A guide to talking to your doctor about OPDIVO

Transcription

1 individuls depicted re models used for illustrtive purposes only. Wht does (nivolumb) tret? is prescription medicine used to tret clssicl Hodgkin Lymphom ( type of blood cncer tht ffects white blood cells known s lymphocytes) if your cncer hs come bck or spred fter you hd n utologous stem cell trnsplnt ( type of stem cell trnsplnt tht uses your own stem cells) nd were treted with the drug Adcetris (brentuximb vedotin) fter stem cell trnsplnt. It is not known if is sfe nd effective in children less thn 18 yers of ge. Select Importnt Sfety Informtion cn cuse problems tht cn sometimes become serious or life-thretening nd cn led to deth. Serious side effects my include lung problems (pneumonitis); intestinl problems (colitis) tht cn led to ters or holes in the intestines; liver problems (heptitis); hormone glnd problems (especilly the thyroid, pituitry, drenl glnds, nd pncres); kidney problems, including nephritis nd kidney filure; skin problems; inflmmtion of the brin (encephlitis); problems in other orgns; severe infusion rections; nd complictions of stem cell trnsplnt tht uses donor stem cells (llogeneic) fter tretment with. A guide to tlking to your doctor bout If you (or loved one) re tlking to your oncologist bout your next tretment option, nd you re considering, this guide my be useful tool. Your doctor is lwys the best source of informtion when it comes to your helth, so when discussing with him or her, sk tht ll nswers re explined clerly so you nd your doctor re ble to mke n informed decision. If you nd your doctor re considering, be sure to discuss your existing helth problems nd ll prescription nd non-prescription medicines, vitmins, nd herbl supplements tht you re currently tking. Your time with your oncologist is vluble. Mke the most of it by sking the most importnt questions for you. Here re some questions you my wnt to consider: How is different from tretments Wht is immunotherpy? I ve been on before? How does work? Wht re the potentil benefits of? How is given? Wht re the possible side effects of? How will I know if is working? Summing up the converstion Once you ve hd chnce to lern bout, you my wnt to sk your doctor if my be tretment option for you. For more informtion, cll or visit Plese see dditionl Importnt Sfety Informtion on the next pge nd U.S. Full Prescribing Informtion nd Mediction Guide for, t the end of this document.

2 Importnt Sfety Informtion (nivolumb) is medicine tht my tret your blood cncer by working with your immune system. cn cuse your immune system to ttck norml orgns nd tissues in mny res of your body nd cn ffect the wy they work. These problems cn sometimes become serious or life-thretening nd cn led to deth. These problems my hppen nytime during tretment or even fter your tretment hs ended. Serious side effects my include: n Lung problems (pneumonitis). Symptoms of pneumonitis my include: new or worsening cough; chest pin; nd shortness of breth. n Intestinl problems (colitis) tht cn led to ters or holes in your intestine. Signs nd symptoms of colitis my include: dirrhe (loose stools) or more bowel movements thn usul; blood in your stools or drk, trry, sticky stools; nd severe stomch-re (bdomen) pin or tenderness. n Liver problems (heptitis). Signs nd symptoms of heptitis my include: yellowing of your skin or the whites of your eyes; severe nuse or vomiting; pin on the right side of your stomch re (bdomen); drowsiness; drk urine (te colored); bleeding or bruising more esily thn norml; nd feeling less hungry thn usul. n Hormone glnd problems (especilly the thyroid, pituitry, drenl glnds, nd pncres). Signs nd symptoms tht your hormone glnds re not working properly my include: hedches tht will not go wy or unusul hedches; extreme tiredness; weight gin or weight loss; dizziness or finting; chnges in mood or behvior, such s decresed sex drive, irritbility, or forgetfulness; hir loss; feeling cold; constiption; voice gets deeper; nd excessive thirst or lots of urine. n Kidney problems, including nephritis nd kidney filure. Signs of kidney problems my include: decrese in the mount of urine; blood in your urine; swelling in your nkles; nd loss of ppetite. n Skin Problems. Signs of these problems my include: rsh; itching; skin blistering; nd ulcers in the mouth or other mucous membrnes. n Inflmmtion of the brin (encephlitis). Signs nd symptoms of encephlitis my include: hedche; fever; tiredness or wekness; confusion; memory problems; sleepiness; seeing or hering things tht re not relly there (hllucintions); seizures; nd stiff neck. n Problems in other orgns. Signs of these problems my include: chnges in eyesight; severe or persistent muscle or joint pins; nd severe muscle wekness. Getting medicl tretment right wy my keep these problems from becoming more serious. Your helthcre provider will check you for these problems during tretment. Your helthcre provider my tret you with corticosteroid or hormone replcement medicines. Your helthcre provider my lso need to dely or completely stop tretment, if you hve severe side effects. cn cuse serious side effects, including: n Severe infusion rections. Tell your doctor or nurse right wy if you get these symptoms during n infusion of : chills or shking; itching or rsh; flushing; difficulty brething; dizziness; fever; nd feeling like pssing out. n Complictions of stem cell trnsplnt tht uses donor stem cells (llogeneic) fter tretment with. These complictions cn be severe nd cn led to deth. Your helthcre provider will monitor you for signs of complictions if you hve n llogeneic stem cell trnsplnt. (continued on next pge)

3 Importnt Sfety Informtion (cont d) Pregnncy nd Nursing: Tell your helthcre provider if you re pregnnt or pln to become pregnnt. cn hrm your unborn bby. Femles who re ble to become pregnnt should use n effective method of birth control during nd for t lest 5 months fter the lst dose of. Tlk to your helthcre provider bout birth control methods tht you cn use during this time. Tell your helthcre provider right wy if you become pregnnt during tretment. Before receiving tretment, tell your helthcre provider if you re brestfeeding or pln to brestfeed. It is not known if psses into your brest milk. Do not brestfeed during tretment. Tell your helthcre provider bout: n Your helth problems or concerns if you hve immune system problems such s Crohn s disese, ulcertive colitis, lupus; hve hd n orgn trnsplnt; hve lung or brething problems; hve liver problems; or hve ny other medicl conditions. n the medicines you tke, including prescription nd over-the-counter medicines, vitmins, nd herbl supplements. The most common side effects of in people with clssicl Hodgkin lymphom include: feeling tired; upper respirtory trct infection; fever; dirrhe; nd cough. These re not ll the possible side effects. For more informtion, sk your helthcre provider or phrmcist. Cll your doctor for medicl dvice bout side effects. You my report side effects to FDA t FDA Plese see U.S. Full Prescribing Informtion nd Mediction Guide for, t the end of this document. For more informtion, cll or visit Bristol-Myers Squibb is committed to helping ptients throughout their tretment Bristol-Myers Squibb Compny. rights reserved. Adcetris is registered trdemrk of Settle Genetics, Inc. nd the logo re trdemrks of Bristol-Myers Squibb Compny. 1506US /16

