6/3/16

1

UpdatesinHematology

ManpreetChahal,PharmD,PhDOncologyPharmacist,SummitCancerCenters,SpokaneWAAdjunctClinicalInstructor,WSUCollegeofPharmacymschahal@wsu.eduNorthwestPharmacyConvenJonJune3,2016

Disclosure •  ReceivedhonorariaonSpeaker’sBureauforPfizerandTakedaOncology

•  ReceivedhonorariaforAdvisoryBoardofPfizerandLilly

Objectives•  SummarizemedicaJonsapprovedforhematologicalindicaJonsandtheirmechanismofacJon

•  IdenJfyappropriatepaJentsandclinicalbenefitsofeachmedicaJon

•  Reviewcommonadverseeffectsandappropriatemanagementstrategies

OurSetting •  SummitCancerCenters•  OutpaJentOncologyClinics

•  SpokaneWA•  SpokaneValleyWA•  PostFallsID•  Satellite–Once-a-monthclinics

•  ColfaxWA•  ColvilleWA•  StMariesID

•  5MedicalOncologists,2NPs•  InfusionCenters•  SpecialtyMedicaJonDispensing

•  RadiaJon•  ClinicalTrials(PhaseII-IV)

Darzalex®(daratumumab) •  IndicaJon•  Relapsed/RefractoryMulJpleMyeloma

•  MOA•  AnJ-CD38monoclonalanJbody•  CD38highlyexpressedonmyelomacells

•  Dosing•  16mg/kgIVweeklyforweeks1-8,every2weeksforweeks9-24andmonthlythereaberunJldiseaseprogression

•  Pre-medicatewithsteroid,anJhistamine&anJpyreJc1hrpriortoallinfusions

•  Post-infusionmedicatewithoralsteroidsondays1&2fordelayedreacJons

•  HowAvailable•  100mg/5mland400mg/20mlvialsinsoluJon

•  REMS•  None

6/3/16

2

Darzalex®(daratumumab) •  ClinicalTrialInformaJon•  Open-label,singlearmmonotherapy•  MostpaJentshighlypre-treated•  Primaryoutcomewasoverallresponserate

5

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.14 CLINICAL STUDIESStudy 1, was an open-label trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 5).

Table 5: Efficacy results for Study 1

N=106

Overall response rate (ORR)95% CI (%)

31 (29.2%)(20.8, 38.9)

Stringent complete response (sCR) 3 (2.8%)

Complete response (CR) 0

Very good partial response (VGPR) 10 (9.4%)

Partial response (PR) 18 (17.0%)

ORR = sCR+CR+VGPR+PRCI = confidence interval

The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).Study 2 was an open-label dose escalation trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).15 REFERENCES1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedDARZALEX is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as:NDC 57894-502-05 contains one 100 mg/5 mL single-dose vialNDC 57894-502-20 contains one 400 mg/20 mL single-dose vial16.2 Storage and StabilityStore in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF).Do not freeze or shake. Protect from light. This product contains no preservative.17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).Infusion ReactionsAdvise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions:• itchy, runny or blocked nose; chills, nausea, throat irritation, cough,

headache, shortness of breath or difficulty breathing [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Interference with Laboratory TestsAdvise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking DARZALEX, in the event of a planned transfusion. Advise patients that DARZALEX can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response.

Manufactured by:Janssen Biotech, Inc. Horsham, PA 19044U.S. License Number 1864© Janssen Biotech, Inc., 2015

DARZALEX™ (daratumumab) injection DARZALEX™ (daratumumab) injection

Darzalex®(daratumumab) •  KeySideEffects•  BlackBoxWarnings–None

•  SevereSideEffects•  InfusionreacJons(pre&postmedicaJonneeded)•  HerpeszosterreacJvaJon(prophylaxisrecommended)

•  Drug-LabInteracJon•  Interfereswithcross-matchingofRBCs,cross-matchpriortostart

•  CommonSideEffects•  FaJgue,backpain,pyrexia,cough,nausea&URIs

Empliciti®(elotuzumab) •  IndicaJon•  Relapsed/RefractoryMulJpleMyeloma,incombinaJonwithlenalidomideanddexamethasone

•  MOA•  AnJ-SLAMF7(CS1)anJbody•  SLAMF7expressedonmyelomaandNKcells

•  Dosing•  10mg/kgIVweeklyx2weeks,thenq2weeksthereaber(JtrateperPI)•  Pre-medicatewithIVsteroid,anJhistamine,H2blocker&anJpyreJc

•  HowAvailable•  300mg&400mgsingledosevials

•  REMS•  None

Empliciti®(elotuzumab)-MOA

50

Mechanism of Action

Liu YC, et al. Blood Lymphat Cancer. 2014 Jun; 2014(4): 15-27. Permission for use granted by DovePress - https://creativecommons.org/licenses/by-nc/3.0/ No changes were made to this image.

