis / Early / 0-1.0
iritis / Delayed / 0-1.0
esophagitis / Delayed / 0-1.0
gastritis / Delayed / 0-1.0
ascites / Delayed / Incidence not known
bullous rash / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
atopic dermatitis / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
photophobia / Early / Incidence not known
Cushing's syndrome / Delayed / Incidence not known
blurred vision / Early / Incidence not known
synovitis / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known

Mild

dizziness / Early / 0-20.0
xerostomia / Early / 0-12.0
xerosis / Delayed / 11.0-11.0
skin hypopigmentation / Delayed / 0-8.0
urticaria / Rapid / 0-2.0
pharyngitis / Delayed / Incidence not known
rhinitis / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
acne vulgaris / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
gonadal suppression / Delayed / Incidence not known
myalgia / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
arthropathy / Delayed / Incidence not known
back pain / Delayed / Incidence not known
vertigo / Early / Incidence not known

Common Brand Names

YERVOY

Dea Class

Rx

Description

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking monoclonal antibody
Used for esophageal cancer, hepatocellular cancer, malignant melanoma (adult and pediatric patients 12 years and older), mesothelioma, microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer (adult and pediatric patients 12 years and older), non-small cell lung cancer, and renal cell carcinoma
Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

Dosage And Indications
For the treatment of malignant melanoma. For the treatment of unresectable or metastatic melanoma, as a single-agent. Intravenous dosage Adults

3 mg/kg IV over 30 minutes repeated every 3 weeks for a total of 4 doses. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. In a multinational, randomized, double-blind, placebo-controlled, phase 3 study (the MDX010-20 study), treatment with ipilimumab (n = 137), a melanoma vaccine consisting of HLA-A*0201-restricted peptides derived from the melanosomal glycoprotein 100 (gp100) (n = 136), or ipilimumab plus gp100 (combination therapy arm; n = 403) was evaluated in adult patients with HLA-A*0201-positive, unresectable stage III or stage IV melanoma who had previously received at least 1 of the following therapies: carboplatin, dacarbazine, fotemustine, interleukin-2, or temozolomide. In this study, 31 evaluable patients with disease progression who had stable disease for 3 months at week 12 or a confirmed partial or complete response received additional courses (reinduction) of ipilimumab-containing therapy. For the primary end point comparison, the median overall survival (OS) time was significantly improved with combination therapy compared with gp100 alone (10 months vs. 6.4 months). In a pre-specified comparison, the OS time was significantly improved with ipilimumab alone compared with gp100 alone (10.1 months vs. 6.4 months) and there was no significant OS difference between the 2 ipilimumab-containing arms. The 12-, 18-, and 24-month OS rates for the single-agent ipilimumab arm were 45.6%, 33.2%, and 23.5%, respectively. The median progression-free survival (PFS) time for single-agent ipilimumab was 2.86 months and the 12-week PFS rate was 57.7%. In an analysis of all patients who survived at least 2 years (n = 94; 20%) or 3 years (n = 42; 16%), the 2- and 3-year OS rates were 25% and 25%, respectively, for patients who received ipilimumab alone. Additionally, disease control (defined as a best response of stable disease or better) was 28.5% at week 24 and 83.3% in patients who received single-agent ipilimumab and survived at least 2 years.

Children and Adolescents 12 years and older

3 mg/kg IV over 30 minutes repeated every 3 weeks for a total of 4 doses. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. Use of ipilimumab in pediatric patients aged 12 and older is based on evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.

For the first-line treatment of unresectable or metastatic melanoma, in combination with dacarbazine†. Intravenous dosage Adults

10 mg/kg IV plus dacarbazine 850 mg/m2 IV repeated every 3 weeks (at weeks 1, 4, 7, and 10) for 4 doses followed by dacarbazine 850 mg/m2 IV every 3 weeks through week 22 (if no progressive disease) as induction therapy resulted in favorable overall survival in a randomized, double-blind, placebo-controlled, phase 3 trial. At week 24, patients with stable disease or an objective response received maintenance therapy with ipilimumab 10 mg/kg IV every 12 weeks until progressive disease.