4 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (nivolumb) injection, for intrvenous use Initil U.S. Approvl: RECENT MAJOR CHANGES Indictions nd Usge (1) 05/2016 Dosge nd Administrtion (2) 05/2016 Wrnings nd Precutions (5) 05/ INDICATIONS AND USAGE is progrmmed deth receptor-1 (PD-1) blocking ntibody indicted for the tretment of ptients with: BRAF V600 wild-type unresectble or metsttic melnom, s single gent. (1.1) BRAF V600 muttion-positive unresectble or metsttic melnom, s single gent. This indiction is pproved under ccelerted pprovl bsed on progressionfree survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. (1.1) Unresectble or metsttic melnom, in combintion with ipilimumb. This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. (1.1) Metsttic non-smll cell lung cncer nd progression on or fter pltinum-bsed chemotherpy. Ptients with EGFR or ALK genomic tumor berrtions should hve disese progression on FDA-pproved therpy for these berrtions prior to receiving. (1.2) Advnced renl cell crcinom who hve received prior nti-ngiogenic therpy. (1.3) Clssicl Hodgkin lymphom tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion brentuximb vedotin. This indiction is pproved under ccelerted pprovl bsed on overll response rte. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in confirmtory trils. (1.4) DOSAGE AND ADMINISTRATION Administer s n intrvenous infusion over 60 minutes. Unresectble or metsttic melnom 3 mg/kg every 2 weeks. (2.1) with ipilimumb: 1 mg/kg, followed by ipilimumb on the sme dy, every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks. (2.1) Metsttic non-smll cell lung cncer 3 mg/kg every 2 weeks. (2.2) Advnced renl cell crcinom 3 mg/kg every 2 weeks. (2.3) Clssicl Hodgkin lymphom 3 mg/kg every 2 weeks. (2.4) DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 ml nd 100 mg/10 ml solution in single-dose vil. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Immune-medited pneumonitis: Withhold for moderte nd permnently discontinue for severe or life-thretening pneumonitis. (5.1) Immune-medited colitis: Withhold (nivolumb) when given s single gent for moderte or severe nd permnently discontinue for life-thretening colitis. Withhold when given with ipilimumb for moderte nd permnently discontinue for severe or life-thretening colitis. (5.2) Immune-medited heptitis: Monitor for chnges in liver function. Withhold for moderte nd permnently discontinue for severe or life-thretening trnsminse or totl bilirubin elevtion. (5.3) Immune-medited endocrinopthies: Withhold for moderte or severe nd permnently discontinue for life-thretening hypophysitis. Withhold for moderte nd permnently discontinue for severe or life-thretening drenl insufficiency. Monitor for chnges in thyroid function. Initite thyroid hormone replcement s needed. Monitor for hyperglycemi. Withhold for severe nd permnently discontinue for life-thretening hyperglycemi. (5.4) Immune-medited nephritis nd renl dysfunction: Monitor for chnges in renl function. Withhold for moderte or severe nd permnently discontinue for life-thretening serum cretinine elevtion. (5.5) Immune-medited rsh: Withhold for severe nd permnently discontinue for life-thretening rsh. (5.6) Immune-medited encephlitis: Monitor for chnges in neurologic function. Withhold for new-onset moderte to severe neurologicl signs or symptoms nd permnently discontinue for immune-medited encephlitis. (5.7) Infusion rections: Discontinue for severe nd life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. (5.9) Complictions of llogeneic HSCT fter : Monitor for hypercute grft-versushost-disese (GVHD), grde cute GVHD, steroid-requiring febrile syndrome, heptic veno-occlusive disese, nd other immune-medited dverse rections. Trnsplnt-relted mortlity hs occurred. (5.10) Embryo-fetl toxicity: Cn cuse fetl hrm. Advise of potentil risk to fetus nd use of effective contrception. (5.11, 8.1, 8.3) ADVERSE REACTIONS Most common dverse rections ( 20%) in ptients with melnom were: s single gent: ftigue, rsh, musculoskeletl pin, pruritus, dirrhe, nd nuse. (6.1) with ipilimumb: ftigue, rsh, dirrhe, nuse, pyrexi, vomiting, nd dyspne. (6.1) Most common dverse rections ( 20%) in ptients with metsttic non-smll cell lung cncer were ftigue, musculoskeletl pin, decresed ppetite, cough, nd constiption. (6.1) Most common dverse rections ( 20%) in ptients with dvnced renl cell crcinom were: sthenic conditions, cough, nuse, rsh, dyspne, dirrhe, constiption, decresed ppetite, bck pin, nd rthrlgi. (6.1) Most common dverse rections ( 20%) in ptients with clssicl Hodgkin lymphom were: ftigue, upper respirtory trct infection, pyrexi, dirrhe, nd cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squibb t or FDA t FDA-1088 or USE IN SPECIFIC POPULATIONS Lcttion: Discontinue brestfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 05/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom 1.2 Metsttic Non-Smll Cell Lung Cncer 1.3 Renl Cell Crcinom 1.4 Clssicl Hodgkin Lymphom 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom 2.2 Recommended Dosge for NSCLC 2.3 Recommended Dosge for RCC 2.4 Recommended Dosge for chl 2.5 Dose Modifictions 2.6 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis 5.2 Immune-Medited Colitis 5.3 Immune-Medited Heptitis 5.4 Immune-Medited Endocrinopthies 5.5 Immune-Medited Nephritis nd Renl Dysfunction 5.6 Immune-Medited Rsh 5.7 Immune-Medited Encephlitis 5.8 Other Immune-Medited Adverse Rections 5.9 Infusion Rections 5.10 Complictions of ogeneic HSCT fter 5.11 Embryo-Fetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Unresectble or Metsttic Melnom 14.2 Metsttic Non-Smll Cell Lung Cncer 14.3 Renl Cell Crcinom 14.4 Clssicl Hodgkin Lymphom 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing informtion re not listed.

