NIVOLUMAB
DESCRIPTION
NIVOLUMAB IS A PROGRAMMED DEATH RECEPTOR-1 (PD-1) BLOCKING ANTIBODY. NIVOLUMAB IS AN IGG4 KAPPA IMMUNOGLOBULIN THAT HAS A CALCULATED MOLECULAR MASS OF 146 KDA. IT IS EXPRESSED IN A RECOMBINANT CHINESE HAMSTER OVARY (CHO) CELL LINE.
OPDIVO IS A STERILE, PRESERVATIVE-FREE, NON-PYROGENIC, CLEAR TO OPALESCENT, COLORLESS TO PALE-YELLOW LIQUID THAT MAY CONTAIN LIGHT (FEW) PARTICLES.
OPDIVO (NIVOLUMAB) INJECTION FOR INTRAVENOUS USE IS SUPPLIED IN SINGLE-DOSE VIALS. EACH ML OF OPDIVO SOLUTION CONTAINS NIVOLUMAB 10 MG, MANNITOL (30 MG), PENTETIC ACID (0.008 MG), POLYSORBATE 80 (0.2 MG), SODIUM CHLORIDE (2.92 MG), SODIUM CITRATE DIHYDRATE (5.88 MG), AND WATER FOR INJECTION, USP. MAY CONTAIN HYDROCHLORIC ACID AND/OR SODIUM HYDROXIDE TO ADJUST PH TO 6.
INDICATIONS
INDICATIONS
UNRESECTABLE OR METASTATIC MELANOMA
OPDIVO, AS A SINGLE AGENT OR IN COMBINATION WITH IPILIMUMAB, IS INDICATED FOR THE TREATMENT OF PATIENTS WITH UNRESECTABLE OR METASTATIC MELANOMA.
ADJUVANT TREATMENT OF MELANOMA
OPDIVO IS INDICATED FOR THE ADJUVANT TREATMENT OF PATIENTS WITH MELANOMA WITH INVOLVEMENT OF LYMPH NODES OR METASTATIC DISEASE WHO HAVE UNDERGONE COMPLETE RESECTION.
METASTATIC NON-SMALL CELL LUNG CANCER
· OPDIVO, IN COMBINATION WITH IPILIMUMAB, IS INDICATED FOR THE FIRST-LINE TREATMENT OF ADULT PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHOSE TUMORS EXPRESS PD-L1 (?1%) AS DETERMINED BY AN FDA-APPROVED TEST [SEE DOSAGE AND ADMINISTRATION], WITH NO EGFR OR ALK GENOMIC TUMOR ABERRATIONS.
· OPDIVO, IN COMBINATION WITH IPILIMUMAB AND 2 CYCLES OF PLATINUM-DOUBLET CHEMOTHERAPY, IS INDICATED FOR THE FIRST-LINE TREATMENT OF ADULT PATIENTS WITH METASTATIC OR RECURRENT NON-SMALL CELL LUNG CANCER (NSCLC), WITH NO EGFR OR ALK GENOMIC TUMOR ABERRATIONS.
· OPDIVO IS INDICATED FOR THE TREATMENT OF PATIENTS WITH METASTATIC NSCLC WITH PROGRESSION ON OR AFTER PLATINUM-BASED CHEMOTHERAPY. PATIENTS WITH EGFR OR ALK GENOMIC TUMOR ABERRATIONS SHOULD HAVE DISEASE PROGRESSION ON FDA-APPROVED THERAPY FOR THESE ABERRATIONS PRIOR TO RECEIVING OPDIVO.
SMALL CELL LUNG CANCER
OPDIVO IS INDICATED FOR THE TREATMENT OF PATIENTS WITH METASTATIC SMALL CELL LUNG CANCER (SCLC) WITH PROGRESSION AFTER PLATINUM-BASED CHEMOTHERAPY AND AT LEAST ONE OTHER LINE OF THERAPY.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE AND DURATION OF RESPONSE [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
ADVANCED RENAL CELL CARCINOMA
· OPDIVO AS A SINGLE AGENT IS INDICATED FOR THE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA (RCC) WHO HAVE RECEIVED PRIOR ANTI-ANGIOGENIC THERAPY.
· OPDIVO, IN COMBINATION WITH IPILIMUMAB, IS INDICATED FOR THE TREATMENT OF PATIENTS WITH INTERMEDIATE OR POOR RISK, PREVIOUSLY UNTREATED ADVANCED RCC.
CLASSICAL HODGKIN LYMPHOMA
OPDIVO IS INDICATED FOR THE TREATMENT OF ADULT PATIENTS WITH CLASSICAL HODGKIN LYMPHOMA (CHL) THAT HAS RELAPSED OR PROGRESSED AFTER:
· AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) AND BRENTUXIMAB VEDOTIN, OR
· 3 OR MORE LINES OF SYSTEMIC THERAPY THAT INCLUDES AUTOLOGOUS HSCT.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
OPDIVO IS INDICATED FOR THE TREATMENT OF PATIENTS WITH RECURRENT OR METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) WITH DISEASE PROGRESSION ON OR AFTER PLATINUM-BASED THERAPY.
UROTHELIAL CARCINOMA
OPDIVO IS INDICATED FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA WHO:
· HAVE DISEASE PROGRESSION DURING OR FOLLOWING PLATINUM-CONTAINING CHEMOTHERAPY
· HAVE DISEASE PROGRESSION WITHIN 12 MONTHS OF NEOADJUVANT OR ADJUVANT TREATMENT WITH PLATINUM-CONTAINING CHEMOTHERAPY.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON TUMOR RESPONSE RATE AND DURATION OF RESPONSE [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
MICROSATELLITE INSTABILITY-HIGH OR MISMATCH REPAIR DEFICIENT METASTATIC COLORECTAL CANCER
OPDIVO, AS A SINGLE AGENT OR IN COMBINATION WITH IPILIMUMAB, IS INDICATED FOR THE TREATMENT OF ADULT AND PEDIATRIC PATIENTS 12 YEARS AND OLDER WITH MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR) METASTATIC COLORECTAL CANCER (CRC ) THAT HAS PROGRESSED FOLLOWING TREATMENT WITH A FLUOROPYRIMIDINE, OXALIPLATIN, AND IRINOTECAN.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE AND DURATION OF RESPONSE [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
HEPATOCELLULAR CARCINOMA
OPDIVO, AS A SINGLE AGENT OR IN COMBINATION WITH IPILIMUMAB, IS INDICATED FOR THE TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) WHO HAVE BEEN PREVIOUSLY TREATED WITH SORAFENIB. THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE AND DURATION OF RESPONSE [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN THE CONFIRMATORY TRIALS.
DOSAGE
DOSAGE AND ADMINISTRATION
PATIENT SELECTION
SELECT PATIENTS WITH METASTATIC NSCLC FOR TREATMENT WITH OPDIVO IN COMBINATION WITH IPILIMUMAB BASED ON PD-L1 EXPRESSION [SEE CLINICAL STUDIES].
INFORMATION ON FDA-APPROVED TESTS FOR THE DETERMINATION OF PD-L1 EXPRESSION IN NSCLC IS AVAILABLE AT: HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS.
RECOMMENDED DOSAGE
THE RECOMMENDED DOSAGES OF OPDIVO AS A SINGLE AGENT ARE PRESENTED IN TABLE 1
TABLE 1: RECOMMENDED DOSAGES FOR OPDIVO AS A SINGLE AGENT
INDICATION RECOMMENDED OPDIVO DOSAGE DURATION OF THERAPY
UNRESECTABLE OR METASTATIC MELANOMA 240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
METASTATIC NON-SMALL CELL LUNG CANCER
ADVANCED RENAL CELL CARCINOMA
CLASSICAL HODGKIN LYMPHOMA
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
UROTHELIAL CARCINOMA
HEPATOCELLULAR CARCINOMA
ADJUVANT TREATMENT OF MELANOMA 240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) UNTIL DISEASE RECURRENCE OR UNACCEPTABLE TOXICITY FOR UP TO 1 YEAR
SMALL CELL LUNG CANCER 240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR) METASTATIC COLORECTAL CANCER ADULT PATIENTS AND PEDIATRIC PATIENTS AGE 12 YEARS AND OLDER AND WEIGHING 40 KG OR MORE: 240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
PEDIATRIC PATIENTS AGE 12 YEARS AND OLDER AND WEIGHING LESS THAN 40 KG: 3 MG/KG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION)
THE RECOMMENDED DOSAGES OF OPDIVO IN COMBINATION WITH IPILIMUMAB OR OTHER THERAPEUTIC AGENTS ARE PRESENTED IN TABLE 2. REFER TO THE RESPECTIVE PRESCRIBING INFORMATION FOR EACH THERAPEUTIC AGENT ADMINISTERED IN COMBINATION WITH OPDIVO FOR THE RECOMMENDED DOSAGE INFORMATION, AS APPROPRIATE.