For the treatment of unresectable or metastatic melanoma, following no more than 1 prior therapy, in combination with sargramostim (GM-CSF)†. Intravenous dosage Adults

10 mg/kg (actual body weight) IV on day 1 repeated every 3 weeks for 4 cycles in combination with sargramostim 250 micrograms (mcg) subcutaneously on days 1 to 14 repeated every 3 weeks for 4 cycles as induction therapy was evaluated in a randomized, phase 2b study. In patients with stable disease or better, maintenance therapy consisted of ipilimumab 10 mg/kg (actual body weight) IV on day 1 repeated every 12 weeks (starting on cycle 8) in combination with sargramostim 250 mcg subcutaneously on days 1 to 14 repeated every 3 weeks (starting on cycle 5). At a median follow-up of 13.3 months, median OS was significantly improved with combination therapy of ipilimumab plus GM-CSF compared to single-agent ipilimumab (17.5 months vs. 12.7 months; p = 0.01).

For the treatment of unresectable or metastatic melanoma, in combination with nivolumab. intravenous dosage Adults

3 mg/kg IV over 30 minutes repeated every 3 weeks for a maximum of 4 doses in combination with nivolumab 1 mg/kg IV repeated every 3 weeks (maximum of 4 doses) followed by single-agent nivolumab until disease progression. Administer ipilimumab after the nivolumab infusion. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. At a minimum follow-up of approximately 60 months, the median overall survival (60 months vs. 19.9 months; hazard ratio (HR) = 0.52; 95% CI 0.42 to 0.64) and progression-free survival (11.5 months vs. 2.9 months; HR = 0.42; 95% CI 0.35 to 0.51) times were significantly improved in patients with previously untreated, unresectable, stage III or stage IV melanoma who received nivolumab plus ipilimumab compared with ipilimumab in a 3-arm, randomized, double-blind, phase 3 trial (CheckMate 067 trial; n = 945).

Children and Adolescents 12 years and older

3 mg/kg IV over 30 minutes repeated every 3 weeks for a maximum of 4 doses in combination with nivolumab 1 mg/kg IV repeated every 3 weeks (maximum of 4 doses) followed by single-agent nivolumab until disease progression. Administer ipilimumab after the nivolumab infusion. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. Use of ipilimumab in pediatric patients aged 12 and older is based on evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.

For the adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm, in patients who have undergone complete resection, including total lymphadenectomy. Intravenous dosage Adults

10 mg/kg IV over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg IV every 12 weeks until disease recurrence or unacceptable toxicity, for up to 3 years. At a median follow-up of 5.3 years, adjuvant treatment with ipilimumab led to a significantly improved median recurrence-free survival (RFS) time (primary endpoint) compared with placebo (27.6 months vs. 17.1 months) in patients with high-risk stage III melanoma after complete lymph-node dissection in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (n = 951; EORTC 18071 trial); the 5-year RFS rate was 40.8% and 30.3%, respectively. Treatment with ipilimumab also resulted in significantly improved 5-year overall survival (65.4% vs. 54.4%) and metastasis-free survival (48.3% vs. 38.9%) rates compared with placebo. In this study, patients had stage IIIA melanoma (with at least one metastasis measuring greater than 1 millimeter in the greatest dimension) or stage IIIB or IIIC melanoma with no in-transit metastases and had not received prior systemic therapy.

For the treatment of unresectable advanced melanoma in patients eligible for local treatment of cutaneous, subcutaneous, and nodal lesions, in combination with talimogene laherparepvec†. Intravenous dosage Adults

Dosage not established. Although overall response rate was improved with talimogene laherparepvec plus ipilimumab therapy compared with ipilimumab alone in a randomized clinical trial; there is not sufficient evidence to support the use of this drug combination for this indication. Ipilimumab 3 mg/kg IV every 3 weeks beginning on day 1 of week 6 for up to 4 infusions in combination with talimogene laherparepvec (given as a dose volume up to 4 mL at a concentration of 1 million plaque-forming units (PFU)/mL intralesionally on day 1 of week 1 followed by up to 4 mL at a concentration of 100 million PFU/mL on day 1 of week 4 and then every 2 weeks until complete response, all injectable tumors have disappeared, confirmed disease progression per modified immune-related response criteria, or intolerance) was evaluated in a multinational, randomized, phase 2 trial (n = 198).[63055]