5 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom (nivolumb) s single gent is indicted for the tretment of ptients with BRAF V600 wild-type unresectble or metsttic melnom [see Clinicl Studies (14.1)]. (nivolumb) s single gent is indicted for the tretment of ptients with BRAF V600 muttion-positive unresectble or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. (nivolumb), in combintion with ipilimumb, is indicted for the tretment of ptients with unresectble or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. 1.2 Metsttic Non-Smll Cell Lung Cncer (nivolumb) is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) with progression on or fter pltinum-bsed chemotherpy. Ptients with EGFR or ALK genomic tumor berrtions should hve disese progression on FDA-pproved therpy for these berrtions prior to receiving [see Clinicl Studies (14.2)]. 1.3 Renl Cell Crcinom (nivolumb) is indicted for the tretment of ptients with dvnced renl cell crcinom (RCC) who hve received prior nti-ngiogenic therpy [see Clinicl Studies (14.3)]. 1.4 Clssicl Hodgkin Lymphom (nivolumb) is indicted for the tretment of ptients with clssicl Hodgkin lymphom (chl) tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion brentuximb vedotin [see Clinicl Studies (14.4)]. This indiction is pproved under ccelerted pprovl bsed on overll response rte. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in confirmtory trils [see Clinicl Studies (14.4)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom The recommended dose of s single gent is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. The recommended dose of is 1 mg/kg dministered s n intrvenous infusion over 60 minutes, followed by ipilimumb on the sme dy, every 3 weeks for 4 doses [see Clinicl Studies (14.1)]. The recommended subsequent dose of, s single gent, is 3 mg/kg s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. Review the Full Prescribing Informtion for ipilimumb prior to initition. 2.2 Recommended Dosge for NSCLC The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.3 Recommended Dosge for RCC The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.4 Recommended Dosge for chl The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.5 Dose Modifictions Recommendtions for modifictions re provided in Tble 1. When is dministered in combintion with ipilimumb, if is withheld, ipilimumb should lso be withheld. There re no recommended dose modifictions for hypothyroidism or hyperthyroidism. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. Discontinue in ptients with severe or life-thretening infusion rections. (nivolumb) Tble 1: Recommended Dose Modifictions for Adverse Rection Severity* Dose Modifiction Grde 2 dirrhe or colitis Withhold dose Colitis Grde 3 dirrhe or colitis Withhold dose when dministered s single gent Permnently discontinue when dministered with ipilimumb Grde 4 dirrhe or colitis Permnently discontinue Pneumonitis Grde 2 pneumonitis Withhold dose Grde 3 or 4 pneumonitis Permnently discontinue Asprtte minotrnsferse (AST)/or lnine minotrnsferse (ALT) more thn 3 nd up to 5 times the upper limit of norml or totl Withhold dose Heptitis bilirubin more thn 1.5 nd up to 3 times the upper limit of norml AST or ALT more thn 5 times the upper limit of norml or totl bilirubin more thn 3 times Permnently discontinue the upper limit of norml Hypophysitis Grde 2 or 3 hypophysitis Withhold dose Grde 4 hypophysitis Permnently discontinue Grde 2 drenl insufficiency Withhold dose Adrenl Insufficiency Grde 3 or 4 drenl insufficiency Permnently discontinue Type 1 Dibetes Mellitus Grde 3 hyperglycemi Withhold dose Grde 4 hyperglycemi Permnently discontinue Nephritis nd Renl Dysfunction Rsh Encephlitis Other Serum cretinine more thn 1.5 nd up to 6 times the upper limit of norml Serum cretinine more thn 6 times the upper limit of norml Grde 3 rsh Grde 4 rsh New-onset moderte or severe neurologic signs or symptoms Immune-medited encephlitis Other Grde 3 dverse rection First occurrence Recurrence of sme Grde 3 dverse rections Life-thretening or Grde 4 dverse rection Requirement for 10 mg per dy or greter prednisone or equivlent for more thn 12 weeks Persistent Grde 2 or 3 dverse rections lsting 12 weeks or longer Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Permnently discontinue Permnently discontinue Permnently discontinue * Toxicity ws grded per Ntionl Cncer Institute Common Terminology Criteri for Adverse Events. Version 4.0 (NCI CTCAE v4). Resume tretment when dverse rection returns to Grde 0 or Preprtion nd Administrtion Visully inspect drug product solution for prticulte mtter nd discolortion prior to dministrtion. is cler to oplescent, colorless to ple-yellow solution. Discrd the vil if the solution is cloudy, discolored, or contins extrneous prticulte mtter other thn few trnslucent-to-white, proteinceous prticles. Do not shke the vil. Preprtion Withdrw the required volume of nd trnsfer into n intrvenous continer. Dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepre n infusion with finl concentrtion rnging from 1 mg/ml to 10 mg/ml.

6 (nivolumb) Mix diluted solution by gentle inversion. Do not shke. Discrd prtilly used vils or empty vils of. Storge of Infusion The product does not contin preservtive. After preprtion, store the infusion either: t room temperture for no more thn 4 hours from the time of preprtion. This includes room temperture storge of the infusion in the IV continer nd time for dministrtion of the infusion or under refrigertion t 2 C to 8 C (36 F to 46 F) for no more thn 24 hours from the time of infusion preprtion. Do not freeze. Administrtion Administer the infusion over 60 minutes through n intrvenous line contining sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not codminister other drugs through the sme intrvenous line. Flush the intrvenous line t end of infusion. When dministered in combintion with ipilimumb, infuse first followed by ipilimumb on the sme dy. Use seprte infusion bgs nd filters for ech infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 ml (10 mg/ml) nd 100 mg/10 ml (10 mg/ml) solution in single-dose vil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis Immune-medited pneumonitis, defined s requiring use of corticosteroids nd no cler lternte etiology, including ftl cses, occurred with tretment. Across clinicl tril experience in ptients receiving, ftl immune-medited pneumonitis occurred in 0.2% (5/2166) of ptients. five ftl cses occurred in dose-finding study with doses of 1 mg/kg (two ptients), 3 mg/kg (two ptients), nd 10 mg/kg (one ptient). Across the clinicl tril experience in 501 ptients with melnom who received with ipilimumb, in Tril 4 (n=94), Tril 7 (n=313), nd n dditionl dose-finding study (n=94), ftl immune-medited pneumonitis occurred in 0.2% (1/501) of ptients. In Tril 4, there were six dditionl ptients who died without resolution of bnorml respirtory findings. Monitor ptients for signs with rdiogrphic imging nd symptoms of pneumonitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for moderte (Grde 2) or greter pneumonitis, followed by corticosteroid tper. Permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) pneumonitis nd withhold until resolution for moderte (Grde 2) pneumonitis [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, immune-medited pneumonitis occurred in 1.8% (14/787) of ptients receiving : two ptients with Grde 3 nd 12 ptients with Grde 2 pneumonitis. The medin time to onset of immune-medited pneumonitis ws 2.2 months (rnge: 25 dys to 9.7 months). Grde 3 pneumonitis led to permnent discontinution in one ptient (0.1%), nd Grde 2 pneumonitis led to withholding of in eight ptients (1.0%). 