Yervoy

Ipilimumab.

Each milliliter contains 5 mg of ipilimumab.
YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
Excipients/Inactive Ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.

PHARMACOLOGY: Mechanism of Action: CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.
Pharmacokinetics: The pharmacokinetics 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. Peak concentration (C_max), trough concentration (C_min), and area under the plasma concentration versus time curve (AUC) of ipilimumab increased dose proportionally within the dose range examined. Upon repeated dosing every 3 weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean C_min at steady-state was 19.4 mcg/mL following repeated doses of 3 mg/kg. The mean value (% coefficient of variation) generated through population pharmacokinetic analysis for the terminal half-life (t_½) was 15.4 days (34%) and for CL was 16.8 mL/h (38%).
YERVOY with nivolumab: When YERVOY 1 mg/kg was administered in combination with nivolumab 3 mg/kg, the CL of ipilimumab and nivolumab were unchanged.
When administered in combination, the CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies and the CL of nivolumab increased by 20% in the presence of anti-nivolumab antibodies.
Specific Populations: The effects of various covariates on the pharmacokinetics of ipilimumab were assessed in population pharmacokinetic analyses. The CL of ipilimumab increased with increasing body weight; however, no dose adjustment is recommended for body weight after administration on a mg/kg basis. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23-88 years), gender, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-Caucasian ethnic groups.
Renal Impairment: The effect of renal impairment on the CL of ipilimumab was evaluated in patients with mild (GFR <90 and ≥60 mL/min/1.73 m²; n=349), moderate (GFR <60 and ≥30 mL/min/1.73 m²; n=82), or severe (GFR <30 and ≥15 mL/min/1.73 m²; n=4) renal impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m²; n=350) in population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function. [See Renal Impairment under Precautions.]
Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST >ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ≤ULN; n=708) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. YERVOY has not been studied in patients with moderate (TB >1.5 x to 3 x ULN and any AST) or severe hepatic impairment (TB >3 x ULN and any AST). [See Hepatic Impairment under Precautions.]
NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies.
Mutagenesis: The genotoxic potential of ipilimumab has not been evaluated.
Impairment of Fertility: Fertility studies have not been performed with ipilimumab.
CLINICAL STUDIES: Unresectable or Metastatic Melanoma: The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study MDX010-20) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund's adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. YERVOY/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.
The major efficacy outcome measure was overall survival (OS) in the YERVOY+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY+gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the YERVOY+gp100, YERVOY, and gp100 arms, respectively, were men. Twenty-nine percent were ≥ 65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either YERVOY-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months.
The OS results are shown in Table 1 and Figure 1. (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the YERVOY+gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the YERVOY arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 months in the YERVOY+gp100 arm and has not been reached in the YERVOY or gp100 arm.
Concurrent Administration with Vemurafenib: A Phase 1 study was conducted to investigate the safety of the concurrent administration of vemurafenib and YERVOY in patients with BRAF^V600-mutated metastatic melanoma not previously treated with CTLA-4-blocking antibodies or with BRAF or MEK inhibitors. Following a 1-month lead-in with monotherapy vemurafenib (960 mg or 720 mg twice daily), patients received combination therapy with YERVOY (3 mg/kg intravenously every 3 weeks) and vemurafenib administered concurrently. Of the 10 patients who received the combination regimen, 6 developed Grade 3 elevation of ALT/AST, 1 of which also developed Grade 3 elevation of total bilirubin. All were asymptomatic and reversible with either interruption or permanent discontinuation of the drugs and/or treatment with corticosteroids. [See Immune-mediated Hepatitis under Precautions.]
Previously Untreated Advanced Renal Cell Carcinoma: CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label study in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.
Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).
Patients were randomized to nivolumab 3 mg/kg plus YERVOY 1 mg/kg (n=425) administered intravenously every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every two weeks or to sunitinib (n=422) administered orally 50 mg daily for 4 weeks followed by 2 weeks off, every cycle. Treatment continued until disease progression or unacceptable toxicity.
The median age was 61 years (range: 21 to 85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and white (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The major efficacy outcome measures were OS, PFS (IRRC-assessed), and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to nivolumab plus YERVOY as compared with sunitinib (Table 2 and Figure 2). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS.
The efficacy results from CHECKMATE-214 are presented in Table 2 and Figure 2. (See Table 2 and Figure 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to nivolumab plus YERVOY (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving nivolumab plus YERVOY compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of nivolumab plus YERVOY in previously untreated renal cell carcinoma with favorable risk disease has not been established.
Malignant Pleural Mesothelioma: CHECKMATE-743 (NCT02899299) was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial. Patients were randomized 1:1 to receive either: YERVOY 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks and nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.
Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.
A total of 605 patients were randomized to receive either YERVOY in combination with nivolumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.
The trial demonstrated a statistically significant improvement in OS for patients randomized to YERVOY in combination with nivolumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 3 and Figure 3. (See Table 3 and Figure 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the YERVOY and nivolumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the YERVOY and nivolumab arm and 8.8 months in the chemotherapy arm.