TABLE 2: RECOMMENDED DOSAGES OF OPDIVO IN COMBINATION WITH OTHER THERAPEUTIC AGENTS
INDICATION RECOMMENDED OPDIVO DOSAGE DURATION OF THERAPY
UNRESECTABLE OR METASTATIC MELANOMA 1 MG/KG EVERY 3 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 3 MG/KG INTRAVENOUSLY OVER 90 MINUTES ON THE SAME DAY IN COMBINATION WITH IPILIMUMAB FOR A MAXIMUM OF 4 DOSES OR UNTIL UNACCEPTABLE TOXICITY, WHICHEVER OCCURS EARLIER
240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) AFTER COMPLETING 4 DOSES OF COMBINATION THERAPY, ADMINISTER AS SINGLE AGENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
METASTATIC NON-SMALL CELL LUNG CANCER EXPRESSING PD-L1 3 MG/KG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 1 MG/KG EVERY 6 WEEKS (30-MINUTE INTRAVENOUS INFUSION) IN COMBINATION WITH IPILIMUMAB UNTIL DISEASE PROGRESSION, UNACCEPTABLE TOXICITY, OR UP TO 2 YEARS IN PATIENTS WITHOUT DISEASE PROGRESSION
METASTATIC OR RECURRENT NON-SMALL CELL LUNG CANCER 360 MG EVERY 3 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 1 MG/KG EVERY 6 WEEKS (30-MINUTE INTRAVENOUS INFUSION) AND HISTOLOGY-BASED PLATINUM DOUBLET CHEMOTHERAPY EVERY 3 WEEKS IN COMBINATION WITH IPILIMUMAB UNTIL DISEASE PROGRESSION, UNACCEPTABLE TOXICITY, OR UP TO 2 YEARS IN PATIENTS WITHOUT DISEASE PROGRESSION
2 CYCLES OF HISTOLOGY-BASED PLATINUM-DOUBLET CHEMOTHERAPY
ADVANCED RENAL CELL CARCINOMA 3 MG/KG EVERY 3 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 1 MG/KG INTRAVENOUSLY OVER 30 MINUTES ON THE SAME DAY IN COMBINATION WITH IPILIMUMAB FOR 4 DOSES
240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) AFTER COMPLETING 4 DOSES OF COMBINATION THERAPY, ADMINISTER AS SINGLE AGENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
MICROSATELLITE INSTABILITY-HIGH (MSIH) OR MISMATCH REPAIR DEFICIENT (DMMR) METASTATIC COLORECTAL CANCER 3 MG/KG EVERY 3 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 1 MG/KG INTRAVENOUSLY OVER 30 MINUTES ON THE SAME DAY IN COMBINATION WITH IPILIMUMAB FOR 4 DOSES
ADULT PATIENTS AND PEDIATRIC PATIENTS AGE 12 YEARS AND OLDER AND WEIGHING 40 KG OR MORE: 240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) AFTER COMPLETING 4 DOSES OF COMBINATION THERAPY, ADMINISTER AS SINGLE AGENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
PEDIATRIC PATIENTS AGE 12 YEARS AND OLDER AND WEIGHING LESS THAN 40 KG: 3 MG/KG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION)
HEPATOCELLULAR CARCINOMA 1 MG/KG EVERY 3 WEEKS (30-MINUTE INTRAVENOUS INFUSION) WITH IPILIMUMAB 3 MG/KG INTRAVENOUSLY OVER 30 MINUTES ON THE SAME DAY IN COMBINATION WITH IPILIMUMAB FOR 4 DOSES
240 MG EVERY 2 WEEKS (30-MINUTE INTRAVENOUS INFUSION) OR 480 MG EVERY 4 WEEKS (30-MINUTE INTRAVENOUS INFUSION) AFTER COMPLETING 4 DOSES OF COMBINATION THERAPY, ADMINISTER AS SINGLE AGENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY
DOSE MODIFICATIONS
RECOMMENDATIONS FOR OPDIVO MODIFICATIONS ARE PROVIDED IN TABLE 3. WHEN OPDIVO IS ADMINISTERED IN COMBINATION WITH IPILIMUMAB, IF OPDIVO IS WITHHELD, IPILIMUMAB SHOULD ALSO BE WITHHELD. REVIEW THE PRESCRIBING INFORMATION FOR IPILIMUMAB FOR RECOMMENDED DOSE MODIFICATIONS.
THERE ARE NO RECOMMENDED DOSE MODIFICATIONS FOR HYPOTHYROIDISM OR HYPERTHYROIDISM.
INTERRUPT OR SLOW THE RATE OF INFUSION IN PATIENTS WITH MILD OR MODERATE INFUSION-RELATED REACTIONS. DISCONTINUE OPDIVO IN PATIENTS WITH SEVERE OR LIFE-THREATENING INFUSION-RELATED REACTIONS.
TABLE 3: RECOMMENDED DOSE MODIFICATIONS FOR OPDIVO
ADVERSE REACTION SEVERITY* DOSE MODIFICATION
COLITIS GRADE 2 DIARRHEA OR COLITIS WITHHOLD DOSEA
GRADE 3 DIARRHEA OR COLITIS WITHHOLD DOSEA WHEN ADMINISTERED AS A SINGLE AGENT
PERMANENTLY DISCONTINUE WHEN ADMINISTERED WITH IPILIMUMAB
GRADE 4 DIARRHEA OR COLITIS PERMANENTLY DISCONTINUE
PNEUMONITIS GRADE 2 PNEUMONITIS WITHHOLD DOSEA
GRADE 3 OR 4 PNEUMONITIS PERMANENTLY DISCONTINUE
HEPATITIS/NON-HCCB ASPARTATE AMINOTRANSFERASE (AST) OR ALANINE AMINOTRANSFERASE (ALT) MORE THAN 3 AND UP TO 5 TIMES THE UPPER LIMIT OF NORMAL (ULN) OR TOTAL BILIRUBIN MORE THAN 1.5 AND UP TO 3 TIMES THE ULN WITHHOLD DOSEA
AST OR ALT MORE THAN 5 TIMES THE ULN OR TOTAL BILIRUBIN MORE THAN 3 TIMES THE ULN PERMANENTLY DISCONTINUE
HEPATITIS/HCCB · IF AST/ALT IS WITHIN NORMAL LIMITS AT BASELINE AND INCREASES TO MORE THAN 3 AND UP TO 5 TIMES THE ULN · IF AST/ALT IS MORE THAN 1 AND UP TO 3 TIMES ULN AT BASELINE AND INCREASES TO MORE THAN 5 AND UP TO 10 TIMES THE ULN · IF AST/ALT IS MORE THAN 3 AND UP TO 5 TIMES ULN AT BASELINE AND INCREASES TO MORE THAN 8 AND UP TO 10 TIMES THE ULN WITHHOLD DOSEC
IF AST OR ALT INCREASES TO MORE THAN 10 TIMES THE ULN OR TOTAL BILIRUBIN INCREASES TO MORE THAN 3 TIMES THE ULN PERMANENTLY DISCONTINUE
HYPOPHYSITIS GRADE 2 OR 3 HYPOPHYSITIS WITHHOLD DOSEA
GRADE 4 HYPOPHYSITIS PERMANENTLY DISCONTINUE
ADRENAL INSUFFICIENCY GRADE 2 ADRENAL INSUFFICIENCY WITHHOLD DOSEA
GRADE 3 OR 4 ADRENAL INSUFFICIENCY PERMANENTLY DISCONTINUE
TYPE 1 DIABETES MELLITUS GRADE 3 HYPERGLYCEMIA WITHHOLD DOSEA
GRADE 4 HYPERGLYCEMIA PERMANENTLY DISCONTINUE
NEPHRITIS AND RENAL DYSFUNCTION SERUM CREATININE MORE THAN 1.5 AND UP TO 6 TIMES THE ULN WITHHOLD DOSEA
SERUM CREATININE MORE THAN 6 TIMES THE ULN PERMANENTLY DISCONTINUE
SKIN GRADE 3 RASH OR SUSPECTED STEVENS-JOHNSON SYNDROME (SJS) OR TOXIC EPIDERMAL NECROLYSIS (TEN) WITHHOLD DOSEA
GRADE 4 RASH OR CONFIRMED SJS OR TEN PERMANENTLY DISCONTINUE
ENCEPHALITIS NEW-ONSET MODERATE OR SEVERE NEUROLOGIC SIGNS OR SYMPTOMS WITHHOLD DOSEA
IMMUNE-MEDIATED ENCEPHALITIS PERMANENTLY DISCONTINUE
OTHER OTHER GRADE 3 ADVERSE REACTION
FIRST OCCURRENCE WITHHOLD DOSEA
RECURRENCE OF SAME GRADE 3 ADVERSE REACTIONS PERMANENTLY DISCONTINUE
LIFE-THREATENING OR GRADE 4 ADVERSE REACTION PERMANENTLY DISCONTINUE
GRADE 3 MYOCARDITIS PERMANENTLY DISCONTINUE
REQUIREMENT FOR 10 MG PER DAY OR GREATER PREDNISONE OR EQUIVALENT FOR MORE THAN 12 WEEKS PERMANENTLY DISCONTINUE
PERSISTENT GRADE 2 OR 3 ADVERSE REACTIONS LASTING 12 WEEKS OR LONGER PERMANENTLY DISCONTINUE
* TOXICITY WAS GRADED PER NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS. VERSION 4.0 (NCI CTCAE V4). A RESUME TREATMENT WHEN ADVERSE REACTION IMPROVES TO GRADE 0 OR 1. B HCC: HEPATOCELLULAR CARCINOMA. C RESUME TREATMENT WHEN AST/ALT RETURNS TO BASELINE.
PREPARATION AND ADMINISTRATION
VISUALLY INSPECT FOR PARTICULATE MATTER AND DISCOLORATION. OPDIVO IS A CLEAR TO OPALESCENT, COLORLESS TO PALE-YELLOW SOLUTION. DISCARD IF CLOUDY, DISCOLORED, OR CONTAINS EXTRANEOUS PARTICULATE MATTER OTHER THAN A FEW TRANSLUCENT-TO-WHITE, PROTEINACEOUS PARTICLES. DO NOT SHAKE.
PREPARATION
· WITHDRAW THE REQUIRED VOLUME OF OPDIVO AND TRANSFER INTO AN INTRAVENOUS CONTAINER.