For the treatment of renal cell cancer (RCC). For the first-line treatment of intermediate or poor risk advanced renal cell cancer (RCC), in combination with nivolumab. Intravenous dosage Adults

1 mg/kg IV over 30 minutes on day 1, following administration of nivolumab (3 mg/kg IV over 30 minutes), every 3 weeks for up to 4 doses. After completion of 4 doses of nivolumab plus ipilimumab, continue nivolumab as monotherapy until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label study, treatment with nivolumab plus ipilimumab significantly improved median overall survival (not estimated vs. 25.9 months) and objective response rate (41.6% vs. 26.5%) compared with sunitinib in patients with intermediate/poor-risk patients with previously untreated RCC; a complete response was achieved in 9.4% of patients in the nivolumab plus ipilimumab arm compared with 1.2% of those who received sunitinib. Median progression-free survival was 11.6 months compared with 8.4 months, respectively. In a separate analysis, the combination of nivolumab plus ipilimumab in patients with favorable-risk disease did not significantly improve overall survival; efficacy in this population has not been established.

For the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. Intravenous dosage Adults

1 mg/kg IV over 30 minutes following administration of nivolumab 3 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab 240 mg IV over 30 minutes as a single agent every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, non-randomized, multiple parallel-cohort, open-label study (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.

Children and Adolescents 12 to 17 years

1 mg/kg IV over 30 minutes following administration of nivolumab 3 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab 240 mg IV over 30 minutes as a single agent every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, non-randomized, multiple parallel-cohort, open-label study (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.

For the treatment of hepatocellular cancer (HCC). For the treatment of hepatocellular cancer (HCC) in patients who have been previously treated with sorafenib, in combination with nivolumab. Intravenous dosage Adults

3 mg/kg IV over 30 minutes on day 1 following administration of nivolumab (1 mg/kg IV over 30 minutes), every 3 weeks for up to 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab (240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks) as a single agent until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicohort, open-label clinical trial, treatment with ipilimumab plus nivolumab followed by nivolumab monotherapy resulted in an overall response rate of 33% (complete response [CR], 8%; partial response [PR], 24%) by RECIST v1.1 and 35% (CR, 12%; PR, 22%) by mRECIST for a median duration of 4.6 months; 88% of patients had a response of at least 6 months, 56% had a response of at least 12 months, and 31% had a response of at least 24 months.

For the treatment of non-small cell lung cancer (NSCLC). For the first-line treatment of EGFR- and ALK-negative metastatic NSCLC in patients whose tumors express PD-L1 (1% or more), in combination with nivolumab.
NOTE: Patients should be selected based on PD-L1 expression. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage Adults

1 mg/kg IV over 30 minutes every 6 weeks in combination with nivolumab (360 mg IV every 3 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label, multi-part trial (CHECKMATE-227), first-line treatment with nivolumab in combination with ipilimumab significantly improved overall survival compared with treatment with a platinum-based doublet for patients with metastatic or recurrent NSCLC and PD-L1 expression of 1% or more (17.1 months vs. 14.9 months); patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy were excluded from the study. The median progression-free survival as assessed by a blinded independent central review (BICR) was 5.1 months versus 5.6 months, respectively; the confirmed objective response rate by BICR was 36% versus 30%, respectively, for a median duration of 23.2 months in the nivolumab/ipilimumab arm and 6.2 months in the platinum doublet arm.

For the first-line treatment of EGFR- and ALK-negative metastatic or recurrent NSCLC, in combination with nivolumab and platinum-doublet chemotherapy. Intravenous dosage Adults

1 mg/kg IV over 30 minutes every 6 weeks and nivolumab (360 mg IV over 30 minutes every 3 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression in combination with platinum-doublet chemotherapy given every 3 weeks for 2 cycles of therapy. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the ipilimumab infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The overall survival time was significantly improved (14.1 months vs. 10.7 months; hazard ratio (HR) = 0.69; 95% CI, 0.55 to 0.87; p = 0.0006) in patient with metastatic or recurrent NSCLC who received first-line treatment with nivolumab and ipilimumab in combination with 2 cycles of platinum-based doublet chemotherapy (n = 361) compared with 4 cycles of platinum-doublet chemotherapy (n = 358) in a randomized, open-label, phase 3 trial (CHECKMATE-9LA). In this trial, platinum-doublet chemotherapy was administered every 3 weeks and consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2 OR cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC (plus optional pemetrexed maintenance therapy); or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. The progression-free survival time was also significantly improved in the nivolumab and ipilimumab plus platinum-based doublet chemotherapy arm compared with platinum-doublet chemotherapy alone arm (6.8 months vs. 5 months; HR = 0.7; 95% CI, 0.57 to 0.86; p = 0.0001).