Unresectable or Metastatic Melanoma: YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.
Advanced Renal Cell Carcinoma: YERVOY, in combination with nivolumab, is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC) [see PHARMACOLOGY: CLINICAL STUDIES: Previously Untreated Advanced Renal Cell Carcinoma under Actions].
Malignant Pleural Mesothelioma: YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Recommended Dosage: The recommended dosages of YERVOY as a single agent are presented in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 5. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate. (See Table 5.)

Click on icon to see table/diagram/image

Recommended Dose Modifications for Adverse Reactions: No dose reduction for YERVOY is recommended. In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue YERVOY for 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 lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for YERVOY or YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 6.
When YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity. (See Table 6.)

Click on icon to see table/diagram/image

Preparation and Administration: Do not shake product.
Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.
Preparation of Solution: Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion.
Withdraw the required volume of YERVOY and transfer into an intravenous bag.
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion.
Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).
Discard partially used vials or empty vials of YERVOY.
Administration Instructions: Do not mix YERVOY with, or administer as an infusion with, other medicinal products.
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.
Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
When administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. Use separate infusion bags and filters for each infusion.

There is no information on overdosage with YERVOY.

YERVOY is contraindicated in patients who are hypersensitive to ipilimumab or to any ingredient in the formulation. [See Description.]

IMMUNE-MEDIATED ADVERSE REACTIONS: YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Immune-mediated Enterocolitis/Colitis, Immune-mediated Hepatitis, Immune-mediated Dermatitis/Skin Adverse Reactions, Immune-mediated Neuropathies and Immune-mediated Endocrinopathies under Precautions.]

YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Warnings.]
When YERVOY is administered in combination with nivolumab, review the nivolumab Full Prescribing Information for information on the serious risks of nivolumab administered after completion of YERVOY with nivolumab.
Immune-mediated Enterocolitis/Colitis: YERVOY as a Single Agent: Metastatic Melanoma: In Study MDX010-20, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.
The median time to onset was 7.4 weeks (range: 1.6-13.4) and 6.3 weeks (range: 0.3-18.9) after the initiation of YERVOY for patients with Grade 3-5 enterocolitis and with Grade 2 enterocolitis, respectively.
Twenty-nine patients (85%) with Grade 3-5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
Of the 34 patients with Grade 3-5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Stool infections work-up (including CMV, other viral etiology, culture, Clostridium difficile, ova, and parasite) should be performed upon presentation of diarrhea or colitis to exclude infectious or other alternate etiologies.
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.
Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-related colitis if other causes are excluded (including CMV infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial, and parasitic etiology).
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated colitis occurred in 10% (52/547) of patients. Median time to onset was 1.7 months (range: 2 days to 19.2 months). Immune-mediated colitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 3.5% and 4.2% of patients, respectively. Approximately 83% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 27 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 89% of patients. Two patients had recurrence of colitis after re-initiation of nivolumab with YERVOY.
Immune-mediated Hepatitis: YERVOY as a Single Agent: Metastatic Melanoma: In Study MDX010-20, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3-5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test (LFT) abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Concurrent Administration with Vemurafenib: In a Phase 1 trial, asymptomatic Grade 3 LFT elevations (ALT/AST with or without total bilirubin) were reported in 6 of 10 patients treated with the combination of YERVOY (3 mg/kg) and vemurafenib (960 mg or 720 mg twice daily) administered concurrently. Based on these data, the concurrent administration of YERVOY and vemurafenib is not recommended outside of a clinical trial. These results do not impact the currently approved use of YERVOY as monotherapy. [See PHARMACOLOGY: CLINICAL STUDIES under Actions.]
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated hepatitis occurred in 7% (38/547) of patients. Median time to onset was 2 months (range: 14 days to 26.8 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 3.7% and 3.1% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.0 month (range: 1 day to 4.0 months). Complete resolution occurred in 87% of patients without recurrence of hepatitis after re-initiation of nivolumab with YERVOY.
Immune-mediated Dermatitis/Skin Adverse Reactions: YERVOY as a Single Agent: Metastatic Melanoma: In Study MDX010-20, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY.
Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
Caution should be used when considering the use of YERVOY in a patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune stimulatory therapy.
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated rash occurred in 16.6% (91/547) of patients. Median time to onset was 1.5 months (range: 1 day to 20.9 months). Immune-mediated rash led to permanent discontinuation of nivolumab with YERVOY in 0.5% and 2.9% of patients, respectively. Approximately 19% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 25 days (range: 1 day to 23.1 months). Complete resolution occurred in 64% of patients. Approximately 3.6% of patients who resumed nivolumab and YERVOY after resolution had recurrence of rash.
Immune-mediated Neuropathies: YERVOY as a Single Agent: Metastatic Melanoma: In Study MDX010-20, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Immune-mediated Endocrinopathies: YERVOY as a Single Agent: Metastatic Melanoma: In Study MDX010-20, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing's syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Hypophysitis: Hypophysitis occurred in 4.6% (25/547) of patients. Median time to onset was 2.8 months (range: 1.3 months to 7.3 months). Hypophysitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.3% and 2.6% of patients, respectively. Approximately 72% of patients with hypophysitis received hormone replacement therapy and 60% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 10 days (range: 1 day to 1.6 months).
Adrenal Insufficiency: Adrenal insufficiency occurred in 7% (41/547) of patients. Median time to onset was 3.4 months (range: 2.0 months to 22.3 months). Adrenal insufficiency led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.3% and 2.0% of patients, respectively. Approximately 93% of patients with adrenal insufficiency received hormone replacement therapy and 18% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 day to 5.6 months).
Hypothyroidism and Hyperthyroidism: Hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Median time to onset was 2.2 months (range: 1 day to 21.4 months). Approximately 76% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 31% of patients.
Hyperthyroidism occurred in 12% (66/547) of patients. Median time to onset was 1.4 months (range: 6 days to 14.2 months). Approximately 14% of patients with hyperthyroidism received methimazole and 3% received carbimazole. Resolution occurred in 85% of patients.
Type 1 Diabetes Mellitus: Diabetes occurred in 2.7% (15/547) of patients. Median time to onset was 3.2 months (range: 19 days to 16.8 months). Nivolumab with YERVOY was withheld in 33% of patients and permanently discontinued in 20% of patients who developed diabetes.
Immune-Mediated Pneumonitis: Immune-mediated pneumonitis, including fatal cases, can occur with nivolumab with YERVOY. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY for life-threatening (Grade 4) pneumonitis.
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. Median time to onset was 2.6 months (range: 8 days to 9.2 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 2.0% and 1.6% of patients, respectively. Approximately 92% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 4 days to 3.2 months). Approximately 8% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 79% of patients without recurrence of pneumonitis after re-initiation of nivolumab with YERVOY.
Immune-Mediated Nephritis and Renal Dysfunction: Immune-mediated nephritis can occur with nivolumab with YERVOY. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY for life-threatening (Grade 4) increased serum creatinine.
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. Median time to onset was 2.5 months (range: 1 day to 13.2 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.1% and 2.7% of patients, respectively. Approximately 76% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 15 days (range: 1 day to 5.9 months). Complete resolution occurred in 64% of patients. One patient had recurrence of nephritis or renal dysfunction after re-initiation of nivolumab with YERVOY.
Immune-Mediated Encephalitis: Immune-mediated encephalitis can occur with nivolumab with YERVOY. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold YERVOY in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue YERVOY for immune-mediated encephalitis.
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Immune-mediated encephalitis occurred in one patient (0.2%) after approximately 4 months of exposure.
Infusion-Related Reactions: Severe infusion-related reactions can occur with nivolumab with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions.
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Infusion-related reactions occurred in 5.1% (28/547) of patients.
Malignant pleural mesothelioma: Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks.
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: YERVOY as a Single Agent: Metastatic Melanoma: The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study MDX010-20: cytopenia, nephritis, pneumonitis, meningitis, pericarditis, uveitis, and iritis, and hemolytic anemia.
Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis. Cases of Vogt-Koyanagi-Harada syndrome have been reported post-marketing. Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT). Follow patients closely for evidence of GVHD and intervene promptly. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT.
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Recommended Dose Modifications for Adverse Reactions under Dosage & Administration.]
Nivolumab with YERVOY: Nivolumab 3 mg/kg with YERVOY 1 mg/kg: Renal Cell Carcinoma: Nivolumab in combination with YERVOY can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Immune-mediated adverse reactions may occur after discontinuation of YERVOY therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold YERVOY, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting YERVOY after completion of corticosteroid taper based on the severity of the event.
Across clinical trials of nivolumab administered as a single agent or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in less than 1.0% of patients: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.
Solid organ transplant rejection has been reported in the post-marketing setting in patients who receive treatment with a CTLA-4 receptor blocking antibody. Treatment with ipilimumab may increase the risk of rejection in solid organ transplant recipients [see Postmarketing Experience under Adverse Reactions].
Renal Impairment: No dose adjustment is needed for patients with renal impairment. [See PHARMACOLOGY: Pharmacokinetics under Actions.]
Hepatic Impairment: No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 x to 1.5 x the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 x to 3.0 x ULN and any AST) or severe (TB >3 x ULN and any AST) hepatic impairment. [See PHARMACOLOGY: Pharmacokinetics under Actions.]
Use in Pregnancy: Embryo-fetal Toxicity: Based on its mechanism of action and data from animal studies, YERVOY can cause fetal harm when administered to a pregnant woman. 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. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Use in Children: The safety and effectiveness for pediatric patients less than 12 years of age has not been established.
Use in the Elderly: Of the 511 patients treated with YERVOY at 3 mg/kg in MDX010-20 (Unresectable or Metastatic Melanoma), 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
Of the 550 patients randomized to nivolumab 3 mg/kg administered with YERVOY 1 mg/kg in CHECKMATE-214 (Renal Cell Carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported.
Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively).
For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab.

