SalvadorMartinAlgarraMedicalOncology

ClínicaUniversidaddeNavarraPamplona,Spain

Disclosures• ParticipationinadvisoryboardsandsponsoredlecturesofBMS,MSD,Roche.

Until2010,immunotherapyhadadisappointinghistoryinmetastaticmelanoma

•HDIL-2andadoptiveTcelltherapywerethetreatmentsabletoinducedurableresponses,but…• just inasmallsubsetofpatients,• atthecostofsignificanttoxicity,and•wereonlyavailableinselectedcenters.

Alexander M. Menzies, Georgina V. Long

Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond

European Journal of Cancer, Volume 49, Issue 15, 2013, 3229–3241

Until2010,immunotherapyhadadisappointinghistoryinmetastaticmelanoma

• Trialswithotherimmune-activeagents,includingbio-chemotherapy,werenegative.

• Severalvaccinesfailedtodemonstrateclinicalbenefit.

Alexander M. Menzies, Georgina V. Long

Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond

European Journal of Cancer, Volume 49, Issue 15, 2013, 3229–3241

• Inonly5years,advancedmelanomahavebeentransformedfromanincurablediseaseintoacurableone,and…

• Weareonlyatthebeginningofdiscoveringitstransversalimpactthroughoutsolidtumoroncology

After2010,theresultsofimmunotherapytrialsonmetastaticmelanomachangedmarkedly

Semin Oncol 42:429-435,2015

• Theimpactofthefirstscheckpointinhibitors:anti–CTLA-4(cytotoxicT-lymphocyteantigen-4)andanti–PD-1/anti– PD-L1(programmeddeath-1receptoranditsligandPD-L1)isunprecedented.

• Breakingtolerancerepresentsamajorparadigmshift…wehaveenteredanewera.

Semin Oncol 42:429-435,2015

ESMO PRECEPTORSHIP PROGRAMMEIMMUNO-ONCOLOGY

From the essentials of tumour immunology to clinical application

T cell activation and inhibition relies upon co-stimulatory (+) or inhibitory signals (−) to prevent widespread autoimmunity

Alexander M. Menzies, Georgina V. Long. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyondModified from

European Journal of Cancer, Volume 49, Issue 15, 2013, 3229–3241

pembrolizumab

T cell regulation

CTLA-4 is involved in the early phase of T cell activation.

PD-1 is expressed on T cells in the periphery, and interacts with PD-L1 expressed on tissues.

EMACheckpointInhibitorsDrugsApprovalinAdvancedMelanomaDateofissueofmarketingauthorisation fortheEuropeanUnion

• Ipilimumab 13/07/2011• Nivolumab 19/06/2015• Pembrolizumab 17/07/2015• Nivolumab with Ipilimumab 1April2016(“… relativetonivolumabmonotherapy,anincreaseinprogression-freesurvival(PFS)forthecombinationofnivolumab withipilimumab isestablishedonlyinpatientswithlowtumour PD-L1expression…”)

•Anti-CTLA-4therapyinMelanoma

Tremelimumab Phase I• IgG2mAb targetingCTLA-4;Dose: 0.03- 15mg/kg• 39patients (34melanoma)• 29melanomapatients evaluable

• 2CR25+y34+mo• 2PR25+y26+mo• 4SD

• 5SD/PRpatients had DFS23+,24+,26+,35+,36+mo after localthx• 15mg/kgtolerablewith diarrea, dermatitisDLT

Ribasetal.JClinOncol2005;23:8968

CamachoLHetalJCO2009Mar 1;27(7):1075-81

Tremelimumab Phase I/II

Ribasetal.ASCO2008:9011

Tremelimumab Phase IIIfailedtodemonstrateasurvivaladvantage

BMCMed.2016;14:20.AdvancesinimmunotherapyformelanomaJasonM.Redman,GeoffreyT.Gibney,andMichaelB.Atkins

• … datafromthisopen-labelstudymayhavebeenaffectedbycrossoverofpatientsinthechemotherapyarmtoIpilimumab,possiblyconfoundinganypotentialsurvivaldifference.

• Evaluationoftremelimumab’s activityincombinationwithotheragentsisongoing.

Tremelimumab Phase III

IpilimumabPhaseI/II

15

Cohort RR SD Duration Control rate

A (n=34) 1 PR 4 246 15%

B (n=30) 1 PR 3 211 13%

C (n=24) 1 PR + 1 CR 7 263 / 275 39%

Weber et al. ASCO 2007: 8523

Hamidetal.JClinOncol2008;26:9025

Response patterns with Ipilimumab in melanoma

PD = progressive disease; RECIST = Response Evaluation Criteria In Solid Tumors; WHO = World Health Organisation.Graphs for illustrative purposes showing responses to ipilimumab in advanced melanoma.