14 ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 18 dys (rnge: 4 dys to 1.2 months). Complete resolution (defined s complete resolution of symptoms with completion of corticosteroids) occurred in 11 ptients. None of the seven ptients who resumed fter resolution hd recurrence of pneumonitis. with Ipilimumb In Trils 4 nd 7, immune-medited pneumonitis occurred in 6% (25/407) of ptients receiving with ipilimumb: 1 ftl, 6 Grde 3, 17 Grde 2, nd 1 Grde 1 pneumonitis. The medin time to onset of immune-medited pneumonitis ws 1.6 months (rnge: 24 dys to 10.1 months). Immune-medited pneumonitis led to permnent discontinution of nd of ipilimumb in nine ptients (2.2%) nd withholding of nd of ipilimumb in 15 ptients (3.7%). Twenty-one ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 30 dys (rnge: 5 dys to 11.8 months). One ptient with Grde 2 pneumonitis required mycophenolic cid in ddition to high-dose corticosteroids. Complete resolution occurred in 17 ptients. Among the eight ptients who resumed with ipilimumb, one hd recurrence of immune-medited pneumonitis. (nivolumb) NSCLC In Tril 3, pneumonitis, including interstitil lung disese, occurred in 3.4% (10/287) of ptients receiving. Of these 10 ptients, there were five ptients with Grde 3, two ptients with Grde 2, nd three ptients with Grde 1 immune-medited pneumonitis. The medin time to onset ws 7.2 months (rnge: 2.7 to 13.1 months). five ptients with Grde 3 nd one of two ptients with Grde 2 pneumonitis received high-dose corticosteroids nd permnently discontinued ; two of these seven were documented rdiogrphiclly to hve complete resolution of pneumonitis. One ptient with Grde 2 pneumonitis hd temporrily withheld, received low-dose corticosteroids, experienced complete resolution, nd ws retreted without recurrence of pneumonitis. RCC In Tril 6, pneumonitis, including interstitil lung disese, occurred in 5% (21/406) of ptients receiving nd 18% (73/397) ptients receiving everolimus. Immunemedited pneumonitis occurred in 4.4% (18/406) of ptients receiving (one with Grde 4, four with Grde 3, twelve with Grde 2, nd one with Grde 1). In two of the ptients, pneumonitis occurred fter they hd received followed by everolimus. One ptient with ongoing pneumonitis died due to disese progression. The medin time to onset ws 3.82 months (rnge: 2 dys to 22.3 months). The medin durtion ws 1.3 months (rnge: 0.3 to 9.8 months). ws permnently discontinued in six ptients. Dose dely occurred in nine ptients. Seven ptients hd complete resolution. Among the six ptients who resumed, three did not hve recurrence of pneumonitis. chl In Trils 8 nd 9, pneumonitis, including interstitil lung disese, occurred in 4.9% (13/263) of ptients receiving. Immune-medited pneumonitis occurred in 3.4% (9/263) of ptients receiving (one Grde 3 nd eight Grde 2). The medin time to onset ws 2.2 months (rnge: 1 dy to 10.1 months). nine ptients received systemic corticosteroids, with resolution in seven. One ptient permnently discontinued due to Grde 2 pneumonitis. Dose dely occurred in three ptients. Five ptients resumed, of whom none hd recurrence of pneumonitis. 5.2 Immune-Medited Colitis Immune-medited colitis, defined s requiring use of corticosteroids with no cler lternte etiology, cn occur with tretment. Monitor ptients for signs nd symptoms of colitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed by corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) colitis. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents followed by corticosteroid tper for moderte (Grde 2) colitis of more thn 5 dys durtion; if worsening or no improvement occurs despite initition of corticosteroids, increse dose to 1 to 2 mg/kg/dy prednisone equivlents. When dministered s single gent, withhold for moderte or severe (Grde 2 or 3) colitis. Permnently discontinue for life-thretening (Grde 4) or for recurrent colitis upon restrting [see Dosge nd Administrtion (2.5)]. When dministered in combintion with ipilimumb, withhold for moderte colitis (Grde 2). Permnently discontinue for severe or life-thretening (Grde 3 or 4) colitis or for recurrent colitis upon restrting [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, dirrhe or colitis occurred in 31% (242/787) of ptients. Immunemedited colitis occurred in 4.1% (32/787) of ptients: 20 ptients with Grde 3, 10 ptients with Grde 2, nd two ptients with Grde 1 colitis. The medin time to onset of immune-medited colitis ws 5.6 months (rnge: 3 dys to 13.1 months). Immune-medited colitis led to permnent discontinution of in seven ptients (0.9%) nd to withholding of in six ptients (0.8%). Thirty ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 4.2 months (rnge: 3 dys to 9.3 months). Three ptients with Grde 2 or 3 colitis required ddition of infliximb to high-dose corticosteroids. Complete resolution (defined s improved to bseline with completion of corticosteroids) occurred in 17 ptients. Among the nine ptients who resumed fter resolution, two hd recurrence of immune-medited colitis. with Ipilimumb In Trils 4 nd 7, dirrhe or colitis occurred in 56% (228/407) of ptients. Immunemedited colitis occurred in 26% (107/407) of ptients: 2 ptients with Grde 4, 60 ptients with Grde 3, 32 ptients with Grde 2, nd 13 ptients with Grde 1 colitis. The medin time to onset of immune-medited colitis ws 1.6 months (rnge: 3 dys to 15.2 months). Immune-medited colitis led to permnent discontinution of nd of ipilimumb in 64 ptients (16%) or to withholding of nd of ipilimumb in 30 ptients (7%). One hundred three ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 11.7 months). Twenty-five ptients required ddition of infliximb to high-dose corticosteroids. Complete resolution occurred in 80 ptients. Among the 29 ptients who resumed with ipilimumb fter resolution, eight hd recurrence of immunemedited colitis. In Tril 4, there were three ptients who died without resolution of immune-medited colitis.