· DILUTE OPDIVO WITH EITHER 0.9% SODIUM CHLORIDE INJECTION, USP OR 5% DEXTROSE INJECTION, USP TO PREPARE AN INFUSION WITH A FINAL CONCENTRATION RANGING FROM 1 MG/ML TO 10 MG/ML. THE TOTAL VOLUME OF INFUSION MUST NOT EXCEED 160 ML.
o FOR ADULT AND PEDIATRIC PATIENTS WITH BODY WEIGHT ?40 KG, DO NOT EXCEED A TOTAL VOLUME OF INFUSION OF 160 ML.
o FOR ADULT AND PEDIATRIC PATIENTS WITH BODY WEIGHT <40 KG, DO NOT EXCEED A TOTAL VOLUME OF INFUSION OF 4 ML/KG OF BODY WEIGHT.
· MIX DILUTED SOLUTION BY GENTLE INVERSION. DO NOT SHAKE.
· DISCARD PARTIALLY USED VIALS OR EMPTY VIALS OF OPDIVO.
· THE PRODUCT DOES NOT CONTAIN A PRESERVATIVE.
· AFTER PREPARATION, STORE THE DILUTED SOLUTION EITHER:
o AT ROOM TEMPERATURE FOR NO MORE THAN 8 HOURS FROM THE TIME OF PREPARATION TO END OF THE INFUSION. DISCARD DILUTED SOLUTION IF NOT USED WITHIN 8 HOURS FROM THE TIME OF PREPARATION; OR
o UNDER REFRIGERATION AT 2°C TO 8°C (36°F TO 46°F) FOR NO MORE THAN 24 HOURS FROM THE TIME OF PREPARATION TO END OF INFUSION. DISCARD DILUTED SOLUTION IF NOT USED WITHIN 24 HOURS FROM THE TIME OF PREPARATION.
· DO NOT FREEZE.
ADMINISTRATION
· ADMINISTER THE INFUSION OVER 30 MINUTES THROUGH AN INTRAVENOUS LINE CONTAINING A STERILE, NON-PYROGENIC, LOW PROTEIN BINDING IN-LINE FILTER (PORE SIZE OF 0.2 MICROMETER TO 1.2 MICROMETER).
· ADMINISTER OPDIVO IN COMBINATION WITH OTHER THERAPEUTIC AGENTS AS FOLLOWS:
o WITH IPILIMUMAB: ADMINISTER OPDIVO FIRST FOLLOWED BY IPILIMUMAB ON THE SAME DAY.
o WITH PLATINUM-DOUBLET CHEMOTHERAPY: ADMINISTER OPDIVO FIRST FOLLOWED BY PLATINUM-DOUBLET CHEMOTHERAPY ON THE SAME DAY
o WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY: ADMINISTER OPDIVO FIRST FOLLOWED BY IPILIMUMAB AND THEN PLATINUM-DOUBLET CHEMOTHERAPY ON THE SAME DAY.
· USE SEPARATE INFUSION BAGS AND FILTERS FOR EACH INFUSION.
· FLUSH THE INTRAVENOUS LINE AT END OF INFUSION.
· DO NOT CO-ADMINISTER OTHER DRUGS THROUGH THE SAME INTRAVENOUS LINE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
INJECTION
40 MG/4 ML (10 MG/ML), 100 MG/10 ML (10 MG/ML), AND 240 MG/24 ML (10 MG/ML) CLEAR TO OPALESCENT, COLORLESS TO PALE-YELLOW SOLUTION IN A SINGLE-DOSE VIAL.
STORAGE AND HANDLING
OPDIVO® (NIVOLUMAB) INJECTION IS AVAILABLE AS FOLLOWS:
CARTON CONTENTS NDC
40 MG/4 ML SINGLE-DOSE VIAL 0003-3772-11
100 MG/10 ML SINGLE-DOSE VIAL 0003-3774-12
240 MG/24 ML SINGLE-DOSE VIAL 0003-3734-13
STORE UNDER REFRIGERATION AT 2°C TO 8°C (36°F TO 46°F). PROTECT FROM LIGHT BY STORING IN THE ORIGINAL PACKAGE UNTIL TIME OF USE. DO NOT FREEZE OR SHAKE.
MANUFACTURED BY: BRISTOL-MYERS SQUIBB COMPANY, PRINCETON, NJ 08543 USA. REVISED: MAY 2020
SIDE EFFECTS & DRUG INTERACTIONS
SIDE EFFECTS
THE FOLLOWING CLINICALLY SIGNIFICANT ADVERSE REACTIONS ARE DESCRIBED ELSEWHERE IN THE LABELING.
· IMMUNE-MEDIATED PNEUMONITIS [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED COLITIS [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED HEPATITIS [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED ENDOCRINOPATHIES [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED NEPHRITIS AND RENAL DYSFUNCTION [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED SKIN ADVERSE REACTIONS [SEE WARNINGS AND PRECAUTIONS]
· IMMUNE-MEDIATED ENCEPHALITIS [SEE WARNINGS AND PRECAUTIONS]
· OTHER IMMUNE-MEDIATED ADVERSE REACTIONS [SEE WARNINGS AND PRECAUTIONS]
· INFUSION-RELATED REACTIONS [SEE WARNINGS AND PRECAUTIONS]
· COMPLICATIONS OF ALLOGENEIC HSCT [SEE WARNINGS AND PRECAUTIONS]
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE DATA IN WARNINGS AND PRECAUTIONS REFLECT EXPOSURE TO OPDIVO AS A SINGLE AGENT IN 1994 PATIENTS ENROLLED IN CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 OR A SINGLE-ARM TRIAL IN NSCLC (N=117); OPDIVO 1 MG/KG WITH IPILIMUMAB 3 MG/KG IN PATIENTS ENROLLED IN CHECKMATE-067 (N=313), CHECKMATE-040 (N=49), OR ANOTHER RANDOMIZED TRIAL (N=94); OPDIVO 3 MG/KG ADMINISTERED WITH IPILIMUMAB 1 MG/KG (N=666) IN PATIENTS ENROLLED IN CHECKMATE-214 OR CHECKMATE-142; OPDIVO 3 MG/KG EVERY 2 WEEKS WITH IPILIMUMAB 1 MG/KG EVERY 6 WEEKS (N=576) IN PATIENTS ENROLLED IN CHECKMATE-227; AND OPDIVO 360 MG WITH IPILIMUMAB 1 MG/KG AND 2 CYCLES OF PLATINUM-DOUBLET CHEMOTHERAPY IN CHECKMATE-9LA (N=361).
UNRESECTABLE OR METASTATIC MELANOMA
PREVIOUSLY TREATED METASTATIC MELANOMA
THE SAFETY OF OPDIVO WAS EVALUATED IN CHECKMATE-037, A RANDOMIZED, OPEN-LABEL TRIAL IN 370 PATIENTS WITH UNRESECTABLE OR METASTATIC MELANOMA [SEE CLINICAL STUDIES]. PATIENTS HAD DOCUMENTED DISEASE PROGRESSION FOLLOWING TREATMENT WITH IPILIMUMAB AND, IF BRAF V600 MUTATION POSITIVE, A BRAF INHIBITOR. THE TRIAL EXCLUDED PATIENTS WITH AUTOIMMUNE DISEASE , PRIOR IPILIMUMAB-RELATED GRADE 4 ADVERSE REACTIONS (EXCEPT FOR ENDOCRINOPATHIES) OR GRADE 3 IPILIMUMAB-RELATED ADVERSE REACTIONS THAT HAD NOT RESOLVED OR WERE INADEQUATELY CONTROLLED WITHIN 12 WEEKS OF THE INITIATING EVENT, PATIENTS WITH A CONDITION REQUIRING CHRONIC SYSTEMIC TREATMENT WITH CORTICOSTEROIDS (>10 MG DAILY PREDNISONE EQUIVALENT) OR OTHER IMMUNOSUPPRESSIVE MEDICATIONS, A POSITIVE TEST FOR HEPATITIS B OR C, AND A HISTORY OF HIV . PATIENTS RECEIVED OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS (N=268) OR INVESTIGATOR'S CHOICE OF CHEMOTHERAPY (N=102): DACARBAZINE 1000 MG/M2 INTRAVENOUSLY EVERY 3 WEEKS OR CARBOPLATIN AUC 6 MG/ML/MIN AND PACLITAXEL 175 MG/M2 INTRAVENOUSLY EVERY 3 WEEKS. THE MEDIAN DURATION OF EXPOSURE WAS 5.3 MONTHS (RANGE: 1 DAY TO 13.8+ MONTHS) IN OPDIVO-TREATED PATIENTS AND WAS 2 MONTHS (RANGE: 1 DAY TO 9.6+ MONTHS) IN CHEMOTHERAPY-TREATED PATIENTS. IN THIS ONGOING TRIAL, 24% OF PATIENTS RECEIVED OPDIVO FOR >6 MONTHS AND 3% OF PATIENTS RECEIVED OPDIVO FOR >1 YEAR.
THE POPULATION CHARACTERISTICS IN THE OPDIVO GROUP AND THE CHEMOTHERAPY GROUP WERE SIMILAR: 66% MALE, MEDIAN AGE 59.5 YEARS, 98% WHITE, BASELINE EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG ) PERFORMANCE STATUS 0 (59%) OR 1 (41%), 74% WITH M1C STAGE DISEASE, 73% WITH CUTANEOUS MELANOMA, 11% WITH MUCOSAL MELANOMA, 73% RECEIVED TWO OR MORE PRIOR THERAPIES FOR ADVANCED OR METASTATIC DISEASE, AND 18% HAD BRAIN METASTASIS . THERE WERE MORE PATIENTS IN THE OPDIVO GROUP WITH ELEVATED LACTATE DEHYDROGENASE (LDH) AT BASELINE (51% VS. 38%).