Figures adapted from Wolchok J, et al. Clin Cancer Res 2009;15:7412–7420.

Time(days)

Tumorch

angefrom

baseline(%

) 50

0

–25

–50

–75

–100

–125

25

100 Therapystart

-63 -21 21 63 105 147 189 231 273 315 357

Responseafterincreaseintumorvolume

BaselineNewlesionsTotal

ThresholdsforresponseorPD(RECIST)

50

25

0

–25

–50

–75

–100

–125

Therapystart

Tumorch

angefrom

baseline(%

)

Time(days)

Stabledisease(RECIST/WHOcriteria)

-63 -21 21 63 105 147 189 231 273 315 357

Tumorch

angefrom

baseline(%

)

Reductionintumorburdenafternewlesions

50

25

0

–25

–50

–75

–100

–125

Time(days)

Therapystart

-63 -21 21 63 105 147 189 231 273 315 357

Tumorch

angefrom

baseline(%

)

50

25

0

–25

–50

–75

–100

–125

Therapystart

Time(days)–63 –21 21 63 105 147 189 231 273 315 357 399 441 483 525

Responseinbaselinelesions(RECIST/WHOcriteria)

MercurynumberONCES15NP00693-01Weber JS et al, Lancet Oncol 16, 375–384, 2015

SurvivalrateafterIpilimumabsecondlineinmelanoma

O´Day et al. ASCO 2009: 9033

PhaseIIItrialIpilimumabsecondline

19

Unresectable Stage III/IV Melanoma HLA-

A2+

Previous treatment with chemotherapy or inmunotherapy

n: 676

RANDOMIZACION

3:1:1

Primary endpoint: Overall SurvivalSecondary endpoint: toxicity

Ipilimumab, the first therapy for unresectable or metastatic melanoma to improve OS in a phase III trial

Median OS, months 95% CI HR P value

Survival rate (%)1-year 2-year

Ipilimumab + gp100 10.0 8.5–11.5 0.68 <0.001 43.6 21.6Ipilimumab 10.1 8.0–13.8 0.66 0.003 45.6 23.5gp100 6.4 5.5–8.7 25.3 13.7

AEs=adverseevents;irAEs =immune-relatedadverseevents..AdaptedfromHodiFS,etal.NEngl JMed.2010;363:711–723;

Prop

ortio

n of

Pat

ient

s Al

ive

(%)

Years

0

20

40

60

80

100

0 1 2 3 4

ThemostfrequentlyreportedirAEs associatedwithipilimumab monotherapy(≥10%,allgrades)inaphaseIIItrialwere:diarrhea(28%),pruritus(24%),andrash(19%)

PhaseIIItrialIpilimumabsecondline

Hodi FS et al. N Engl J Med 2010;363:711-723

Subgroup Analyses of Overall Survival

Hodi FS et al. N Engl J Med 2010;363:711-723

• MedianOSinpatientsreceivingipilimumabplusgp100andipilimumabalonewere10.0and10.1 months,vs6.4 monthsinthosethatreceivedgp100alone.

• 1and2yearOS ratesfortheipilimumab-alonearm,of45.6 %and23.5 %,respectively,withsimilarratesfortheipilimumabplusgp100.

• 1-yearOSratewashigherthanpreviouslyreportedusinganyotherexperimentalregimenforadvancedmelanoma.

PhaseIIItrialIpilimumabsecondline

FirstlinephaseIIIIpilimumabtrial

Untreated unresectable stage III/IV Melanoma

n: 502

1:1

RANDOMIZACION

INDUCTION MANTEINANCE

Ipilimumab 10mg/Kgx4cevery21days

Ipilimumab 10mg/Kgevery12weeks

Placebox4cevery21days

Placebo every 12 weeks

Week1 Week 24Week 12

Dacarbacine 850mg/m2X8cevery21days

Dacarbacine 850mg/m2X8cevery21days

Similarresultsinfirstandsecondline

• Nolongtermdifferencesinsurvival• ChemotherapytoxicitymaylimitIpilimumabadministration

• ChemotherapymaydepleteCD4lymphocytes

• CombinationwithFotemustine withsimilarresults

• IpilimumabdemonstratedclinicalactivityinearlyphasetrialsandwasapprovedbytheFDAfollowingthereleaseofphaseIIIdata,whichshowedasignificantlyimprovedOS

Kaplan-Meier estimates of overall survival in patients treated with ipilimumabplus dacarbazine (DTIC) or placebo plus DTIC in phase III CA184-024 study.

Michele Maio et al. JCO 2015;33:1191-1196

MS(95%CI):11.4mo (10.7–12.1)

3yOS%(95%CI):22mo(20–24)1,861patientsfrom10prospectiveand2retrospectivestudieswithIpilimumab

SchadendorfD,etal.JClinOncol.2015;33:1889-1894.