7 (nivolumb) NSCLC In Tril 3, dirrhe or colitis occurred in 17% (50/287) of ptients receiving. Immune-medited colitis occurred in 2.4% (7/287) of ptients: three ptients with Grde 3, two ptients with Grde 2, nd two ptients with Grde 1. The medin time to onset in these seven ptients ws 2.7 months (rnge: 4 weeks to 19 months). seven ptients received corticosteroids; six of these seven received high-dose corticosteroids for medin durtion of 2.9 weeks (rnge: 1 week to 2.1 months). One ptient with Grde 3 colitis permnently discontinued. seven ptients experienced complete resolution. Five of the seven ptients were retreted fter complete resolution without recurrence of dirrhe or colitis. RCC In Tril 6, dirrhe or colitis occurred in 25% (100/406) of ptients receiving nd 32% (126/397) of ptients receiving everolimus. Immune-medited dirrhe or colitis occurred in 3.2% (13/406) of ptients receiving (five ptients with Grde 3, seven with Grde 2, nd one with Grde 1). The medin time to onset ws 4.8 months (rnge: 2 dys to 15.6 months). The medin durtion ws 1.3 months (rnge: 0.2 to 3.9 months). ws permnently discontinued in four ptients. Dose dely occurred in nine ptients. Twelve ptients hd complete resolution. Among the nine ptients who resumed fter resolution, four hd no recurrence of dirrhe or colitis. chl In Trils 8 nd 9, dirrhe or colitis occurred in 30% (80/263) of ptients receiving. Immune-medited dirrhe (Grde 3) occurred in 1.1% (3/263) of ptients. 5.3 Immune-Medited Heptitis Immune-medited heptitis, defined s requiring use of corticosteroids nd no cler lternte etiology, cn occur with tretment. Monitor ptients for bnorml liver tests prior to nd periodiclly during tretment. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) trnsminse elevtions, with or without concomitnt elevtion in totl bilirubin. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for severe (Grde 3) or life-thretening (Grde 4) trnsminse elevtions, with or without concomitnt elevtion in totl bilirubin. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) immune-medited heptitis [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, immune-medited heptitis occurred in 2.3% (18/787) of ptients receiving : three ptients with Grde 4, 11 ptients with Grde 3, nd four ptients with Grde 2 heptitis. The medin time to onset ws 3.7 months (rnge: 6 dys to 9 months). Immune-medited heptitis led to permnent discontinution of in five ptients (0.6%) nd withholding of in six ptients (0.8%). 18 ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 28 dys (rnge: 5 dys to 2 months). One ptient with Grde 3 heptitis required the ddition of mycophenolic cid to high-dose corticosteroids. Complete resolution (defined s improved to bseline with completion of corticosteroids) occurred in 13 ptients. Among the four ptients who resumed fter resolution, one hd recurrence of immune-medited heptitis. with Ipilimumb In Trils 4 nd 7, immune-medited heptitis occurred in 13% (51/407) of ptients receiving with ipilimumb: eight ptients with Grde 4, 37 ptients with Grde 3, five ptients with Grde 2, nd one ptient with Grde 1 heptitis. The medin time to onset ws 2.1 months (rnge: 15 dys to 11 months). Immune-medited heptitis led to permnent discontinution of nd of ipilimumb in 26 ptients (6%) nd withholding of nd of ipilimumb in 21 ptients (5%). Forty-seven ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 1.1 month (rnge: 1 dy to 13.2 months). One ptient (Grde 3 heptitis) required infliximb, nd four ptients (three ptients with Grde 3 or 4 trnsminse increses nd one ptient with Grde 3 utoimmune heptitis) required mycophenolic cid in ddition to high-dose corticosteroids. Complete resolution occurred in 38 ptients. Among the nine ptients who resumed with ipilimumb fter resolution, one hd recurrence of heptitis. NSCLC In Tril 3, one ptient developed immune-medited heptitis (0.3%) fter 7.8 months of exposure. The event resolved following temporry withholding of nd high-dose corticosteroid therpy. Immune-medited heptitis recurred following resumption of, resulting in permnent discontinution. (nivolumb) RCC In Tril 6, there ws n incresed incidence of liver test bnormlities compred to bseline with increses in AST (33% vs. 39%), lkline phosphtse (32% vs. 32%), ALT (22% vs. 31%), nd totl bilirubin (9% vs. 3.5%) in the nd everolimus rms, respectively. Immune-medited heptitis requiring systemic immunosuppression occurred in 1.5% (6/406) of ptients receiving (five with Grde 3 nd one with Grde 2). None of the six ptients hd liver metstses. The medin time to onset ws 3.7 months (rnge: 14 dys to 5.3 months). The medin durtion ws 1.8 months (rnge: 0.9 to 16.3 months). ws permnently discontinued in four ptients. Dose dely occurred in ll ptients. Five ptients hd complete resolution. Among the three ptients who resumed, two hd no recurrence of liver test bnormlities. One ptient with immune-medited nephritis developed heptic filure on the dte of deth. chl In Trils 8 nd 9, heptitis occurred in 11% (30/263) of ptients receiving. Immune-medited heptitis occurred in 3.4% (9/263) of ptients (seven with Grde 3 nd two with Grde 2), with medin time to onset of 2.4 months (rnge 1.5 to 6 months). Three ptients permnently discontinued, nd five ptients hd dose dely. nine ptients received systemic corticosteroids nd one ptient lso received mycophenolic cid, with resolution in seven ptients. Among the six ptients who resumed, one hd recurrence of the event. 5.4 Immune-Medited Endocrinopthies Hypophysitis Hypophysitis cn occur with tretment. Monitor ptients for signs nd symptoms of hypophysitis. Administer corticosteroids t dose of 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) or greter hypophysitis. Withhold for moderte (Grde 2) or severe (Grde 3) nd permnently discontinue for life-thretening (Grde 4) hypophysitis [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, hypophysitis occurred in 0.9% (7/787) of ptients: two ptients with Grde 3, three ptients with Grde 2, nd two ptients with Grde 1 hypophysitis. The medin time to onset ws 5.5 months (rnge: 1.6 to 11 months). Hypophysitis led to withholding of in one ptient (0.1%). Three ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 22 dys (rnge: 5 to 26 dys). with Ipilimumb In Trils 4 nd 7, hypophysitis occurred in 9% (36/407) of ptients: eight ptients with Grde 3, 25 ptients with Grde 2, nd three ptients with Grde 1 hypophysitis. The medin time to onset ws 2.7 months (rnge: 27 dys to 5.5 months). Hypophysitis led to permnent discontinution of nd of ipilimumb in four ptients (1.0%) nd withholding of nd of ipilimumb in 16 ptients (3.9%). Twenty ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 19 dys (rnge: 1 dy to 2.0 months). RCC In Tril 6, hypophysitis occurred in 0.5% (2/406) of ptients receiving. The time to onset for the Grde 3 event ws 9.2 months nd for the Grde 1 event ws 3.2 months. Both ptients received steroid replcement doses. The Grde 3 event resulted in permnent discontinution nd the other ptient with the Grde 1 event discontinued due to progressive disese. Neither ptient hd complete resolution or resumed tretment with. Adrenl Insufficiency Adrenl insufficiency cn occur with tretment. Monitor ptients for signs nd symptoms of drenl insufficiency during nd fter tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, drenl insufficiency occurred in 1% (8/787) of ptients: two ptients with Grde 3, five ptients with Grde 2, nd one ptient with Grde 1 drenl insufficiency. The medin time to onset ws 3.6 months (rnge: 15 dys to 5.0 months). Adrenl insufficiency led to withholding of in four ptients (0.5%). One ptient received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for 11 dys. with Ipilimumb In Trils 4 nd 7, drenl insufficiency occurred in 5% (21/407) of ptients: one ptient with Grde 4, seven ptients with Grde 3, 11 ptients with Grde 2, nd two ptients with Grde 1 drenl insufficiency. The medin time to onset ws 3.0 months (rnge: 21 dys to 9.4 months). Adrenl insufficiency led to permnent discontinution of nd of ipilimumb in two ptients (0.5%) nd withholding of nd of ipilimumb in seven ptients (1.7%). Seven ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 9 dys (rnge: 1 dy to 2.7 months).

