WARNING
IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY CAN RESULT IN SEVERE AND FATAL IMMUNE-MEDIATED ADVERSE REACTIONS DUE TO T-CELL ACTIVATION AND PROLIFERATION. THESE IMMUNE-MEDIATED REACTIONS MAY INVOLVE ANY ORGAN SYSTEM; HOWEVER, THE MOST COMMON SEVERE IMMUNE-MEDIATED ADVERSE REACTIONS ARE ENTEROCOLITIS, HEPATITIS, DERMATITIS (INCLUDING TOXIC EPIDERMAL NECROLYSIS), NEUROPATHY, AND ENDOCRINOPATHY. THE MAJORITY OF THESE IMMUNE-MEDIATED REACTIONS INITIALLY MANIFESTED DURING TREATMENT; HOWEVER, A MINORITY OCCURRED WEEKS TO MONTHS AFTER DISCONTINUATION OF YERVOY.
PERMANENTLY DISCONTINUE YERVOY AND INITIATE SYSTEMIC HIGH-DOSE CORTICOSTEROID THERAPY FOR SEVERE IMMUNE-MEDIATED REACTIONS. [SEE DOSAGE AND 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 WARNINGS AND PRECAUTIONS]
INDICATIONS
YERVOY (IPILIMUMAB) IS INDICATED FOR THE TREATMENT OF UNRESECTABLE OR METASTATIC MELANOMA.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
50 MG/10 ML (5 MG/ML)
200 MG/40 ML (5 MG/ML)
STORAGE AND HANDLING
YERVOY IS AVAILABLE AS FOLLOWS:
CARTON CONTENTS NDC
ONE 50 MG VIAL (5 MG/ML), SINGLE-USE VIAL NDC 0003-2327-11
ONE 200 MG VIAL (5 MG/ML), SINGLE-USE VIAL NDC 0003-2328-22
STORE YERVOY UNDER REFRIGERATION AT 2°C TO 8°C (36°F TO 46°F). DO NOT FREEZE. PROTECT VIALS FROM LIGHT.
MANUFACTURED BY: BRISTOL-MYERS SQUIBB COMPANY PRINCETON, NJ 08543 USA. REV MARCH 2015
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSING
THE RECOMMENDED DOSE OF YERVOY IS 3 MG/KG ADMINISTERED INTRAVENOUSLY OVER 90 MINUTES EVERY 3 WEEKS FOR A TOTAL OF 4 DOSES.
RECOMMENDED DOSE MODIFICATIONS
" WITHHOLD SCHEDULED DOSE OF YERVOY FOR ANY MODERATE IMMUNE-MEDIATED ADVERSE REACTIONS OR FOR SYMPTOMATIC ENDOCRINOPATHY. FOR PATIENTS WITH COMPLETE OR PARTIAL RESOLUTION OF ADVERSE REACTIONS (GRADE 0-1), AND WHO ARE RECEIVING LESS THAN 7.5 MG PREDNISONE OR EQUIVALENT PER DAY, RESUME YERVOY AT A DOSE OF 3 MG/KG EVERY 3 WEEKS UNTIL ADMINISTRATION OF ALL 4 PLANNED DOSES OR 16 WEEKS FROM FIRST DOSE, WHICHEVER OCCURS EARLIER.
" PERMANENTLY DISCONTINUE YERVOY FOR ANY OF THE FOLLOWING:
" PERSISTENT MODERATE ADVERSE REACTIONS OR INABILITY TO REDUCE CORTICOSTEROID DOSE TO 7.5 MG PREDNISONE OR EQUIVALENT PER DAY.
" FAILURE TO COMPLETE FULL TREATMENT COURSE WITHIN 16 WEEKS FROM ADMINISTRATION OF FIRST DOSE.
" SEVERE OR LIFE-THREATENING ADVERSE REACTIONS, INCLUDING ANY OF THE FOLLOWING:
" COLITIS WITH ABDOMINAL PAIN, FEVER, ILEUS, OR PERITONEAL SIGNS; INCREASE IN STOOL FREQUENCY (7 OR MORE OVER BASELINE), STOOL INCONTINENCE, NEED FOR INTRAVENOUS HYDRATION FOR MORE THAN 24 HOURS, GASTROINTESTINAL HEMORRHAGE, AND GASTROINTESTINAL PERFORATION
" ASPARTATE AMINOTRANSFERASE (AST) OR ALANINE AMINOTRANSFERASE (ALT) > 5 TIMES THE UPPER LIMIT OF NORMAL OR TOTAL BILIRUBIN > 3 TIMES THE UPPER LIMIT OF NORMAL
" STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, OR RASH COMPLICATED BY FULL THICKNESS DERMAL ULCERATION, OR NECROTIC, BULLOUS, OR HEMORRHAGIC MANIFESTATIONS
" SEVERE MOTOR OR SENSORY NEUROPATHY, GUILLAIN-BARRÉ SYNDROME, OR MYASTHENIA GRAVIS
" SEVERE IMMUNE-MEDIATED REACTIONS INVOLVING ANY ORGAN SYSTEM (EG, NEPHRITIS, PNEUMONITIS, PANCREATITIS, NON-INFECTIOUS MYOCARDITIS)
" IMMUNE-MEDIATED OCULAR DISEASE THAT IS UNRESPONSIVE TO TOPICAL IMMUNOSUPPRESSIVE THERAPY
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-TOWHITE, 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.