SchadendorfD,etal.ClinOncol.2015;33:1889-1894.

IPIat3mg/kg(n=965)

IPIat10mg/kg(n=706)

OtherDosingRegimens(n=190)

MedianOS,mo(95%CI)

11.4(10.3-12.5)

11.1(9.9-13.0)

12.4(10.4-15.1)

3-ysurvivalrates,(95%CI)

21%,(17-24)

24%,(21-28)

20%.(14%-26)

SchadendorfD,etal.JClinOncol.2015;33:1889-1894.

MedianOSshowedaplateauat21%inthesurvivalcurvebeginningaroundyear3

• CTLA4wasthefirstimmunecheckpointreceptortobetargeted• Long-termsurvivaldatafrom10prospectiveand2retrospectivetrials(N=1861patients)

CA184-169: Study Design

IPI 3 mg/kgQ3W × 4(n = 362)

IPI 10 mg/kgQ3W × 4(n = 365)

IPI 3 mg/kgQ3W × 4(n = 32)

IPI 10 mg/kgQ3W × 4(n = 23)

Previously Treated/Untreated Metastatic MELb

(N = 727)Stratification• M0 + M1a + M1b

vs M1c withoutbrain metastases vsM1c with brain metastases

• Prior treatment (y/n)• ECOG PS (0/1) Week 1 Week 24

Ran

dom

ize

1:1

aAfter initial response (or stable disease ≥3 months) and subsequent progressive disease in the absence of intolerable toxicity.bPatients could not be treated with BRAF/PD-1 therapy.ECOG PS = Eastern Cooperative Oncology Group performance status; Q3W = every 3 weeks.

• Enrollment period: March 2012 to August 2012• No crossover allowed between treatment arms

Initial treatment phase Re-treatment phasea

OS: Randomized Patients

31

Aliv

e (%

)

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 21 27 33 39 45 483 9 18 24 30 36 4215

IPI 10 mg/kgIPI 3 mg/kg

OSIPI 10 mg/kg

n = 365IPI 3 mg/kg

n = 362Events (%) 262 (72) 279 (77)Median (95% CI), mo 15.7 (11.6, 17.8) 11.5 (9.9, 13.3)

HR (95% CI) 0.84 (0.70, 0.99)Log-rank P value 0.04

Minimum OS follow-up: ~43 mo

Number of patients at risk

IPI 10 mg/kg 365 253 196 151 126 118 105 16 0306 217 161 137 120 111 94181

IPI 3 mg/kg 362 253 168 118 95 83 76 8 0310 205 131 107 87 80 71146

54%

48% 38%

31% 31%

23%

Summary/Conclusions

• Significant improvement in OS with IPI 10 mg/kg vs IPI 3 mg/kg in patients with untreated melanoma.

• No differences were observed for the secondary endpoints of PFS/RR.• IPI 10 mg/kg was associated with higher rates of treatment-related

AEs and AEs leading to discontinuation• Although the treatment landscape has evolved for first-line, the

clinical utility of IPI in refractory patients warrants further evaluation

32

JournalofNeuro-Oncology2014,Volume118: 109–116EfficacyandsafetyofipilimumabinpatientswithadvancedmelanomaandbrainmetastasesQueiroloPetal.

ipilimumab inpatientswithmelanomaandbrainmetastases

Efficacyandsafetyofipilimumab inpatientswithpre-treated,uvealmelanoma

Ann Oncol. 2013;24(11):2911-2915.

•Adjuvanttherapy

AdjuvantInterferon

DFS5y GS5yearsIFNalfa2b 37% 46%Observation 26% 37%

Kirkwood JM,elal.JClin Oncol 14:7-171996

Alexander M M Eggermont , AMM et al The Lancet Oncology, 2015

Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

N Engl J Med 2016;375:1845-1855

Study Overview

The 5-year survival rate with ipulimumab was 11 percentage points higher than that with placebo

(65% vs. 54%), but there were substantial immune-related toxic effects.

Kaplan–Meier Estimates of Recurrence-free Survival (RFS), Overall Survival, and Distant Metastasis–free Survival (DMFS).

Eggermont AMM et al. N Engl J Med 2016;375:1845-1855

Conclusions

• As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis–free survival than placebo.

• There are more immune-related adverse events with ipilimumab than with placebo.

Eggermont AMM et al. N Engl J Med 2016;375:1845-1855

Study Overview

•AntiPD-1therapyinMelanoma

PEMBROLIZUMAB

• 44%OR• 10mg/Kg>50%RR• RRnot modified by priorIpilimumab

Hamidetal2013NEJM

2013

Robert C et al. N Engl J Med 2015;372:2521-2532

Progression-free and Overall Survival.