8 (nivolumb) NSCLC In Tril 3, 0.3% (1/287) of -treted ptients developed drenl insufficiency. RCC In Tril 6, drenl insufficiency occurred in 2.0% (8/406) of ptients receiving (three with Grde 3, four with Grde 2, nd one with Grde 1). The medin time to onset ws 5.8 months (rnge: 22 dys to 20.9 months). ws permnently discontinued in one ptient. Dose dely occurred in five ptients. chl In Trils 8 nd 9, drenl insufficiency (Grde 2) occurred in 0.4% (1/263) of ptients receiving. Hypothyroidism nd Hyperthyroidism Thyroid disorders cn occur with tretment. Monitor thyroid function prior to nd periodiclly during tretment. Administer hormone-replcement therpy for hypothyroidism. Initite medicl mngement for control of hyperthyroidism. There re no recommended dose djustments of for hypothyroidism or hyperthyroidism. Melnom s Single Agent In Trils 1, 5, nd 7, hypothyroidism or thyroiditis occurred in 9% (73/787) of ptients: one ptient with Grde 3, 37 ptients with Grde 2, nd 35 ptients with Grde 1 hypothyroidism. The medin time to onset ws 2.8 months (rnge: 15 dys to 13.8 months). Resolution occurred in 26 ptients. Mngement of hypothyroidism included levothyroxine in 56 ptients. Hyperthyroidism occurred in 4.4% (35/787) of ptients receiving : one ptient with Grde 3, 12 ptients with Grde 2, nd 22 ptients with Grde 1 hyperthyroidism. The medin time to onset ws 1.4 months (rnge: 1 dy to 13.4 months). Resolution occurred in 27 ptients. Mngement of hyperthyroidism included methimzole (five ptients), crbimzole (four ptients), nd propylthiourcil (two ptients). with Ipilimumb In Trils 4 nd 7, hypothyroidism or thyroiditis occurred in 22% (89/407) of ptients: six ptients with Grde 3, 47 ptients with Grde 2, nd 36 ptients with Grde 1 hypothyroidism. The medin time to onset ws 2.1 months (rnge: 1 dy to 10.1 months). Resolution occurred in 40 ptients. Mngement of hypothyroidism included levothyroxine (65 ptients). Hyperthyroidism occurred in 8% (34/407) of ptients receiving with ipilimumb: four ptients with Grde 3, 17 ptients with Grde 2, nd 13 ptients with Grde 1 hyperthyroidism. The medin time to onset ws 23 dys (rnge: 3 dys to 3.7 months). Resolution occurred in 32 ptients. Mngement of hyperthyroidism included methimzole (ten ptients) nd crbimzole (eight ptients). NSCLC In Tril 3, Grde 1 or Grde 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) of ptients receiving nd 0% (0/268) of ptients receiving docetxel, while elevted thyroid stimulting hormone (TSH) occurred in 17% of ptients receiving nd 5% of ptients receiving docetxel. The medin time to onset of hypothyroidism/thyroiditis ws 2.9 months (rnge: 1.4 to 11.8 months). 20 ptients received levothyroxine. Two ptients received corticosteroids; one of whom received high-dose corticosteroids. Complete resolution of hypothyroidism occurred in one ptient. ws temporrily withheld due to hypothyroidism/thyroiditis in three ptients; no ptients discontinued due to hypothyroidism/thyroiditis. Grde 1 or Grde 2 hyperthyroidism occurred in 1.4% (4/287) of ptients. The medin time to onset ws 2 months (rnge: 4.1 weeks to 2.8 months). Two of four ptients received methimzole nd one ptient lso received tretment with high-dose corticosteroids. four ptients experienced complete resolution. RCC In Tril 6, thyroid disese occurred in 11% (43/406) of ptients on, including one Grde 3 event, nd in 12/397 (3.0%) ptients on everolimus. Hypothyroidism/ thyroiditis occurred in 8% (33/406) of ptients receiving (two ptients with Grde 3, 17 ptients with Grde 2, nd 14 ptients with Grde 1). The medin time to onset ws 4.6 months (rnge: 15 dys to 13.6 months). Twenty-eight of the 33 ptients received levothyroxine. No events led to permnent discontinution. Dose dely occurred in four ptients. Four ptients, including three ptients tht never required levothyroxine, hd complete resolution nd three of these four ptients continued throughout the event. Hyperthyroidism occurred in 2.5% (10/406) of ptients receiving (five ptients with Grde 2 nd five ptients with Grde 1). The medin time to onset ws 3 months (rnge: 24 dys to 14.2 months). No events led to permnent discontinution. Seven ptients hd complete resolution. Seven were treted through the event nd two hd dose dely with no recurrence of hyperthyroidism when ws resumed. Four ptients developed hyperthyroidism followed by hypothyroidism. (nivolumb) chl In Trils 8 nd 9, hypothyroidism/thyroiditis occurred in 12% (32/263) of ptients receiving (18 with Grde 2 nd 14 with Grde 1). The medin time to onset ws 2.8 months (rnge: 1 dy to 16.6 months). Twenty of the 32 ptients received levothyroxine. Two ptients hd dose dely. No immunosuppressnt therpy ws required for hypothyroidism. Hyperthyroidism occurred in 1.5% (4/263) of ptients receiving (three Grde 2 nd one Grde 1). The time to onset rnged from 1 to 2.5 months. Type 1 Dibetes Mellitus Type 1 dibetes mellitus cn occur with tretment. Monitor for hyperglycemi. Administer insulin for type 1 dibetes nd withhold in cses of severe (Grde 3) hyperglycemi until metbolic control is chieved. Permnently discontinue for life-thretening (Grde 4) hyperglycemi. Melnom s Single Agent In Trils 1, 5, nd 7, dibetes mellitus or dibetic ketocidosis occurred in 0.8% (6/787) of ptients: two ptients with Grde 3, three ptients with Grde 2, nd one ptient with Grde 1 events. The medin time to onset ws 3.6 months (rnge: 1.4 to 12 months). Four ptients initited insulin nd four ptients initited orl hypoglycemic therpy. with Ipilimumb In Trils 4 nd 7, dibetes mellitus or dibetic ketocidosis occurred in 1.5% (6/407) of ptients: three ptients with Grde 4, one ptient with Grde 3, one ptient with Grde 2, nd one ptient with Grde 1 events. The medin time to onset ws 2.5 months (rnge: 1.3 to 4.4 months). Grde 4 dibetes led to permnent discontinution of nd of ipilimumb in one ptient nd Grde 3 dibetes led to withholding of nd of ipilimumb in one ptient. Six ptients initited insulin nd four ptients initited orl hypoglycemic therpy. RCC In Tril 6, hyperglycemic dverse events occurred in 9% (37/406) of ptients. Dibetes mellitus or dibetic ketocidosis occurred in 1.5% (6/406) of ptients receiving (three ptients with Grde 3, two ptients with Grde 2, nd one ptient with Grde 1). The medin time to onset ws 7.8 months (rnge: 2.3 to 21.8 months). Four ptients received insulin. One ptient ws on corticosteroids prior to the event. No events led to permnent discontinution. Dose dely occurred in one ptient. One ptient hd ongoing hyperglycemi when ws resumed. chl In Trils 8 nd 9, dibetes mellitus occurred in 0.8% (2/263) of ptients receiving (one Grde 3 nd one Grde 1). 