SERIOUS ADVERSE REACTIONS OCCURRED IN 41% OF PATIENTS RECEIVING OPDIVO. OPDIVO WAS DISCONTINUED FOR ADVERSE REACTIONS IN 9% OF PATIENTS. TWENTY-SIX PERCENT OF PATIENTS RECEIVING OPDIVO HAD A DOSE INTERRUPTION FOR AN ADVERSE REACTION. GRADE 3 AND 4 ADVERSE REACTIONS OCCURRED IN 42% OF PATIENTS RECEIVING OPDIVO. THE MOST FREQUENT GRADE 3 AND 4 ADVERSE REACTIONS REPORTED IN 2% TO <5% OF PATIENTS RECEIVING OPDIVO WERE ABDOMINAL PAIN, HYPONATREMIA , INCREASED ASPARTATE AMINOTRANSFERASE , AND INCREASED LIPASE. THE MOST COMMON ADVERSE REACTION (REPORTED IN ?20% OF PATIENTS) WAS RASH.
TOXICITY WAS GRADED PER NCI CTCAE V4. A INCLUDES MACULOPAPULAR RASH, ERYTHEMATOUS RASH, PRURITIC RASH, FOLLICULAR RASH, MACULAR RASH, PAPULAR RASH, PUSTULAR RASH, VESICULAR RASH, AND ACNEIFORM DERMATITIS. B INCLUDES RHINITIS, PHARYNGITIS, AND NASOPHARYNGITIS.
CLINICALLY IMPORTANT ADVERSE REACTIONS IN <10% OF PATIENTS WHO RECEIVED OPDIVO WERE:
CARDIAC DISORDERS: VENTRICULAR ARRHYTHMIA
EYE DISORDERS: IRIDOCYCLITIS
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: INFUSION-RELATED REACTIONS
INVESTIGATIONS: INCREASED AMYLASE, INCREASED LIPASE
NERVOUS SYSTEM DISORDERS: DIZZINESS, PERIPHERAL AND SENSORY NEUROPATHY,
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: EXFOLIATIVE DERMATITIS, ERYTHEMA MULTIFORME, VITILIGO, PSORIASIS
PREVIOUSLY UNTREATED METASTATIC MELANOMA
CHECKMATE-066
THE SAFETY OF OPDIVO WAS ALSO EVALUATED IN CHECKMATE-066, A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED TRIAL IN 411 PREVIOUSLY UNTREATED PATIENTS WITH BRAF V600 WILD-TYPE UNRESECTABLE OR METASTATIC MELANOMA [SEE CLINICAL STUDIES]. THE TRIAL EXCLUDED PATIENTS WITH AUTOIMMUNE DISEASE AND PATIENTS REQUIRING CHRONIC SYSTEMIC TREATMENT WITH CORTICOSTEROIDS (>10 MG DAILY PREDNISONE EQUIVALENT) OR OTHER IMMUNOSUPPRESSIVE MEDICATIONS. PATIENTS RECEIVED OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS (N=206) OR DACARBAZINE 1000 MG/M2 INTRAVENOUSLY EVERY 3 WEEKS (N=205). THE MEDIAN DURATION OF EXPOSURE WAS 6.5 MONTHS (RANGE: 1 DAY TO 16.6 MONTHS) IN OPDIVO-TREATED PATIENTS. IN THIS TRIAL, 47% OF PATIENTS RECEIVED OPDIVO FOR >6 MONTHS AND 12% OF PATIENTS RECEIVED OPDIVO FOR >1 YEAR.
THE TRIAL POPULATION CHARACTERISTICS IN THE OPDIVO GROUP AND DACARBAZINE GROUP: 59% MALE, MEDIAN AGE 65 YEARS, 99.5% WHITE, 61% WITH M1C STAGE DISEASE, 74% WITH CUTANEOUS MELANOMA, 11% WITH MUCOSAL MELANOMA, 4% WITH BRAIN METASTASIS, AND 37% WITH ELEVATED LDH AT BASELINE. THERE WERE MORE PATIENTS IN THE OPDIVO GROUP WITH ECOG PERFORMANCE STATUS 0 (71% VS. 59%).
SERIOUS ADVERSE REACTIONS OCCURRED IN 36% OF PATIENTS RECEIVING OPDIVO. ADVERSE REACTIONS LED TO PERMANENT DISCONTINUATION OF OPDIVO IN 7% OF PATIENTS AND DOSE INTERRUPTION IN 26% OF PATIENTS; NO SINGLE TYPE OF ADVERSE REACTION ACCOUNTED FOR THE MAJORITY OF OPDIVO DISCONTINUATIONS. GRADE 3 AND 4 ADVERSE REACTIONS OCCURRED IN 41% OF PATIENTS RECEIVING OPDIVO.
THE MOST FREQUENT GRADE 3 AND 4 ADVERSE REACTIONS REPORTED IN ?2% OF PATIENTS RECEIVING OPDIVO WERE INCREASED GAMMA-GLUTAMYLTRANSFERASE (3.9%) AND DIARRHEA (3.4%). THE MOST COMMON ADVERSE REACTIONS (REPORTED IN ?20% OF PATIENTS AND AT A HIGHER INCIDENCE THAN IN THE DACARBAZINE ARM) WERE FATIGUE, MUSCULOSKELETAL PAIN, RASH, AND PRURITUS .
TOXICITY WAS GRADED PER NCI CTCAE V4. A INCLUDES PERIORBITAL EDEMA, FACE EDEMA, GENERALIZED EDEMA, GRAVITATIONAL EDEMA, LOCALIZED EDEMA, PERIPHERAL EDEMA, PULMONARY EDEMA, AND LYMPHEDEMA. B INCLUDES BACK PAIN, BONE PAIN, MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL DISCOMFORT, MYALGIA, NECK PAIN, PAIN IN EXTREMITY, PAIN IN JAW, AND SPINAL PAIN. C INCLUDES MACULOPAPULAR RASH, ERYTHEMATOUS RASH, PRURITIC RASH, FOLLICULAR RASH, MACULAR RASH, PAPULAR RASH, PUSTULAR RASH, VESICULAR RASH, DERMATITIS, ALLERGIC DERMATITIS, EXFOLIATIVE DERMATITIS, ACNEIFORM DERMATITIS, DRUG ERUPTION, AND SKIN REACTION. D INCLUDES RHINITIS, VIRAL RHINITIS, PHARYNGITIS, AND NASOPHARYNGITIS.
CLINICALLY IMPORTANT ADVERSE REACTIONS IN <10% OF PATIENTS WHO RECEIVED OPDIVO WERE:
NERVOUS SYSTEM DISORDERS: PERIPHERAL NEUROPATHY
CHECKMATE-067
THE SAFETY OF OPDIVO, ADMINISTERED WITH IPILIMUMAB OR AS A SINGLE AGENT, WAS EVALUATED IN CHECKMATE-067, A RANDOMIZED (1:1:1), DOUBLE-BLIND TRIAL IN 937 PATIENTS WITH PREVIOUSLY UNTREATED, UNRESECTABLE OR METASTATIC MELANOMA [SEE CLINICAL STUDIES]. THE TRIAL EXCLUDED PATIENTS WITH AUTOIMMUNE DISEASE, A MEDICAL CONDITION REQUIRING SYSTEMIC TREATMENT WITH CORTICOSTEROIDS (MORE THAN 10 MG DAILY PREDNISONE EQUIVALENT) OR OTHER IMMUNOSUPPRESSIVE MEDICATION WITHIN 14 DAYS OF THE START OF STUDY THERAPY, A POSITIVE TEST RESULT FOR HEPATITIS B OR C, OR A HISTORY OF HIV.
PATIENTS WERE RANDOMIZED TO RECEIVE:
· OPDIVO 1 MG/KG OVER 60 MINUTES WITH IPILIMUMAB 3 MG/KG BY INTRAVENOUS INFUSION EVERY 3 WEEKS FOR 4 DOSES FOLLOWED BY OPDIVO AS A SINGLE AGENT AT A DOSE OF 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS (OPDIVO AND IPILIMUMAB ARM; N=313), OR
· OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS (OPDIVO ARM; N=313), OR
· IPILIMUMAB 3 MG/KG BY INTRAVENOUS INFUSION EVERY 3 WEEKS FOR UP TO 4 DOSES (IPILIMUMAB ARM; N=311).
· THE MEDIAN DURATION OF EXPOSURE TO OPDIVO WAS 2.8 MONTHS (RANGE: 1 DAY TO 36.4 MONTHS) FOR THE OPDIVO AND IPILIMUMAB ARM AND 6.6 MONTHS (RANGE: 1 DAY TO 36.0 MONTHS) FOR THE OPDIVO ARM. IN THE OPDIVO AND IPILIMUMAB ARM, 39% WERE EXPOSED TO OPDIVO FOR ?6 MONTHS AND 30% EXPOSED FOR >1 YEAR. IN THE OPDIVO ARM, 53% WERE EXPOSED FOR ?6 MONTHS AND 40% FOR >1 YEAR.
THE POPULATION CHARACTERISTICS WERE: 65% MALE, MEDIAN AGE 61 YEARS, 97% WHITE, BASELINE ECOG PERFORMANCE STATUS 0 (73%) OR 1 (27%), 93% WITH AMERICAN JOINT COMMITTEE ON CANCER (AJCC) STAGE IV DISEASE, 58% WITH M1C STAGE DISEASE; 36% WITH ELEVATED LDH AT BASELINE, 4% WITH A HISTORY OF BRAIN METASTASIS, AND 22% HAD RECEIVED ADJUVANT THERAPY .