Empliciti®(elotuzumab) •  ClinicalTrailInformaJon•  Randomized,open-labeltrial•  Lenalidomide&dexamethasone+/-elotuzumab

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionElotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo.

12.2 Pharmacodynamics

Cardiac Electrophysiology

EMPLICITI does not prolong the QT interval to any clinically relevant extent in combination with lenalidomide and dexamethasone at the recommended dose or as monotherapy (at a dose 2 times the recommended dose).

12.3 PharmacokineticsElotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance. The administration of the recommended 10 mg/kg EMPLICITI regimen in combination with lenalidomide/dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 μg/mL (52%).

Elimination: The clearance of elotuzumab decreased from a geometric mean (CV%) of 17.5 (21.2%) to 5.8 (31%) mL/day/kg with an increase in dose from 0.5 (i.e., 0.05 times the recommended dosage) to 20 mg/kg (i.e., 2 times the recommended dosage). Based on a population PK model, when elotuzumab is given in combination with lenalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 82.4 (48%) days.

Specific Populations

Clinically significant differences were not observed in the pharmacokinetics of elotuzumab based on age (37-88 years), gender, race, baseline LDH, albumin, renal impairment ranging from mild to severe (creatinine clearance (CLcr) 15 to 89 mL/min) renal impairment, end-stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis, and mild (NCI-CTEP) hepatic impairment. The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic impairment is unknown.

Body weight: The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity or mutagenicity data are available for elotuzumab in animals or humans. Fertility studies have not been performed for elotuzumab.

14 CLINICAL STUDIES

The efficacy and safety of EMPLICITI in combination with lenalidomide and dexamethasone were evaluated in a randomized, open-label trial in patients with multiple myeloma who had received one to three prior therapies and had documented progression following their most recent therapy.

Eligible patients were randomized in a 1:1 ratio to receive either EMPLICITI in combination with lenalidomide and low-dose dexamethasone or lenalidomide and low-dose dexamethasone. Treatment was administered in 4-week cycles until disease progression or unacceptable toxicity. EMPLICITI 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to EMPLICITI infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without EMPLICITI, dexamethasone 40 mg was administered as a single oral dose weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumor response was conducted every 4 weeks.

A total of 646 patients were randomized to receive treatment: 321 to EMPLICITI in combination with lenalidomide and low-dose dexamethasone and 325 to lenalidomide and low-dose dexamethasone.

Demographics and baseline disease characteristics were balanced between treatment arms. The median age was 66 years (range, 37-91); 57% of patients were 65 years or older; 60% of patients were male; whites comprised 84% of the study population, Asians 10%, and blacks 4%. The ECOG performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients, and ISS Stage was I in 43%, II in 32%, and III in 21% of patients. The cytogenetic categories of del 17p and t(4;14) were present in 32% and 9% of patients, respectively. The median number of prior therapies was 2. Thirty-five percent (35%)

of patients were refractory (progression during or within 60 days of last therapy) and 65% were relapsed (progression after 60 days of last therapy). Prior therapies included stem cell transplant (55%), bortezomib (70%), melphalan (65%), thalidomide (48%), and lenalidomide (6%).

The efficacy of EMPLICITI was evaluated by progression-free survival (PFS) as assessed by hazard ratio, and overall response rate (ORR) as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation (EBMT) response criteria. Efficacy results are shown in Table 7 and Figure 1. The median number of treatment cycles was 19 for the EMPLICITI group and 14 for the comparator arm with a minimum follow-up of two years.

Table 7: Efficacy Results

EMPLICITI + Lenalidomide/

Dexamethasone N=321

Lenalidomide/ Dexamethasone

N=325

PFSHazard Ratio [95% CI] 0.70 [0.57, 0.85] Stratified log-rank test p-value* 0.0004Median PFS in months [95% CI] 19.4 [16.6, 22.2] 14.9 [12.1, 17.2]ResponseOverall Response (ORR)† n (%) 252 (78.5) 213 (65.5) [95% CI] [73.6, 82.9] [60.1, 70.7] p-value‡ 0.0002 Complete Response (CR + sCR)†,§ n (%)

14 (4.4)¶ 24 (7.4)

Very Good Partial Response (VGPR)† n (%)

91 (28.3) 67 (20.6)

Partial Response (PR)† n (%) 147 (45.8) 122 (37.5)

* p-value based on the log-rank test stratified by ß2 microglobulins (<3.5 mg/L vs ≥3.5 mg/L), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other).