5.5 Immune-Medited Nephritis nd Renl Dysfunction Immune-medited nephritis, defined s renl dysfunction or Grde 2 incresed cretinine, requirement for corticosteroids, nd no cler lternte etiology, cn occur with tretment. Monitor ptients for elevted serum cretinine prior to nd periodiclly during tretment. Withhold for moderte (Grde 2) or severe (Grde 3) incresed serum cretinine nd dminister corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents followed by corticosteroid tper. If worsening or no improvement occurs, increse dose of corticosteroids to 1 to 2 mg/kg/dy prednisone equivlents nd permnently discontinue. Permnently discontinue nd dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed by corticosteroid tper for life-thretening (Grde 4) incresed serum cretinine [see Dosge nd Administrtion (2.5) nd Adverse Rections (6.1)]. Melnom s Single Agent In Trils 1, 5, nd 7, nephritis nd renl dysfunction of ny grde occurred in 5% (40/787) of ptients. Immune-medited nephritis nd renl dysfunction occurred in 0.8% (6/787) of ptients: four ptients with Grde 3 nd two ptients with Grde 2 cses. The medin time to onset of immune-medited nephritis nd renl dysfunction ws 4.8 months (rnge: 1 to 7.5 months). Immune-medited nephritis nd renl dysfunction led to withholding of in four ptients (0.5%). Six ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 16 dys (rnge: 1 dy to 9.9 months). Complete resolution (defined s improved to bseline with completion of corticosteroids) occurred in three ptients. Three ptients resumed fter resolution without recurrence of nephritis or renl dysfunction. with Ipilimumb In Trils 4 nd 7, immune-medited nephritis nd renl dysfunction occurred in 2.2% (9/407) of ptients: four ptients with Grde 4, three ptients with Grde 3, nd two ptients with Grde 2 cses. The medin time to onset ws 2.7 months (rnge: 9 dys to 7.9 months). Immune-medited nephritis nd renl dysfunction led to permnent discontinution of nd of ipilimumb in three ptients (0.7%) nd withholding of nd of ipilimumb in two ptients (0.5%). Six ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 13.5 dys (rnge: 1 dy to 1.1 months). Complete resolution occurred in nine ptients. Two ptients resumed with ipilimumb fter resolution without recurrence of nephritis or renl dysfunction.

9 (nivolumb) NSCLC In Tril 3, immune-medited renl dysfunction (Grde 2) occurred in 0.3% (1/287) of ptients. The time to onset in this ptient ws 1.5 months. The ptient permnently discontinued, received high-dose corticosteroids, nd experienced complete resolution. RCC In Tril 6, renl injury occurred in 7% (27/406) of ptients on nd 3.0% (12/397) of ptients on everolimus, rther thn lbortory cretinine. Immune-medited nephritis nd renl dysfunction occurred in 3.2% (13/406) of ptients receiving (one with Grde 5, one with Grde 4, five with Grde 3, nd six with Grde 2). The medin time to onset ws 5.4 months (rnge: 1.1 to 12.3 months). Medin durtion ws 1.4 months (rnge: 0.1 to 18 months). ws permnently discontinued in five ptients. Dose dely occurred in eight ptients. Five ptients hd complete resolution. Two ptients resumed fter complete resolution nd hd no recurrence of nephritis. chl In Trils 8 nd 9, nephritis nd renl dysfunction occurred in 4.9% (13/263) of ptients treted with. This included one reported cse (0.3%) of utoimmune nephritis (Grde 3). 5.6 Immune-Medited Rsh Immune-medited rsh cn occur with tretment. Severe rsh (including rre cses of ftl toxic epiderml necrolysis) occurred in the clinicl progrm of. Monitor ptients for rsh. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for severe (Grde 3) or life-thretening (Grde 4) rsh. Withhold for severe (Grde 3) rsh nd permnently discontinue for life-thretening (Grde 4) rsh [see Dosge nd Administrtion (2.5)]. Melnom s Single Agent In Trils 1, 5, nd 7, immune-medited rsh occurred in 9% (72/787) of ptients: seven ptients with Grde 3, 15 ptients with Grde 2, nd 50 ptients with Grde 1 rsh. The medin time to onset ws 2.8 months (rnge: 3 dys to 13.8 months). Immunemedited rsh led to permnent discontinution of in one ptient (0.1%) nd withholding of in six ptients (0.8%). Seven ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 15 dys (rnge: 4 dys to 1.0 months). Complete resolution (defined s complete resolution of symptoms with completion of corticosteroids) occurred in 32 ptients (44%). Among the 35 ptients who resumed fter resolution, one hd recurrence. with Ipilimumb In Trils 4 nd 7, immune-medited rsh occurred in 22.6% (92/407) of ptients: 15 ptients with Grde 3, 31 ptients with Grde 2, nd 46 ptients with Grde 1 rsh. The medin time to onset ws 18 dys (rnge: 1 dy to 9.7 months). Immune-medited rsh led to permnent discontinution of nd of ipilimumb in two ptients (0.5%) nd withholding of nd of ipilimumb in 16 ptients (3.9%). Sixteen ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 14 dys (rnge: 2 dys to 4.7 months). Complete resolution occurred in 43 ptients. Among the 54 ptients who resumed nd ipilimumb fter resolution, three hd recurrence. NSCLC In Tril 3, immune-medited rsh occurred in 6% (17/287) of ptients receiving. Grde 3 rsh developed in four ptients (1.4%), of whom one discontinued tretment. RCC In Tril 6, rsh occurred in 28% (112/406) of ptients on nd 36% (143/397) of ptients on everolimus. Immune-medited rsh, defined s rsh treted with systemic or topicl corticosteroids, occurred in 7% (30/406) of ptients receiving (four with Grde 3, seven with Grde 2, nd nineteen with Grde 1). The medin time to onset ws 3.2 months (rnge: 2 dys to 25.8 months). Medin durtion ws 2.6 months (rnge: 0.3 to 9.4 months). Four ptients