SERIOUS ADVERSE REACTIONS (74% AND 44%), ADVERSE REACTIONS LEADING TO PERMANENT DISCONTINUATION (47% AND 18%) OR TO DOSING DELAYS (58% AND 36%), AND GRADE 3 OR 4 ADVERSE REACTIONS (72% AND 51%) ALL OCCURRED MORE FREQUENTLY IN THE OPDIVO AND IPILIMUMAB ARM RELATIVE TO THE OPDIVO ARM.
THE MOST FREQUENT (?10%) SERIOUS ADVERSE REACTIONS IN THE OPDIVO AND IPILIMUMAB ARM AND THE OPDIVO ARM, RESPECTIVELY, WERE DIARRHEA (13% AND 2.2%), COLITIS (10% AND 1.9%), AND PYREXIA (10% AND 1.0%). THE MOST FREQUENT ADVERSE REACTIONS LEADING TO DISCONTINUATION OF BOTH DRUGS IN THE OPDIVO AND IPILIMUMAB ARM AND OF OPDIVO IN THE OPDIVO ARM, RESPECTIVELY, WERE COLITIS (10% AND 0.6%), DIARRHEA (8% AND 2.2%), INCREASED ALT (4.8% AND 1.0%), INCREASED AST (4.5% AND 0.6%), AND PNEUMONITIS (1.9% AND 0.3%).
THE MOST COMMON (?20%) ADVERSE REACTIONS IN THE OPDIVO AND IPILIMUMAB ARM WERE FATIGUE, DIARRHEA, RASH, NAUSEA, PYREXIA, PRURITUS, MUSCULOSKELETAL PAIN, VOMITING, DECREASED APPETITE, COUGH, HEADACHE, DYSPNEA , UPPER RESPIRATORY TRACT INFECTION, ARTHRALGIA , AND INCREASED TRANSAMINASES. THE MOST COMMON (?20%) ADVERSE REACTIONS IN THE OPDIVO ARM WERE FATIGUE, RASH, MUSCULOSKELETAL PAIN, DIARRHEA, NAUSEA, COUGH, PRURITUS, UPPER RESPIRATORY TRACT INFECTION, DECREASED APPETITE, HEADACHE, CONSTIPATION, ARTHRALGIA, AND VOMITING.
TOXICITY WAS GRADED PER NCI CTCAE V4. A INCLUDES ASTHENIA AND FATIGUE. B INCLUDES PUSTULAR RASH, DERMATITIS, ACNEIFORM DERMATITIS, ALLERGIC DERMATITIS, ATOPIC DERMATITIS, BULLOUS DERMATITIS, EXFOLIATIVE DERMATITIS, PSORIASIFORM DERMATITIS, DRUG ERUPTION, EXFOLIATIVE RASH, ERYTHEMATOUS RASH, GENERALIZED RASH, MACULAR RASH, MACULOPAPULAR RASH, MORBILLIFORM RASH, PAPULAR RASH, PAPULOSQUAMOUS RASH, AND PRURITIC RASH. C INCLUDES BACK PAIN, BONE PAIN, MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL DISCOMFORT, MYALGIA, NECK PAIN, PAIN IN EXTREMITY, AND SPINAL PAIN. D INCLUDES UPPER RESPIRATORY TRACT INFECTION, NASOPHARYNGITIS, PHARYNGITIS, AND RHINITIS. E INCLUDES HYPERTENSION AND BLOOD PRESSURE INCREASED.
CLINICALLY IMPORTANT ADVERSE REACTIONS IN <10% OF PATIENTS WHO RECEIVED OPDIVO WITH IPILIMUMAB OR OPDIVO AS A SINGLE AGENT WERE:
GASTROINTESTINAL DISORDERS: STOMATITIS, INTESTINAL PERFORATION
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: VITILIGO
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: MYOPATHY, SJOGREN'S SYNDROME,SPONDYLOARTHROPATHY, MYOSITIS (INCLUDING POLYMYOSITIS)
NERVOUS SYSTEM DISORDERS: NEURITIS, PERONEAL NERVE PALSY
ADJUVANT TREATMENT OF MELANOMA
THE SAFETY OF OPDIVO AS A SINGLE AGENT WAS EVALUATED IN CHECKMATE-238, A RANDOMIZED (1:1), DOUBLE-BLIND TRIAL IN 905 PATIENTS WITH COMPLETELY RESECTED STAGE IIIB/C OR STAGE IV MELANOMA RECEIVED OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS (N=452) OR IPILIMUMAB 10 MG/KG BY INTRAVENOUS INFUSION EVERY 3 WEEKS FOR 4 DOSES THEN EVERY 12 WEEKS BEGINNING AT WEEK 24 FOR UP TO 1 YEAR (N=453) [SEE CLINICAL STUDIES]. THE MEDIAN DURATION OF EXPOSURE WAS 11.5 MONTHS IN OPDIVO-TREATED PATIENTS AND WAS 2.7 MONTHS IN IPILIMUMABTREATED PATIENTS. IN THIS ONGOING TRIAL, 74% OF PATIENTS RECEIVED OPDIVO FOR >6 MONTHS.
SERIOUS ADVERSE REACTIONS OCCURRED IN 18% OF OPDIVO-TREATED PATIENTS. STUDY THERAPY WAS DISCONTINUED FOR ADVERSE REACTIONS IN 9% OF OPDIVO-TREATED PATIENTS AND 42% OF IPILIMUMABTREATED PATIENTS. TWENTY-EIGHT PERCENT OF OPDIVO-TREATED PATIENTS HAD AT LEAST ONE OMITTED DOSE FOR AN ADVERSE REACTION. GRADE 3 OR 4 ADVERSE REACTIONS OCCURRED IN 25% OF OPDIVO-TREATED PATIENTS.
THE MOST FREQUENT GRADE 3 AND 4 ADVERSE REACTIONS REPORTED IN ?2% OF OPDIVO-TREATED PATIENTS WERE DIARRHEA AND INCREASED LIPASE AND AMYLASE . THE MOST COMMON ADVERSE REACTIONS (AT LEAST 20%) WERE FATIGUE, DIARRHEA, RASH, MUSCULOSKELETAL PAIN, PRURITUS, HEADACHE, NAUSEA, UPPER RESPIRATORY INFECTION , AND ABDOMINAL PAIN. THE MOST COMMON IMMUNE-MEDIATED ADVERSE REACTIONS WERE RASH (16%), DIARRHEA/COLITIS (6%), AND HEPATITIS (3%).
METASTATIC NON-SMALL CELL LUNG CANCER
FIRST-LINE TREATMENT OF METASTATIC NSCLC: IN COMBINATION WITH IPILIMUMAB
THE SAFETY OF OPDIVO IN COMBINATION WITH IPILIMUMAB WAS EVALUATED IN CHECKMATE-227, A RANDOMIZED, MULTICENTER, MULTI-COHORT, OPEN-LABEL TRIAL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC OR RECURRENT NSCLC WITH NO EGFR OR ALK GENOMIC TUMOR ABERRATIONS [SEE CLINICAL STUDIES]. THE TRIAL EXCLUDED PATIENTS WITH UNTREATED BRAIN METASTASES, CARCINOMATOUS MENINGITIS , ACTIVE AUTOIMMUNE DISEASE, OR MEDICAL CONDITIONS REQUIRING SYSTEMIC IMMUNOSUPPRESSION . PATIENTS RECEIVED OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 30 MINUTES EVERY 2 WEEKS AND IPILIMUMAB 1 MG/KG BY INTRAVENOUS INFUSION OVER 30 MINUTES EVERY 6 WEEKS OR PLATINUM-DOUBLET CHEMOTHERAPY EVERY 3 WEEKS FOR 4 CYCLES. THE MEDIAN DURATION OF THERAPY IN OPDIVO AND IPILIMUMAB-TREATED PATIENTS WAS 4.2 MONTHS (RANGE: 1 DAY TO 25.5 MONTHS): 39% OF PATIENTS RECEIVED OPDIVO AND IPILIMUMAB FOR >6 MONTHS AND 23% OF PATIENTS RECEIVED OPDIVO AND IPILIMUMAB FOR >1 YEAR. THE POPULATION CHARACTERISTICS WERE: MEDIAN AGE 64 YEARS (RANGE: 26 TO 87); 48% WERE ?65 YEARS OF AGE, 76% WHITE, AND 67% MALE. BASELINE ECOG PERFORMANCE STATUS WAS 0 (35%) OR 1 (65%), 85% WERE FORMER/CURRENT SMOKERS, 11% HAD BRAIN METASTASES, 28% HAD SQUAMOUS HISTOLOGY AND 72% HAD NON-SQUAMOUS HISTOLOGY.
SERIOUS ADVERSE REACTIONS OCCURRED IN 58% OF PATIENTS. OPDIVO AND IPILIMUMAB WERE DISCONTINUED FOR ADVERSE REACTIONS IN 24% OF PATIENTS AND 53% HAD AT LEAST ONE DOSE WITHHELD FOR AN ADVERSE REACTION.
THE MOST FREQUENT (?2%) SERIOUS ADVERSE REACTIONS WERE PNEUMONIA , DIARRHEA/COLITIS, PNEUMONITIS, HEPATITIS, PULMONARY EMBOLISM , ADRENAL INSUFFICIENCY, AND HYPOPHYSITIS. FATAL ADVERSE REACTIONS OCCURRED IN 1.7% OF PATIENTS; THESE INCLUDED EVENTS OF PNEUMONITIS (4 PATIENTS), MYOCARDITIS , ACUTE KIDNEY INJURY, SHOCK , HYPERGLYCEMIA , MULTI-SYSTEM ORGAN FAILURE , AND RENAL FAILURE. THE MOST COMMON (?20%) ADVERSE REACTIONS WERE FATIGUE, RASH, DECREASED APPETITE, MUSCULOSKELETAL PAIN, DIARRHEA/COLITIS, DYSPNEA, COUGH, HEPATITIS, NAUSEA, AND PRURITUS.