† European Group for Blood and Marrow Transplantation (EBMT) criteria.‡ p-value based on the Cochran-Mantel-Haenszel chi-square test stratified by ß2 microglobulins

(<3.5 mg/L vs ≥3.5 mg/L), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other).

§ Complete response (CR) + stringent complete response (sCR).¶ EMPLICITI’s interference with the assessment of myeloma protein with immunofixation

and serum protein electrophoresis assay may interfere with correct response classification [see Drug Interactions (7)].

Figure 1: Progression-Free Survival

0

10

20

30

40

50

60

70

80

90

100

Prob

abilit

y Pr

ogre

ssio

n Fr

ee (%

)

E-LdNo. of Subjects at Risk

Ld

Progression-Free Survival (Months)

321325

0

279249

4 8

232192

12

195158

16

157123

32

127

28

4221

24

8548

36

1

4020

12889

HR (95% CI): 0.70 (0.57, 0.85)p-value: 0.0004

LdE-Ld

The 1- and 2-year rates of PFS for EMPLICITI in combination with lenalidomide and dexamethasone treatment were 68% and 41%, respectively, compared with 57% and 27%, respectively, for lenalidomide and dexamethasone treatment.

EMPLICITI™ (elotuzumab) EMPLICITI™ (elotuzumab)

Empliciti®(elotuzumab) •  KeySideEffects•  BlackBoxWarnings–None

•  SevereSideEffects•  Secondprimarymalignancies•  InfusionreacJons•  InfecJon•  Hepatotoxcicity

•  CommonSideEffects•  FaJgue,diarrhea,fever,cough,peripheralneuropathy,nasopharyngiJsandpneumonia

6/3/16

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Ninlaro®(ixazomib) •  IndicaJon•  Relapsed/RefractoryMulJpleMyeloma,incombinaJonwithlenalidomideanddexamethasone

•  MOA•  Proteosomeinhibitor

•  Dosing•  4mgorallydays1,8and15ofeach28daycycle

•  HowAvailable•  4mg,3mgand2.3mgcapsules

•  REMS•  None

Ninlaro®(ixazomib)-MOA

82

Mechanism of Action

Boccadoro, et al. Cancer Cell Int. 2005 Jun 1;5(1):18. Permission for use granted by BioMed Central Ltd - https://creativecommons.org/licenses/by-nc/3.0/ No changes were made to this image.

Ninlaro®(ixazomib) •  ClinicalTrailInformaJon•  Randomized,double-blind,placebocontrolledtrail•  IxazomibORplacebo+lenalidomideanddexamethasone

Page 17 of 23 

 

The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results. Response was assessed every four weeks until disease progression.

The approval of NINLARO was based upon a statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in Table 7 and shown in Figure 1.

Table 7: Progression-Free Survival and Response Rate

NE: Not evaluable. *Hazard ratio is based on a stratified Cox’s proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen. †P-value is based on the stratified log-rank test.

The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in the placebo regimen for responders in the response evaluable population.

NINLARO + Lenalidomide and Dexamethasone

(N = 360)

Placebo + Lenalidomide and Dexamethasone

(N = 362) Progression-free Survival PFS Events, n (%) 129 (36) 157 (43) Median (months) (95% CI)

20.6 (17.0, NE)

14.7 (12.9, 17.6)

Hazard Ratio* (95% CI)

0.74 (0.59, 0.94)

p-value† 0.012 Response Rate Overall Response Rate, n (%) 282 (78) 259 (72)

Complete Response 42 (12) 24 (7) Very Good Partial Response 131 (36) 117 (32) Partial Response 109 (30) 118 (33)

Ninlaro®(ixazomib) •  KeySideEffects•  BlackBoxWarnings–None

•  SevereSideEffects•  Peripheralneuropathy•  Hepatotoxcicity•  Embryo-fetaltoxicity

•  CommonSideEffects•  N/V/D,rash,fluidretenJon,thrombocytopenia

Imbruvica®(ibrutinib) •  IndicaJon•  ChroniclymphocyJcleukemia(CLL),1stline

•  MOA•  Brutontyrosinekinase(btk)inhibitor

•  Dosing•  420mgpooncedaily

•  HowAvailable•  140mgcapsules

•  REMS•  None

Imbruvica®(ibrutinib)-MOA

6/3/16

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Imbruvica®(ibrutinib) •  ClinicalTrailInformaJon•  Randomized,mulJcenter,double-blind,placebocontrolledtrail•  IbruJnibORplaceboincombinaJonwithbendamusJne&rituximab