Pregnancy: Risk Summary: Based on data from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. 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 dose-related manner [See Data as follows]. The effects of Ipilimumab are likely to be greater during the second or third trimesters of pregnancy. Human IgG1 is 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. There is insufficient human data for YERVOY exposure in pregnant women. Advise pregnant women of the potential risk to a fetus.
YERVOY is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweigh the potential risk.
Data: Animal Data: In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortions, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urgogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the 3 mg/kg dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3-4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
Lactation: Risk Summary: It is not known whether ipilimumab is secreted in human milk. In monkeys, ipilimumab was present in milk. There are no data to assess the effect of YERVOY on milk production. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.
Data: In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug.
Females and Males of Reproductive Potential: Contraception: Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [See Pregnancy as previously mentioned]. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose of YERVOY.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Immune-mediated enterocolitis/colitis [see Immune-mediated Enterocolitis/Colitis under Precautions].
Immune-mediated hepatitis [see Immune-mediated Hepatitis under Precautions].
Immune-mediated dermatitis/skin adverse reactions [see Immune-mediated Dermatitis/Skin Adverse Reactions under Precautions].
Immune-mediated neuropathies [see Immune-mediated Neuropathies under Precautions].
Immune-mediated endocrinopathies [see Immune-mediated Endocrinopathies under Precautions].
Immune-mediated pneumonitis [see Immune-Mediated Pneumonitis under Precautions].
Immune-mediated nephritis and renal dysfunction [see Immune-Mediated Nephritis and Renal Dysfunction under Precautions].
Immune-mediated encephalitis [see Immune-Mediated Encephalitis under Precautions].
Infusion reactions [see Infusion-Related Reactions under Precautions].
Other immune-mediated adverse reactions, including ocular manifestations [see Other Immune-mediated Adverse Reactions, Including Ocular Manifestations under Precautions].
Embryo-fetal toxicity [see Use in Pregnancy: Embryo-fetal Toxicity under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.
Unresectable or Metastatic Melanoma: The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study MDX010-20). [See PHARMACOLOGY: CLINICAL STUDIES under Actions.] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1-4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.
The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.
Table 7 presents selected adverse reactions from Study MDX010-20, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3-5 events. (See Table 7.)

Click on icon to see table/diagram/image

Table 8 presents the per-patient incidence of severe, life-threatening or fatal immune-mediated adverse reactions from Study MDX010-20. (See Table 8.)