TABLES 12 AND 13 SUMMARIZE SELECTED ADVERSE REACTIONS AND LABORATORY ABNORMALITIES, RESPECTIVELY, IN CHECKMATE-227.
TABLE 12: ADVERSE REACTIONS IN ?10% OF PATIENTS RECEIVING OPDIVO AND IPILIMUMAB CHECKMATE-227
ADVERSE REACTION OPDIVO AND IPILIMUMAB (N=576) PLATINUM-DOUBLET CHEMOTHERAPY (N=570)
ALL GRADES (%) GRADES 3-4 (%) ALL GRADES (%) GRADES 3-4 (%)
GENERAL
FATIGUEA 44 6 42 4.4
PYREXIA 18 0.5 11 0.4
EDEMAB 14 0.2 12 0.5
SKIN AND SUBCUTANEOUS TISSUE
RASHC 34 4.7 10 0.4
PRURITUSD 21 0.5 3.3 0
METABOLISM AND NUTRITION
DECREASED APPETITE 31 2.3 26 1.4
MUSCULOSKELETAL AND CONNECTIVE TISSUE
MUSCULOSKELETAL PAINE 27 1.9 16 0.7
ARTHRALGIA 13 0.9 2.5 0.2
GASTROINTESTINAL
DIARRHEA/COLITISF 26 3.6 16 0.9
NAUSEA 21 1.0 42 2.5
CONSTIPATION 18 0.3 27 0.5
VOMITING 13 1.0 18 2.3
ABDOMINAL PAING 10 0.2 9 0.7
RESPIRATORY, THORACIC, AND MEDIASTINAL
DYSPNEAH 26 4.3 16 2.1
COUGHI 23 0.2 13 0
HEPATOBILIARY
HEPATITISJ 21 9 10 1.2
ENDOCRINE
HYPOTHYROIDISMK 16 0.5 1.2 0
HYPERTHYROIDISML 10 0 0.5 0
INFECTIONS AND INFESTATIONS
PNEUMONIAM 13 7 8 4.0
NERVOUS SYSTEM
HEADACHE 11 0.5 6 0
A INCLUDES FATIGUE AND ASTHENIA .
B INCLUDES EYELID EDEMA, FACE EDEMA, GENERALIZED EDEMA, LOCALIZED EDEMA, EDEMA, EDEMA PERIPHERAL, AND PERIORBITAL EDEMA.
C INCLUDES AUTOIMMUNE DERMATITIS, DERMATITIS, DERMATITIS ACNEIFORM, DERMATITIS ALLERGIC, DERMATITIS ATOPIC, DERMATITIS BULLOUS, DERMATITIS CONTACT, DERMATITIS EXFOLIATIVE, DERMATITIS PSORIASIFORM, GRANULOMATOUS DERMATITIS, RASH GENERALIZED, DRUG ERUPTION, DYSHIDROTIC ECZEMA, ECZEMA, EXFOLIATIVE RASH, NODULAR RASH, RASH, RASH ERYTHEMATOUS, RASH GENERALIZED, RASH MACULAR, RASH MACULO-PAPULAR, RASH PAPULAR, RASH PRURITIC, RASH PUSTULAR, TOXIC SKIN ERUPTION.
D INCLUDES PRURITUS AND PRURITUS GENERALIZED.
E INCLUDES BACK PAIN, BONE PAIN, MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL DISCOMFORT, MUSCULOSKELETAL PAIN, MYALGIA, AND PAIN IN EXTREMITY.
F INCLUDES COLITIS, COLITIS MICROSCOPIC, COLITIS ULCERATIVE, DIARRHEA, ENTERITIS INFECTIOUS, ENTEROCOLITIS, ENTEROCOLITIS INFECTIOUS, AND ENTEROCOLITIS VIRAL.
G INCLUDES ABDOMINAL DISCOMFORT, ABDOMINAL PAIN, ABDOMINAL PAIN LOWER, ABDOMINAL PAIN UPPER, AND ABDOMINAL TENDERNESS.
H INCLUDES DYSPNEA AND DYSPNEA EXERTIONAL.
I INCLUDES COUGH AND PRODUCTIVE COUGH.
J INCLUDES ALANINE AMINOTRANSFERASE INCREASED, ASPARTATE AMINOTRANSFERASE INCREASED, AUTOIMMUNE HEPATITIS, BLOOD BILIRUBIN INCREASED, HEPATIC ENZYME INCREASED, HEPATIC FAILURE, HEPATIC FUNCTION ABNORMAL, HEPATITIS, HEPATITIS E, HEPATOCELLULAR INJURY, HEPATOTOXICITY, HYPERBILIRUBINEMIA, IMMUNE-MEDIATED HEPATITIS, LIVER FUNCTION TEST ABNORMAL, LIVER FUNCTION TEST INCREASED, TRANSAMINASES INCREASED.
K INCLUDES AUTOIMMUNE THYROIDITIS, BLOOD THYROID STIMULATING HORMONE INCREASED, HYPOTHYROIDISM, PRIMARY HYPOTHYROIDISM, THYROIDITIS, AND TRI-IODOTHYRONINE FREE DECREASED.
L CONTAINS BLOOD THYROID STIMULATING HORMONE DECREASED, HYPERTHYROIDISM, AND TRI-IODOTHYRONINE FREE INCREASED.
M INCLUDES LOWER RESPIRATORY TRACT INFECTION, LOWER RESPIRATORY TRACT INFECTION BACTERIAL, LUNG INFECTION, PNEUMONIA, PNEUMONIA ADENOVIRAL, PNEUMONIA ASPIRATION, PNEUMONIA BACTERIAL, PNEUMONIA KLEBSIELLA, PNEUMONIA INFLUENZAL, PNEUMONIA VIRAL, ATYPICAL PNEUMONIA, ORGANIZING PNEUMONIA.
OTHER CLINICALLY IMPORTANT ADVERSE REACTIONS IN CHECKMATE-227 WERE:
SKIN AND SUBCUTANEOUS TISSUE: URTICARIA , ALOPECIA , ERYTHEMA MULTIFORME , VITILIGO
GASTROINTESTINAL: STOMATITIS, PANCREATITIS , GASTRITIS
MUSCULOSKELETAL AND CONNECTIVE TISSUE: ARTHRITIS , POLYMYALGIA RHEUMATICA , RHABDOMYOLYSIS
NERVOUS SYSTEM: PERIPHERAL NEUROPATHY , AUTOIMMUNE ENCEPHALITIS
BLOOD AND LYMPHATIC SYSTEM: EOSINOPHILIA
EYE DISORDERS: BLURRED VISION, UVEITIS
CARDIAC: ATRIAL FIBRILLATION , MYOCARDITIS
TABLE 13: LABORATORY VALUES WORSENING FROM BASELINEA OCCURRING IN ?20% OF PATIENTS ON OPDIVO AND IPILIMUMAB -CHECKMATE-227
LABORATORY ABNORMALITY OPDIVO AND IPILIMUMAB PLATINUM-DOUBLET CHEMOTHERAPY
GRADES 1-4 (%) GRADES 3-4 (%) GRADES 1-4 (%) GRADES 3-4 (%)
HEMATOLOGY
ANEMIA 46 3.6 78 14
LYMPHOPENIA 46 5 60 15
CHEMISTRY
HYPONATREMIA 41 12 26 4.9
INCREASED AST 39 5 26 0.4
INCREASED ALT 36 7 27 0.7
INCREASED LIPASE 35 14 14 3.4
INCREASED ALKALINE PHOSPHATASE 34 3.8 20 0.2
INCREASED AMYLASE 28 9 18 1.9
HYPOCALCEMIA 28 1.7 17 1.3
HYPERKALEMIA 27 3.4 22 0.4
INCREASED CREATININE 22 0.9 17 0.2
A EACH TEST INCIDENCE IS BASED ON THE NUMBER OF PATIENTS WHO HAD BOTH BASELINE AND AT LEAST ONE ON-STUDY LABORATORY MEASUREMENT AVAILABLE: OPDIVO AND IPILIMUMAB GROUP (RANGE: 494 TO 556 PATIENTS) AND CHEMOTHERAPY GROUP (RANGE: 469 TO 542 PATIENTS).
FIRST-LINE TREATMENT OF METASTATIC OR RECURRENT NSCLC: IN COMBINATION WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY
THE SAFETY OF OPDIVO IN COMBINATION WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY WAS EVALUATED IN CHECKMATE-9LA [SEE CLINICAL STUDIES]. PATIENTS RECEIVED EITHER OPDIVO 360 MG ADMINISTERED EVERY 3 WEEKS IN COMBINATION WITH IPILIMUMAB 1 MG/KG ADMINISTERED EVERY 6 WEEKS AND PLATINUM-DOUBLET CHEMOTHERAPY ADMINISTERED EVERY 3 WEEKS FOR 2 CYCLES; OR PLATINUM-DOUBLET CHEMOTHERAPY ADMINISTERED EVERY 3 WEEKS FOR 4 CYCLES. THE MEDIAN DURATION OF THERAPY IN OPDIVO IN COMBINATION WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY WAS 6 MONTHS (RANGE: 1 DAY TO 19 MONTHS): 50% OF PATIENTS RECEIVED OPDIVO AND IPILIMUMAB FOR >6 MONTHS AND 13% OF PATIENTS RECEIVED OPDIVO AND IPILIMUMAB FOR >1 YEAR.