For the treatment of mesothelioma.
NOTE: The FDA has designated ipilimumab as an orphan drug for the treatment of mesothelioma.
For the first-line treatment of unresectable malignant pleural mesothelioma, in combination with nivolumab. Intravenous dosage Adults

1 mg/kg IV over 30 minutes every 6 weeks, in combination with nivolumab (360 mg IV over 30 minutes every 3 weeks), until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with ipilimumab in combination with nivolumab significantly improved median overall survival compared with pemetrexed plus either cisplatin or carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma in a randomized, open-label trial (CHECKMATE-743) (18.1 months vs. 14.1 months). Median progression-free survival was 6.8 months in the nivolumab plus ipilimumab arm compared with 7.2 months in patients receiving chemotherapy. The overall response rate was 40% versus 43%, for a median duration of 11 months and 6.7 months, respectively.

For the first-line treatment of esophageal cancer, in particular unresectable advanced or metastatic esophageal squamous cell cancer (ESCC), in combination with nivolumab. Intravenous dosage Adults

1 mg/kg IV over 30 minutes every 6 weeks in combination with nivolumab (3 mg/kg IV every 2 weeks OR 360 mg IV every 3 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with ipilimumab plus nivolumab significantly improved the median overall survival time compared with fluorouracil plus cisplatin (13.7 months vs. 9.1 months) in patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell cancer and at least 1% of tumor cells expressing PD-L1 in a multicenter, randomized, open-label, phase 3 clinical trial (CHECKMATE-648); median overall survival was also significantly improved with ipilimumab and nivolumab in the overall population (12.8 months vs. 10.7 months). Median progression-free survival (PFS) was shorter with immunotherapy compared with chemotherapy in patients with at least 1% PD-L1 expression (4 months vs. 4.4 months) and in those in the overall population (2.9 months vs. 5.6 months). The overall response rate was also higher in patients treated with nivolumab plus ipilimumab in both the PD-L1 positive population (35.4% vs. 20%) and the overall population (27.7% vs. 27%). Complete responses (CR) occurred in 17.7% of PD-L1 positive immunotherapy patients and in 11.1% of those in the overall population; CR occurred in 5.1% of PD-L1 positive patients who received chemotherapy and in 6.2% of those in the overall population. The median duration of response for PD-L1 positive patients was 11.8 months versus 5.7 months, respectively; the median duration of response in the overall population was 11.1 versus 7.1 months, respectively.

Dosing Considerations
Hepatic Impairment

Treatment-Related Immune-Mediated HepatitisNo Tumor Involvement of the Liver OR Tumor Involvement of the Liver and non-Hepatocellular Carcinoma (HCC)AST or ALT level of more than 3 to 5 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. AST or ALT level more than 5 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).Tumor Involvement of the Liver and HCCBaseline AST or ALT level at the ULN or less: Hold or permanently discontinue ipilimumab based on recommendations for hepatitis with no tumor involvement of the liver.Baseline AST or ALT level of more than 1 to 3 times the ULNAST or ALT level of more than 5 to 10 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Baseline AST or ALT level of more than 3 to 5 times the ULNAST or ALT level of more than 8 to 10 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Any Baseline AST or ALT levelAST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

Renal Impairment

Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Grade 4 increased SCr level: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

Drug Interactions

Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vemurafenib: (Moderate) Concurrent use of vemurafenib and ipilimumab led to elevated transaminase levels in the majority of patients with BRAF V600-mutation positive melanoma in a small dose finding study; this study was closed due to adverse hepatic effects. Grade 3 elevated transaminase levels occurred in 6 of 10 patients who received combination therapy with vemurafenib (960 mg or 720 mg PO twice daily) plus ipilimumab (3 mg/kg IV every 3 weeks) in a phase I dose finding study; grade 2 or 3 elevated total bilirubin levels were reported in 2 patients in this study.