received orl nd 26 received topicl corticosteroids. Two ptients permnently discontinued nd dose dely occurred in two ptients. Seventeen ptients hd complete resolution. Thirteen ptients who continued on or experienced dose dely hd no recurrence of rsh. chl In Trils 8 nd 9, rsh occurred in 22% (58/263) of ptients receiving. Immune-medited rsh occurred in 7% (18/263), with medin time to onset of 2.2 months (rnge: 1 dy to 8.5 months). Of these 18 cses, four were Grde 3, three were Grde 2, nd 11 were Grde 1. Nine ptients received systemic corticosteroids with or without topicl steroids, nd the remining nine ptients received topicl corticosteroids lone. Three ptients hd dose dely. No ptients permnently discontinued due to rsh. 5.7 Immune-Medited Encephlitis Immune-medited encephlitis cn occur with tretment. Withhold in ptients with new-onset moderte to severe neurologic signs or symptoms nd evlute to rule out infectious or other cuses of moderte to severe neurologic deteriortion. Evlution my include, but not be limited to, consulttion with neurologist, brin MRI, (nivolumb) nd lumbr puncture. If other etiologies re ruled out, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for ptients with immune-medited encephlitis, followed by corticosteroid tper. Permnently discontinue for immune-medited encephlitis [see Dosge nd Administrtion (2.4)]. In Tril 3, ftl limbic encephlitis occurred in one ptient (0.3%) receiving fter 7.2 months of exposure. ws discontinued; corticosteroids were dministered. In Tril 7, encephlitis ws identified in one ptient receiving with ipilimumb (0.2%) fter 1.7 months of exposure. In Trils 8 nd 9, encephlitis occurred in two ptients (0.8%) fter llogeneic HSCT fter [see Wrnings nd Precutions (5.10)]. 5.8 Other Immune-Medited Adverse Rections Other cliniclly significnt immune-medited dverse rections cn occur with. Immune-medited dverse rections my occur fter discontinution of therpy. For ny suspected immune-medited dverse rections, exclude other cuses. Bsed on the severity of the dverse rection, permnently discontinue or withhold, dminister high-dose corticosteroids, nd if pproprite, initite hormone-replcement therpy. Upon improvement to Grde 1 or less, initite corticosteroid tper nd continue to tper over t lest 1 month. Consider restrting fter completion of corticosteroid tper bsed on the severity of the event [see Dosge nd Administrtion (2.5)]. In less thn 1.0% of ptients receiving s single gent or in combintion with ipilimumb in Trils 1, 3, 4, 5, 6, 7, 8, nd 9 (n=2150), the following cliniclly significnt, immune-medited dverse rections occurred: uveitis, iritis, pncretitis, fcil nd bducens nerve presis, demyelintion, polymylgi rheumtic, utoimmune neuropthy, Guillin-Brré syndrome, hypopituitrism, systemic inflmmtory response syndrome, gstritis, duodenitis, nd srcoidosis. Across clinicl trils of s single gent dministered t doses of 3 mg/kg nd 10 mg/kg, the following dditionl cliniclly significnt, immune-medited dverse rections were identified: motor dysfunction, vsculitis, nd mysthenic syndrome. 5.9 Infusion Rections Severe infusion rections hve been reported in less thn 1.0% of ptients in clinicl trils of. Discontinue in ptients with severe or life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. Melnom In Trils 1, 5, nd 7, infusion-relted rections occurred in 2.7% (21/787) of ptients receiving : two ptients with Grde 3, eight ptients with Grde 2, nd 11 ptients with Grde 1 infusion-relted rections. In Trils 4 nd 7, infusion-relted rections occurred in 2.5% (10/407) of ptients receiving with ipilimumb: six ptients with Grde 2 nd four ptients with Grde 1 infusion-relted rections. NSCLC In Tril 3, Grde 2 infusion rections requiring corticosteroids occurred in 1.0% (3/287) of ptients receiving. RCC In Tril 6, hypersensitivity/infusion-relted rections occurred in 6% (25/406) of ptients receiving nd 1.0% (4/397) of ptients receiving everolimus. The medin time to onset in the group ws 1.4 months (rnge: 1 dy to 27.6 months). Seven ptients received corticosteroids on the dy of dministrtion. Two ptients discontinued, one for Grde 4 rection nd one for Grde 2 event. No events led to dose dely. Interruption of the infusion ws required in ten ptients. chl In Trils 8 nd 9, hypersensitivity/infusion-relted rections occurred in 16% (42/263) of ptients receiving : Two ptients with Grde 3, 24 with Grde 2, nd 16 with Grde 1 rections. Ten ptients received systemic corticosteroids. Infusion ws interrupted in seven ptients. Two ptients hd dose dely. No events led to permnent discontinution of Complictions of ogeneic HSCT fter Complictions, including ftl events, occurred in ptients who received llogeneic HSCT fter. Outcomes were evluted in 17 ptients from Trils 8 nd 9 who underwent llogeneic HSCT fter discontinuing (15 with reduced-intensity conditioning, two with myelobltive conditioning). The medin ge t HSCT ws 33 (rnge: 18 to 56), nd medin of 9 doses of hd been dministered (rnge: 4 to 16). Six of 17 ptients (35%) died from complictions of llogeneic HSCT fter. Five deths occurred in the setting of severe or refrctory GVHD. Grde 3 or higher cute GVHD ws reported in 5/17 ptients (29%). Hypercute GVHD, defined s GVHD occurring within 14 dys fter stem cell infusion, ws reported in 2 ptients (20%). A steroid-requiring febrile syndrome, without n identified infectious cuse, ws reported in six ptients (35%) within the first 6 weeks post-trnsplnttion, with five ptients responding to steroids. Two cses of encephlitis were reported: one cse of Grde 3 lymphocytic encephlitis without n identified infectious cuse, which occurred nd resolved on steroids, nd one cse of Grde 3 suspected virl encephlitis which ws resolved with ntivirl tretment. Heptic veno-occlusive disese (VOD) occurred in one ptient, who received reduced-intensity conditioned llogeneic SCT nd died of GVHD nd multi-orgn filure. Other cses of heptic VOD fter reduced-intensity conditioned llogeneic HSCT hve lso been reported in ptients with lymphom who received PD-1 receptor blocking ntibody before trnsplnttion. Cses of ftl hypercute GVHD hve lso been reported.