Click on icon to see table/diagram/image

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.
Adverse reactions reported in patients treated with YERVOY 3 mg/kg in clinical trials are presented in Table 9.
These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Rates of immune-related adverse reactions in HLA-A2*0201-positive patients who received YERVOY in MDX010-20 were similar to those observed in the overall clinical program.
The safety profile of YERVOY 3 mg/kg in chemotherapy-naïve patients pooled across Phase 2 and 3 clinical trials (N=75; treated) and in treatment-naïve patients in a retrospective observational study (N=120) was similar to that in previously-treated advanced melanoma. (See Table 9.)

Click on icon to see table/diagram/image

Additional adverse reactions not listed in Table 9 have been reported in patients who received other doses (either < or > 3 mg/kg) of YERVOY in clinical trials of melanoma. These additional reactions occurred at a frequency of <1%: meningism, myocarditis, pericardial effusion (pericarditis), cardiomyopathy, autoimmune hepatitis, erythema multiforme, autoimmune nephritis, autoimmune thyroiditis, hyperpituitarism, secondary adrenocortical insufficiency, hypoparathyroidism, thyroiditis, episcleritis, blepharitis, eye oedema, scleritis, temporal arteritis, Raynaud's phenomenon, proctitis, palmar-plantar erythrodysaesthesia syndrome, psoriasis, hematuria, proteinuria, decreased blood thyroid stimulating hormone, decreased blood gonadotrophin, decreased thyroxine, leukopenia, polycythaemia, myasthenia gravis-like symptoms, cytokine release syndrome, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been very rarely reported with YERVOY in post-marketing use.
Previously Untreated Renal Cell Carcinoma: The safety of nivolumab 3 mg/kg, administered with YERVOY 1 mg/kg was evaluated in CHECKMATE-214, a randomized open-label trial in which 1082 patients with previously untreated advanced RCC received nivolumab 3 mg/kg in combination with YERVOY 1 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at the 3 mg/kg dose (n=547) every 2 weeks or sunitinib administered orally 50 mg daily for 4 weeks followed by 2 weeks off, every cycle (n=535) [see PHARMACOLOGY: CLINICAL STUDIES under Actions]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in nivolumab plus YERVOY-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the nivolumab plus YERVOY arm were exposed to treatment for greater than 6 months, and 38% of patients were exposed to treatment for greater than 1 year.
Study therapy was discontinued for adverse reactions in 31% of nivolumab plus YERVOY patients and in 21% of sunitinib patients. Fifty-four percent (54%) of patients receiving nivolumab plus YERVOY and 43% of patients receiving sunitinib had a drug delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction; dose reductions were not permitted in the nivolumab plus YERVOY treatment group. Serious adverse reactions occurred in 59% of patients receiving nivolumab plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients treated with nivolumab plus YERVOY were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea.
The most common adverse reactions (reported in at least 20% of nivolumab plus YERVOY-treated patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. Table 10 summarizes adverse reactions that occurred in greater than 15% of nivolumab plus YERVOY-treated patients. (See Table 10.)

Click on icon to see table/diagram/image

The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of nivolumab plus YERVOY-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Table 11 summarizes the laboratory abnormalities that occurred in greater than 15% of nivolumab plus YERVOY-treated patients. (See Table 11.)

Click on icon to see table/diagram/image

First-line Treatment of Unresectable Malignant Pleural Mesothelioma: In Combination with Nivolumab: The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see PHARMACOLOGY: CLINICAL STUDIES under Actions]. Patients received either YERVOY 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks and nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received YERVOY and nivolumab for >6 months and 24% of patients received YERVOY and nivolumab for >1 year.
Serious adverse reactions occurred in 54% of patients who were treated with YERVOY in combination with nivolumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.
Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4.7% of patients permanently discontinued YERVOY alone due to adverse reactions.
The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.
Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743. (See Tables 12 and 13.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Postmarketing Experience: The following adverse reactions have been identified during post approval use of YERVOY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH).
Immune system disorders: graft-versus-host disease, solid organ transplant rejection.
Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ipilimumab in the studies described as follows with the incidences of antibodies in other studies or to other products may be misleading.
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.
Of the patients who were treated with ipilimumab and nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies was 6.3% and there were no patients with neutralizing antibodies against ipilimumab with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks. There was no evidence of increased incidence of infusion reactions in the presence of anti-ipilimumab antibodies. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% and the incidence of neutralizing antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks.
Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% had neutralizing antibodies against nivolumab.

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Protect YERVOY from light by storing in the original carton until time of use. Do not freeze or shake.

Cancer Immunotherapy

L01FX04 - ipilimumab ; Belongs to the class of other monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

S