How Supplied

YERVOY Intravenous Inj Sol: 1mL, 5mg

Maximum Dosage
Adults

10 mg/kg IV every 3 weeks.

Geriatric

10 mg/kg IV every 3 weeks.

Adolescents

3 mg/kg IV every 3 weeks.

Children

12 years: 3 mg/kg IV every 3 weeks.
1 to 11 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction of CTLA-4 with its ligands CD80/CD86. Blockade of CTLA-4 augments T-cell activation and proliferation, including tumor infiltrating T-effector cells. The inhibition of CTLA-4 signaling may cause a decrease in T-cell regulatory function resulting in an increase in T-cell antitumor responsiveness.

Pharmacokinetics

Ipilimumab is administered intravenously. The pharmacokinetic parameters of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses; the pharmacokinetics of ipilimumab are linear over this dose range. Upon repeated dosing of ipilimumab every 3 weeks, ipilimumab clearance was found to be time-invariant and minimal systemic accumulation (1.5-fold or less) was observed. Steady state concentration was reached by the third dose. In a population pharmacokinetic analysis, the terminal half-life was 15.4 days (coefficient of variance (CV), 34%) and the systemic clearance was 16.8 mL/hour (CV, 38%). The clearance of ipilimumab was unchanged when ipilimumab 1 mg/kg or 3 mg/kg was administered every 3 weeks in combination with nivolumab (3 mg/kg or 1 mg/kg). Ipilimumab clearance values increased by 30% when administered every 6 weeks in combination with nivolumab 3 mg/kg IV every 2 weeks and increased by 22% when administered every 6 weeks in combination with nivolumab 360 mg IV every 3 weeks plus chemotherapy compared to ipilimumab monotherapy. Ipilimumab clearance was also unchanged in the presence of anti-ipilimumab antibodies.

Intravenous Route

In a pharmacokinetic study, peak concentration, trough concentration (Cmin), and area under the curve of ipilimumab were found to be dose proportional within the dose range examined; steady-state concentrations were reached by the third dose. The mean ipilimumab Cmin achieved at steady-state with the 3 mg/kg regimen was 19.4 mcg/mL; the mean Cmin at 10 mg/kg was 58.1 mcg/mL.

Pregnancy And Lactation
Pregnancy

Based on its mechanism of action and data from animal studies, ipilimumab may cause fetal harm if used during pregnancy. Ipilimumab is an immunoglobulin G1 antibody and may cross the placental barrier. The risk of fetal harm is likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Report any pregnancies to Bristol-Myers Squibb at 1-844-593-7869. There have been reports of healthy infants born following exposure to ipilimumab or ipilimumab plus nivolumab in utero.  A prematurely infant (gestational age, 24 weeks) with no signs of intrauterine growth inhibition was delivered via cesarean section after maternal use of ipilimumab plus nilotinib during pregnancy. During the first year, the infant had some typical preterm issues. At 6 months of corrected age, the infant had modestly elevated tonus of the lower extremities combined with a slight delay in motor development but showed age-appropriate speech and social emotional development and no evidence of melanoma. Immune checkpoint inhibitors, such as ipilimumab, may affect immune regulatory pathways play a role in autoimmune disease. However, there is a lack of preclinical evidence that the CTLA-4 axis plays a critical role in fetal-immune tolerance. In animal reproduction studies in pregnant cynomolgus monkeys, dose-related increases in the rate of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality were observed when ipilimumab was administered during the third trimester at doses resulting in AUC values of 2.6 to 7.2 times higher than the clinical human dose of 3 mg/kg. Developmental abnormalities including 1 case of unilateral renal agenesis of the left kidney and ureter and 1 case of an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema were also reported.

Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during ipilimumab therapy and for 3 months after the final dose. It is not known if it has effects on the breastfed child or on milk production. Use ipilimumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because ipilimumab is a large protein molecule (molecular weight of 148,000 Daltons), the amount of drug in milk is likely to be very low but may increase with additional doses. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.