SERIOUS ADVERSE REACTIONS OCCURRED IN 57% OF PATIENTS WHO WERE TREATED WITH OPDIVO IN COMBINATION WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY. THE MOST FREQUENT (>2%) SERIOUS ADVERSE REACTIONS WERE PNEUMONIA, DIARRHEA, FEBRILE NEUTROPENIA , ANEMIA , ACUTE KIDNEY INJURY, MUSCULOSKELETAL PAIN, DYSPNEA, PNEUMONITIS, AND RESPIRATORY FAILURE . FATAL ADVERSE REACTIONS OCCURRED IN 7 (2%) PATIENTS, AND INCLUDED HEPATIC TOXICITY, ACUTE RENAL FAILURE , SEPSIS , PNEUMONITIS, DIARRHEA WITH HYPOKALEMIA , AND MASSIVE HEMOPTYSIS IN THE SETTING OF THROMBOCYTOPENIA .
STUDY THERAPY WITH OPDIVO IN COMBINATION WITH IPILIMUMAB AND PLATINUM-DOUBLET CHEMOTHERAPY WAS PERMANENTLY DISCONTINUED FOR ADVERSE REACTIONS IN 24% OF PATIENTS AND 56% HAD AT LEAST ONE TREATMENT WITHHELD FOR AN ADVERSE REACTION. THE MOST COMMON (>20%) ADVERSE REACTIONS WERE FATIGUE, MUSCULOSKELETAL PAIN, NAUSEA, DIARRHEA, RASH, DECREASED APPETITE, CONSTIPATION, AND PRURITUS.
TABLES 14 AND 15 SUMMARIZE SELECTED ADVERSE REACTIONS AND LABORATORY ABNORMALITIES, RESPECTIVELY, IN CHECKMATE-9LA.
SECOND-LINE TREATMENT OF METASTATIC NSCLC
THE SAFETY OF OPDIVO WAS EVALUATED IN CHECKMATE-017, A RANDOMIZED OPEN-LABEL, MULTICENTER TRIAL IN PATIENTS WITH METASTATIC SQUAMOUS NSCLC AND PROGRESSION ON OR AFTER ONE PRIOR PLATINUM DOUBLET-BASED CHEMOTHERAPY REGIMEN AND IN CHECKMATE-057, A RANDOMIZED, OPEN-LABEL, MULTICENTER TRIAL IN PATIENTS WITH METASTATIC NON-SQUAMOUS NSCLC AND PROGRESSION ON OR AFTER ONE PRIOR PLATINUM DOUBLET-BASED CHEMOTHERAPY REGIMEN [SEE CLINICAL STUDIES]. THESE TRIALS EXCLUDED PATIENTS WITH ACTIVE AUTOIMMUNE DISEASE, MEDICAL CONDITIONS REQUIRING SYSTEMIC IMMUNOSUPPRESSION, OR WITH SYMPTOMATIC INTERSTITIAL LUNG DISEASE. PATIENTS RECEIVED OPDIVO 3 MG/KG OVER 60 MINUTES BY INTRAVENOUS INFUSION EVERY 2 WEEKS OR DOCETAXEL 75 MG/M2 INTRAVENOUSLY EVERY 3 WEEKS. THE MEDIAN DURATION OF THERAPY IN OPDIVO-TREATED PATIENTS IN CHECKMATE-017 WAS 3.3 MONTHS (RANGE: 1 DAY TO 21.7+ MONTHS) AND IN CHECKMATE-057 WAS 2.6 MONTHS (RANGE: 0 TO 24.0+ MONTHS). IN CHECKMATE-017, 36% OF PATIENTS RECEIVED OPDIVO FOR AT LEAST 6 MONTHS AND 18% OF PATIENTS RECEIVED OPDIVO FOR AT LEAST 1 YEAR AND IN CHECKMATE-057, 30% OF PATIENTS RECEIVED OPDIVO FOR >6 MONTHS AND 20% OF PATIENTS RECEIVED OPDIVO FOR >1 YEAR.
ACROSS BOTH TRIALS, THE MEDIAN AGE OF OPDIVO-TREATED PATIENTS WAS 61 YEARS (RANGE: 37 TO 85); 38% WERE ?65 YEARS OF AGE, 61% WERE MALE, AND 91% WERE WHITE. TEN PERCENT OF PATIENTS HAD BRAIN METASTASES AND ECOG PERFORMANCE STATUS WAS 0 (26%) OR 1 (74%).
IN CHECKMATE-057, IN THE OPDIVO ARM, SEVEN DEATHS WERE DUE TO INFECTION INCLUDING ONE CASE OF PNEUMOCYSTIS JIROVECII PNEUMONIA, FOUR WERE DUE TO PULMONARY EMBOLISM , AND ONE DEATH WAS DUE TO LIMBIC ENCEPHALITIS. SERIOUS ADVERSE REACTIONS OCCURRED IN 46% OF PATIENTS RECEIVING OPDIVO. OPDIVO WAS DISCONTINUED IN 11% OF PATIENTS AND WAS DELAYED IN 28% OF PATIENTS FOR AN ADVERSE REACTION.
THE MOST FREQUENT SERIOUS ADVERSE REACTIONS REPORTED IN ?2% OF PATIENTS RECEIVING OPDIVO WERE PNEUMONIA, PULMONARY EMBOLISM, DYSPNEA, PYREXIA, PLEURAL EFFUSION , PNEUMONITIS, AND RESPIRATORY FAILURE. ACROSS BOTH TRIALS, THE MOST COMMON ADVERSE REACTIONS (?20%) WERE FATIGUE, MUSCULOSKELETAL PAIN, COUGH, DYSPNEA, AND DECREASED APPETITE.
TABLES 16 AND 17 SUMMARIZE SELECTED ADVERSE REACTIONS AND LABORATORY ABNORMALITIES, RESPECTIVELY, IN CHECKMATE-057.
OTHER CLINICALLY IMPORTANT ADVERSE REACTIONS OBSERVED IN OPDIVO-TREATED PATIENTS AND WHICH OCCURRED AT A SIMILAR INCIDENCE IN DOCETAXEL-TREATED PATIENTS AND NOT LISTED ELSEWHERE IN SECTION 6 INCLUDE: FATIGUE/ASTHENIA (48% ALL GRADES, 5% GRADE 3-4), MUSCULOSKELETAL PAIN (33% ALL GRADES), PLEURAL EFFUSION (4.5% ALL GRADES), PULMONARY EMBOLISM (3.3% ALL GRADES).
SMALL CELL LUNG CANCER
THE SAFETY OF OPDIVO WAS EVALUATED IN CHECKMATE-032, A MULTICENTER, MULTI-COHORT, OPEN-LABEL, ONGOING TRIAL THAT ENROLLED 245 PATIENTS WITH SCLC WITH DISEASE PROGRESSION AFTER PLATINUM-BASED CHEMOTHERAPY [SEE CLINICAL STUDIES]. THE TRIAL EXCLUDED PATIENTS WITH ACTIVE AUTOIMMUNE DISEASE, MEDICAL CONDITIONS REQUIRING SYSTEMIC IMMUNOSUPPRESSION, OR WITH SYMPTOMATIC INTERSTITIAL LUNG DISEASE. PATIENTS RECEIVED OPDIVO 3 MG/KG BY INTRAVENOUS INFUSION OVER 60 MINUTES EVERY 2 WEEKS. THE MEDIAN DURATION OF THERAPY IN OPDIVO-TREATED PATIENTS WAS 1 MONTH (RANGE: 0 TO 44.2+ MONTHS): 17% OF PATIENTS RECEIVED OPDIVO FOR >6 MONTHS AND 9% OF PATIENTS RECEIVED OPDIVO FOR >1 YEAR.
THE POPULATION CHARACTERISTICS WERE: MEDIAN AGE 63 YEARS (RANGE: 29 TO 83), 92% WHITE, AND 60% MALE. BASELINE ECOG PERFORMANCE STATUS WAS 0 (30%) OR 1 (70%), 94% WERE FORMER/CURRENT SMOKERS, 56% RECEIVED ONE PRIOR LINE OF THERAPY, AND 44% RECEIVED TWO OR MORE PRIOR LINES OF THERAPY.
SERIOUS ADVERSE REACTIONS OCCURRED IN 45% OF PATIENTS. OPDIVO WAS DISCONTINUED FOR ADVERSE REACTIONS IN 10% OF PATIENTS AND 25% OF PATIENTS HAD AT LEAST ONE DOSE WITHHELD FOR AN ADVERSE REACTION.
THE MOST FREQUENT (?2%) SERIOUS ADVERSE REACTIONS WERE PNEUMONIA, DYSPNEA, PNEUMONITIS, PLEURAL EFFUSION, AND DEHYDRATION. THE MOST COMMON (?20%) ADVERSE REACTIONS WERE FATIGUE, DECREASED APPETITE, MUSCULOSKELETAL PAIN, DYSPNEA, NAUSEA, DIARRHEA, CONSTIPATION, AND COUGH.
THE TOXICITY PROFILE OBSERVED IN PATIENTS WITH METASTATIC SCLC WAS GENERALLY SIMILAR TO THAT OBSERVED IN PATIENTS WITH OTHER SOLID TUMORS WHO RECEIVED OPDIVO AS A SINGLE AGENT.