28

Table 15: Efficacy Results in Study 4

Endpoint IMBRUVICA + BR

N=289 Placebo + BR

N=289 Progression Free Survivala Number of events (%) 56 (19.4) 183 (63.3) Median (95% CI), months Not reached   13.3 (11.3, 13.9)  HR (95% CI) 0.20 (0.15, 0.28) Overall Response Ratea 82.7%  67.8% a IRC evaluated, Twenty four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm

achieved complete response BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio

Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Study 4

Imbruvica®(ibrutinib) •  KeySideEffects•  BlackBoxWarnings–None

•  SevereSideEffects•  Hemorrhage•  InfecJons•  Cytopenias•  Afib•  HTN•  TLS

•  CommonSideEffects•  Neutropenia,thrombocytopenia,diarrhea,anemia,rash

Venclexta®(venetoclax) •  IndicaJon•  ChroniclymphocyJcleukemia(CLL)with17pdeleJon,2ndlinetherapy

•  MOA•  BCL-2inhibitor

•  Dosing•  20mgdailyfor7days,Jtrateupto400mgpodailyperPI

•  HowAvailable•  Tablets–10mg,50mg,100mg

•  REMS•  None

Venclexta®(venetoclax)-MOA

Venclexta®(venetoclax) •  ClinicalTrailInformaJon•  Open-label,singlearm,mulJcenterclinicaltrial•  PaJentswithCLLwithconfirmed17pdeleJonandpost1lineoftherapy

CLL FISH Probe Kit, which is FDA approved for selection of patients for VENCLEXTA treatment. Patients received VENCLEXTA via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of VENCLEXTA orally once daily until disease progression or unacceptable toxicity.

The efficacy of VENCLEXTA was evaluated by overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).

Table 9 summarizes the baseline demographic and disease characteristics of the study population.

Table 9. Baseline Patient Characteristics Characteristics N=106

Age, years; median (range) 67 (37-83) White; % 97.1 Male; % 65.1 ECOG performance status; % 0 1 2

39.6 51.9 8.5

Tumor burden; % Absolute lymphocyte count ≥25 x 109/L One or more nodes ≥5 cm

50.0 52.8

Number of prior therapies; median (range) 2.5 (1-10) Time since diagnosis, months; median (range)a 79.4 (1.2-385.6) aN=105.

The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 10.

Table 10. Efficacy Results for Patients with Previously Treated CLL with 17p Deletion by IRC

VENCLEXTA N=106

ORR, n (%) (95% CI)

85 (80.2) (71.3, 87.3)

CR + CRi, n (%) CR, n (%) CRi, n (%)

8 (7.5) 6 (5.7) 2 (1.9)

nPR, n (%) 3 (2.8) PR, n (%) 74 (69.8) CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = independent review

Venclexta®(venetoclax) •  KeySideEffects•  BlackBoxWarnings–None

•  ContraindicaJons•  ConcomitantusewithstrongCYP3Ainhibitors

•  SevereSideEffects•  TLS

•  Assessriskandpre-medicatepaJents,ensureadequatehydraJon•  Neutropenia•  Embryo-Fetaltoxicity

•  CommonSideEffects•  Neutropenia,diarrhea,nausea,anemia,UTI,thrombocytopeniaandfaJgue

•  ImmunizaJon–donotadministerlivealenuatedvaccinespriorto,duringorabervenetoclaxtreatment

6/3/16

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Opdivo®(nivolumab) •  IndicaJon•  RelapsedClassicalhodgkinlymphomapostHSCTandposttransplantAdcetristreatment

•  MOA•  AnJ-PD1anJbody,immunotherapy

•  Dosing•  3mg/kgIVevery2weeks

•  HowAvailable•  40mg/4mlsingle-dosevial&100mg/10mlsingle-dosevial

•  REMS•  None

Opdivo®(nivolumab)-MOA

Opdivo®(nivolumab) •  ClinicalTrailInformaJon•  Single-arm,open-label,mulJcentertrial

OPDIVO® (nivolumab) OPDIVO® (nivolumab)

Table 18: Efficacy Results - Trial 6

OPDIVO (n=410)

Everolimus (n=411)

Overall SurvivalEvents (%) 183 (45) 215 (52)Median survival in months (95% CI) 25.0 (21.7, NE) 19.6 (17.6, 23.1)Hazard ratio (95% CI) 0.73a (0.60, 0.89) p-value 0.0018b

Confirmed Objective Response Rate (95% CI)

21.5% (17.6, 25.8) 3.9% (2.2, 6.2)

Median duration of response in months (95% CI)

23.0 (12.0, NE) 13.7 (8.3, 21.9)

Median time to onset of confirmed response in months (min, max)

3.0 (1.4, 13.0) 3.7 (1.5, 11.2)

a Hazard ratio is obtained from a Cox proportional hazards model stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region with treatment as the sole covariate.

b p-value is obtained from a two-sided log-rank test stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region. The corresponding O’Brien-Fleming efficacy boundary significance level is 0.0148.