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN OTHER SECTIONS OF THE LABELING.
" IMMUNE-MEDIATED ENTEROCOLITIS [SEE WARNINGS AND PRECAUTIONS].
" IMMUNE-MEDIATED HEPATITIS [SEE WARNINGS AND PRECAUTIONS].
" IMMUNE-MEDIATED DERMATITIS [SEE WARNINGS AND PRECAUTIONS].
" IMMUNE-MEDIATED NEUROPATHIES [SEE WARNINGS AND PRECAUTIONS].
" IMMUNE-MEDIATED ENDOCRINOPATHIES [SEE WARNINGS AND PRECAUTIONS].
" OTHER IMMUNE-MEDIATED ADVERSE REACTIONS, INCLUDING OCULAR MANIFESTATIONS [SEE WARNINGS AND 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.
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 1). [SEE CLINICAL STUDIES] 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 1 PRESENTS SELECTED ADVERSE REACTIONS FROM STUDY 1, 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.
TABLE 1: SELECTED ADVERSE REACTIONS IN STUDY 1
SYSTEM ORGAN CLASS/ PREFERRED TERM PERCENTAGE (%) OF PATIENTSA
YERVOY 3 MG/KG
N=131 YERVOY 3 MG/KG + GP100
N=380 GP100
N=132
ANY GRADE GRADE 3-5 ANY GRADE GRADE 3-5 ANY GRADE GRADE 3-5
GASTROINTESTINAL DISORDERS
DIARRHEA 32 5 37 4 20 1
COLITIS 8 5 5 3 2 0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PRURITUS 31 0 21 < 1 11 0
RASH 29 2 25 2 8 0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
FATIGUE 41 7 34 5 31 3
A INCIDENCES PRESENTED IN THIS TABLE ARE BASED ON REPORTS OF ADVERSE EVENTS REGARDLESS OF CAUSALITY.
TABLE 2 PRESENTS THE PER-PATIENT INCIDENCE OF SEVERE, LIFE-THREATENING, OR FATAL IMMUNE-MEDIATED ADVERSE REACTIONS FROM STUDY 1.
TABLE 2: SEVERE TO FATAL IMMUNE-MEDIATED ADVERSE REACTIONS IN STUDY 1
ACROSS CLINICAL STUDIES THAT UTILIZED YERVOY DOSES RANGING FROM 0.3 TO 10 MG/KG, THE FOLLOWING ADVERSE REACTIONS WERE ALSO REPORTED (INCIDENCE LESS THAN 1% UNLESS OTHERWISE NOTED): URTICARIA (2%), LARGE INTESTINAL ULCER, ESOPHAGITIS, ACUTE RESPIRATORY DISTRESS SYNDROME, RENAL FAILURE, AND INFUSION REACTION.
BASED ON THE EXPERIENCE IN THE ENTIRE CLINICAL PROGRAM FOR MELANOMA, THE INCIDENCE AND SEVERITY OF ENTEROCOLITIS AND HEPATITIS APPEAR TO BE DOSE DEPENDENT.
IMMUNOGENICITY
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.
IMMUNOGENICITY ASSAY RESULTS ARE HIGHLY DEPENDENT ON SEVERAL FACTORS INCLUDING ASSAY SENSITIVITY AND SPECIFICITY, ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATIONS, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF INCIDENCE OF ANTIBODIES TO YERVOY WITH THE INCIDENCES OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
READ THE YERVOY (IPILIMUMAB INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
CTLA-4 IS A NEGATIVE REGULATOR OF T-CELL ACTIVITY. IPILIMUMAB IS A MONOCLONAL ANTIBODY THAT 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 (CMAX ), 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%).
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 USE IN SPECIFIC POPULATIONS]
HEPATIC IMPAIRMENT
THE EFFECT OF HEPATIC IMPAIRMENT ON THE CL OF IPILIMUMAB WAS EVALUATED IN PATIENTS WITH MILD HEPATIC IMPAIRMENT (TB 1.0 × TO 1.5 × 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 × TO 3 × ULN AND ANY AST) OR SEVERE HEPATIC IMPAIRMENT (TB > 3 × ULN AND ANY AST). [SEE USE IN SPECIFIC POPULATIONS]
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
IN ADDITION TO THE SEVERE FINDINGS OF ABORTION, STILLBIRTHS, AND POSTNATAL DEATHS OBSERVED IN PREGNANT CYNOMOLGUS MONKEYS THAT RECEIVED IPILIMUMAB EVERY 3 WEEKS FROM THE ONSET OF ORGANOGENESIS IN THE FIRST TRIMESTER THROUGH PARTURITION [SEE USE IN SPECIFIC POPULATIONS], DEVELOPMENTAL ABNORMALITIES WERE IDENTIFIED IN THE UROGENITAL SYSTEM OF 2 INFANT MONKEYS EXPOSED IN UTERO TO 30 MG/KG OF IPILIMUMAB (7.2 TIMES THE AUC IN HUMANS AT THE CLINICALLY RECOMMENDED 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.
CLINICAL STUDIES
THE SAFETY AND EFFICACY OF YERVOY WERE INVESTIGATED IN A RANDOMIZED (3:1:1), DOUBLE-BLIND, DOUBLE-DUMMY STUDY (STUDY 1) 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 3 AND FIGURE 1.
TABLE 3: OVERALL SURVIVAL RESULTS
FIGURE 1: OVERALL SURVIVAL
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.