ADVANCED RENAL CELL CARCINOMA
PREVIOUSLY TREATED RENAL CELL CARCINOMA
THE SAFETY OF OPDIVO WAS EVALUATED IN CHECKMATE-025, A RANDOMIZED OPEN-LABEL TRIAL IN 803 PATIENTS WITH ADVANCED RCC WHO HAD EXPERIENCED DISEASE PROGRESSION DURING OR AFTER AT LEAST ONE ANTI-ANGIOGENIC TREATMENT REGIMEN RECEIVED OPDIVO 3 MG/KG OVER 60 MINUTES BY INTRAVENOUS INFUSION EVERY 2 WEEKS (N=406) OR EVEROLIMUS 10 MG DAILY (N=397) [SEE CLINICAL STUDIES]. THE MEDIAN DURATION OF TREATMENT WAS 5.5 MONTHS (RANGE: 1 DAY TO 29.6+ MONTHS) IN OPDIVO-TREATED PATIENTS AND 3.7 MONTHS (RANGE: 6 DAYS TO 25.7+ MONTHS) IN EVEROLIMUS-TREATED PATIENTS.
RATE OF DEATH ON TREATMENT OR WITHIN 30 DAYS OF THE LAST DOSE WAS 4.7% ON THE OPDIVO ARM. SERIOUS ADVERSE REACTIONS OCCURRED IN 47% OF PATIENTS RECEIVING OPDIVO. STUDY THERAPY WAS DISCONTINUED FOR ADVERSE REACTIONS IN 16% OF OPDIVO PATIENTS. FORTY-FOUR PERCENT (44%) OF PATIENTS RECEIVING OPDIVO HAD A DOSE INTERRUPTION FOR AN ADVERSE REACTION.
THE MOST FREQUENT SERIOUS ADVERSE REACTIONS IN AT LEAST 2% OF PATIENTS WERE: ACUTE KIDNEY INJURY, PLEURAL EFFUSION, PNEUMONIA, DIARRHEA, AND HYPERCALCEMIA . THE MOST COMMON ADVERSE REACTIONS (?20%) WERE FATIGUE, COUGH, NAUSEA, RASH, DYSPNEA, DIARRHEA, CONSTIPATION, DECREASED APPETITE, BACK PAIN, AND ARTHRALGIA. THE MOST COMMON LABORATORY ABNORMALITIES WHICH HAVE WORSENED COMPARED TO BASELINE IN ?30% OF PATIENTS INCLUDE INCREASED CREATININE, LYMPHOPENIA, ANEMIA, INCREASED AST, INCREASED ALKALINE PHOSPHATASE, HYPONATREMIA, INCREASED TRIGLYCERIDES , AND HYPERKALEMIA . IN ADDITION, AMONG PATIENTS WITH TSH < ULN AT BASELINE, A GREATER PROPORTION OF PATIENTS EXPERIENCED A TREATMENT-EMERGENT ELEVATION OF TSH >ULN IN THE OPDIVO GROUP COMPARED TO THE EVEROLIMUS GROUP (26% AND 14%, RESPECTIVELY).
TABLES 18 AND 19 SUMMARIZE ADVERSE REACTIONS AND LABORATORY ABNORMALITIES, RESPECTIVELY, IN CHECKMATE-025.
PREVIOUSLY UNTREATED RENAL CELL CARCINOMA
THE SAFETY OF OPDIVO WITH IPILIMUMAB WAS EVALUATED IN CHECKMATE-214, A RANDOMIZED OPEN-LABEL TRIAL IN 1082 PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED RCC RECEIVED OPDIVO 3 MG/KG OVER 60 MINUTES WITH IPILIMUMAB 1 MG/KG INTRAVENOUSLY EVERY 3 WEEKS FOR 4 DOSES FOLLOWED BY OPDIVO AS A SINGLE AGENT AT A DOSE OF 3 MG/KG BY INTRAVENOUS INFUSION EVERY 2 WEEKS (N=547) OR SUNITINIB 50 MG ORALLY DAILY FOR THE FIRST 4 WEEKS OF A 6-WEEK CYCLE (N=535) [SEE CLINICAL STUDIES]. THE MEDIAN DURATION OF TREATMENT WAS 7.9 MONTHS (RANGE: 1 DAY TO 21.4+ MONTHS) IN OPDIVO AND IPILIMUMAB-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 OPDIVO AND IPILIMUMAB ARM WERE EXPOSED TO TREATMENT FOR >6 MONTHS AND 38% OF PATIENTS WERE EXPOSED TO TREATMENT FOR >1 YEAR.
SERIOUS ADVERSE REACTIONS OCCURRED IN 59% OF PATIENTS RECEIVING OPDIVO AND IPILIMUMAB. STUDY THERAPY WAS DISCONTINUED FOR ADVERSE REACTIONS IN 31% OF OPDIVO AND IPILIMUMAB PATIENTS. FIFTY-FOUR PERCENT (54%) OF PATIENTS RECEIVING OPDIVO AND IPILIMUMAB HAD A DOSE INTERRUPTION FOR AN ADVERSE REACTION.
THE MOST FREQUENT SERIOUS ADVERSE REACTIONS REPORTED IN ?2% OF PATIENTS TREATED WITH OPDIVO AND IPILIMUMAB 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 ?20% OF PATIENTS) WERE FATIGUE, RASH, DIARRHEA, MUSCULOSKELETAL PAIN, PRURITUS, NAUSEA, COUGH, PYREXIA, ARTHRALGIA, AND DECREASED APPETITE. THE MOST COMMON LABORATORY ABNORMALITIES WHICH HAVE WORSENED COMPARED TO BASELINE IN ?30% OF OPDIVO AND IPILIMUMAB-TREATED PATIENTS INCLUDE INCREASED LIPASE, ANEMIA, INCREASED CREATININE, INCREASED ALT, INCREASED AST, HYPONATREMIA, INCREASED AMYLASE, AND LYMPHOPENIA.
TABLES 20 AND 21 SUMMARIZE ADVERSE REACTIONS AND LABORATORY ABNORMALITIES, RESPECTIVELY, THAT OCCURRED IN >15% OF OPDIVO AND IPILIMUMAB-TREATED PATIENTS IN CHECKMATE-214.
TABLE 20: ADVERSE REACTIONS IN >15% OF PATIENTS RECEIVING OPDIVO AND IPILIMUMAB CHECKMATE-214
ADVERSE REACTION OPDIVO AND IPILIMUMAB (N=547) SUNITINIB (N=535)
GRADES 1-4 (%) GRADES 3-4 (%) GRADES 1-4 (%) GRADES 3-4 (%)
ADVERSE REACTION 99 65 99 76
GENERAL
FATIGUEA 58 8 69 13
PYREXIA 25 0.7 17 0.6
EDEMAB 16 0.5 17 0.6
SKIN AND SUBCUTANEOUS TISSUE
RASHC 39 3.7 25 1.1
PRURITUS/GENERALIZED PRURITUS 33 0.5 11 0
GASTROINTESTINAL
DIARRHEA 38 4.6 58 6
NAUSEA 30 2.0 43 1.5
VOMITING 20 0.9 28 2.1
ABDOMINAL PAIN 19 1.6 24 1.9
CONSTIPATION 17 0.4 18 0
MUSCULOSKELETAL AND CONNECTIVE TISSUE
MUSCULOSKELETAL PAIND 37 4.0 40 2.6
ARTHRALGIA 23 1.3 16 0
RESPIRATORY, THORACIC AND MEDIASTINAL
COUGH/PRODUCTIVE COUGH 28 0.2 25 0.4
DYSPNEA/EXERTIONAL DYSPNEA 20 2.4 21 2.1
METABOLISM AND NUTRITION
DECREASED APPETITE 21 1.8 29 0.9
NERVOUS SYSTEM
HEADACHE 19 0.9 23 0.9
ENDOCRINE
HYPOTHYROIDISM 18 0.4 27 0.2
TOXICITY WAS GRADED PER NCI CTCAE V4. A INCLUDES ASTHENIA. B INCLUDES PERIPHERAL EDEMA, PERIPHERAL SWELLING. C INCLUDES DERMATITIS DESCRIBED AS ACNEIFORM, BULLOUS, AND EXFOLIATIVE, DRUG ERUPTION, RASH DESCRIBED AS EXFOLIATIVE, ERYTHEMATOUS, FOLLICULAR, GENERALIZED, MACULAR, MACULOPAPULAR, PAPULAR, PRURITIC, AND PUSTULAR, FIXED-DRUG ERUPTION. D INCLUDES BACK PAIN, BONE PAIN, MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL DISCOMFORT, MYALGIA, NECK PAIN, PAIN IN EXTREMITY, SPINAL PAIN.
TABLE 21: LABORATORY VALUES WORSENING FROM BASELINEA OCCURRING IN >15% OF PATIENTS ON OPDIVO AND IPILIMUMAB -CHECKMATE-214
LABORATORY ABNORMALITY OPDIVO AND IPILIMUMAB SUNITINIB
GRADES 1-4 (%) GRADES 3-4 (%) GRADES 1-4 (%) GRADES 3-4 (%)
CHEMISTRY
INCREASED LIPASE 48 20 51 20
INCREASED CREATININE 42 2.1 46 1.7
INCREASED ALT 41 7 44 2.7
INCREASED AST 40 4.8 60 2.1
INCREASED AMYLASE 39 12 33 7
HYPONATREMIA 39 10 36 7
INCREASED ALKALINE PHOSPHATASE 29 2.0 32 1.0
HYPERKALEMIA 29 2.4 28 2.9
HYPOCALCEMIA 21 0.4 35 0.6
HYPOMAGNESEMIA 16 0.4 26 1.6
HEMATOLOGY
ANEMIA 43 3.0 64 9
LYMPHOPENIA 36 5 63 14
A EACH TEST INCIDENCE IS BASED ON THE NUMBER OF PATIENTS WHO HAD BOTH BASELINE AND AT LEAST ONE ON-STUDY LABORATORY MEASUREMENT AVAILABLE: OPDIVO AND IPILIMUMAB GROUP (RANGE: 490 TO 538 PATIENTS) AND SUNITINIB GROUP (RANGE: 485 TO 523 PATIENTS).