Figure 10: Overall Survival - Trial 6

Prob

abilit

y of

Sur

vival

OPDIVONumber at Risk

Everolimus

Overall Survival (Months)

410

411

389

366

359

324

337

287

305

265

213

187

139

115

29 373

20 261

0

0

275

241

EverolimusOPDIVO

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 3324 27 30

14.4 Classical Hodgkin Lymphoma

Two studies evaluated the efficacy of OPDIVO as a single agent in patients with cHL after failure of autologous HSCT and post-transplantation brentuximab vedotin.

Trial 8 was a single-arm, open-label, multicenter, multicohort study in cHL. Trial 9 was an open-label, multicenter, dose escalation study that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance less than 40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.

Efficacy was evaluated by objective response rate (ORR) as determined by an independent radiographic review committee (IRRC). Additional outcome measures included duration of response. Efficacy was evaluated in 95 patients in Trials 8 and 9 combined who had received brentuximab vedotin after failure of autologous HSCT. The median age was 37 years (range: 18 to 72). The majority were male (64%) and white (87%). Patients had received a median of 5 prior systemic regimens (range: 3 to 15).

Results are shown in Table 19. Patients received a median of 17 doses of OPDIVO (range 3 to 48), with a median duration of therapy of 8.3 months (range 1.9 to 24 months).

Table 19: Efficacy in cHL after Autologous HSCT and Brentuximab Vedotin

Trial 8 and Trial 9 (n=95)

Objective Response Rate, n (%)a

(95% CI)62 (65%) (55, 75)

Complete Remission Rate (95% CI)

7 (7%) (3, 15)

Partial Remission Rate (95% CI)

55 (58%) (47, 68)

Median Duration of Response (months) (95% CI) Range

8.7 (6.8, NE)

0.0+, 23.1+

Median Time to Response (months) Range

2.1 0.7, 5.7

a Per 2007 revised International Working Group criteria.

16 HOW SUPPLIED/STORAGE AND HANDLING

OPDIVO® (nivolumab) 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

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:

• Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.2)].

• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.3)].

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.4)].

• Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.5)].

• Rash: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.6)].

• Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Warnings and Precautions (5.7)].

• Infusion Reactions: Advise patients of the potential risk of infusion reaction [see Warnings and Precautions (5.9)].

• Complications of allogeneic HSCT after OPDIVO: Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.10)].

• Females of Reproductive Potential: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations (8.3)].

• Lactation: Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations (8.2)].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

U.S. License No. 1713

Opdivo®(nivolumab)•  KeySideEffects•  BlackBoxWarnings–None

•  SevereSideEffects•  PneumoniJs•  ColiJs•  HepaJJs•  NephriJs•  InfusionreacJon

•  CommonSideEffects•  FaJgue,rash,pruritus,diarrheaandnausea

Assessment

Assessment WhichofthefollowingtherapeuJcagentsinterfereswithcross-matchingofRBCs?

A.  ElotuzumabB.  DaratumumabC.  IbruJnibD.  Nivolumab

6/3/16

6

Assessment PaJentsshouldavoidlivealenuatedvaccinespriorto,duringandabertreatmentwithwhichofthefollowingtherapeuJcagent?

A.  ElotuzumabB.  DaratumumabC.  VenetoclaxD.  Nivolumab

Assessment PneumoniJsisasevereadverseeffectofthefollowingagent:

A.  ElotuzumabB.  DaratumumabC.  IbruJnibD.  Nivolumab

References •  Darzalex(daratumumab).PrescribingInformaJon.November2015.JanssenBiotech,Inc.

•  EmpliciJ(elotuzumab).PrescribingInformaJon.November2015.Bristol-MyersSquibbCompany.

•  Ninlaro(ixazomib).PrescribingInformaJon.November2015.TakedaPharmaceuJcalCompany.

•  Imbruvica(ibruJnib).PrescribingInformaJon.May2016.JansenBiotech,Inc.

•  Venclexta(venetoclax).PrescribingInformaJon.April2016.AbbVie,Inc.

•  Opdivo(nivolumab).PrescribingInformaJon.May2016,Bristol-MyersSquibbCompany.

Questions???

mschahal@wsu.edu

GoCougs!!