Original Article

Pembrolizumab versus Ipilimumab in Advanced Melanoma

N Engl J Med 372(26):2521-2532, 2015

Prespecified Subgroup Analysis of Progression-free and Overall Survival, According to Pembrolizumab Regimen.

Robert C et al. N Engl J Med 2015;372:2521-2532

N Engl J Med 372(26):2521-2532, 2015

Study Overview

In a multinational, randomized study, pembrolizumab produced significantly improved progression-free and overall

survival and less high-grade toxicity than did ipilimumab in patients with metastatic

melanoma.

N Engl J MedVolume 372(26):2521-2532

June 25, 2015

KEYNOTE-006Trial:pembrolizumab vsIpilimumab

• The6-moPFSrateswere47.3%,46.4%,and26.5%forpembrolizumab Q3W,pembrolizumab Q2W,andIPI

• OSwasimprovedoverIPIafter202deathsoccurred(HR0.60;95%CI(0.43-0.84),P =.0013forQ2W;HR0.56,95%CI(0.40-0.78),P =.0003forQ3W)andORRwas33%vs12%,P =.00002

• 6-moOSrateswere85%,88%,and75%.PFSandOSbenefitsofpembrolizumab wereobservedacrossallsubgroupsassessed

• At12monthsposttreatment,OSrateswere74%and68%forthe2pembrolizumabarms,respectively,and58%forIPI

• Theoutcomewithpembrolizumab wassuperiortoIPIinallsubset analysesofprespecifiedgroups,includingPD-L1-positivevsPD-L1-negativetumors

RibasA,etal.AACR2015.AbstractCT101.

NIVOLUMAB

Nivolumab PhaseIStudy:MelanomaPatients

• Studydesign– Nivolumab IVq2wover8-wkcyclesforupto12cycles– Dosingforpatientswithmelanoma:0.1,0.3,1,3,and10mg/kg

• Eligibility:1-5previoussystemicregimens,noactivebrainmetastases,nochronicautoimmunecondition

Sznol M, et al. ASCO 2013.

Nivolumab PhaseIStudy:ResponseinMelanoma

• ORR:31%(acrossdoses)– 41%at3mg/kg– 4%unconventionalresponses– 45%ofresponsesevidentat8wks

• Medianresponsedurationof2yrs

Sznol M et al. ASCO 2013..

ChangeinTargetT

umor

Lesio

ns(%

)

10.0

0.10.31.03.0

Dose, mg/kg200

150

100

50

0

-50

-100

Topalian 2012NEJM

Nivolumab PhaseIStudy:ResponseinMelanoma

• MedianOSwas22.0months.

• 1- and2-yearsurvivalrateswere62%and43%,respectivelyd

Topalian SL,etal.JClinOncol.2014;32:1020-1030

Nivolumab PhaseIStudy:SurvivalinMelanoma

OSPa

tient

s (%

)

Mos Since Treatment Initiation

100908070605040302010

00 3 6 9 1215182124273033363942454851

Died/TreatedMedian, Mos

(95% CI)

60/107 16.8 (12.5-31.6)

1-yr OS: 62%

2-yr OS: 43%

Sznol M, et al. ASCO 2013

PFS

Patie

nts

(%)

Mos Since Treatment Initiation

1009080706050403020100

0 3 6 9 12 15 18 21 24 27 30 33 36

Events/TreatedMedian, Mos

(95% CI)

77/107 3.7 (1.9-9.1)

1-yr PFS: 36%2-yr PFS: 27%

Median PFS: 3.7 mos

Nivolumab PhaseIStudy:SurvivalinMelanoma

Phase IIItrials ofnivolumab 3mg/kgCA209-037yCA209-066

MARZO2015LANCET ENERO2015NEJM

Nivo postIpi:Phase 3CA209-037

Treatuntilprogression*

orunacceptable

toxicity

R2:1

Nivolumab3mg/kgIVQ2W

Investigator’schoiceofchemotherapy(ICC):

• Dacarbazine 1000mg/m2 Q3W

OR• CarboplatinAUC6IVandpaclitaxel175mg/m2 Q3W

Advancedmelanomawhoprogressedafteripilimumab(N=405)

Stratifiedby:

• PD-L1expression†

• BRAFstatus• BORtoprioripilimumab

OpenLabel

Treatment N†CR+PR,

nORR,

%(95%CI)

BestOverallResponse, %

CR PR SD PD UNK

Nivolumab 120 38 32 (24–41) 3 28 23 35 10

ICC 47 5 11 (4–23) 0 11 34 32 23

Weber JS et al, Lancet Oncol 16, 375–384, 2015

Time to and duration of response

Weber JS et al, Lancet Oncol 16, 375–384, 2015

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, ontrolled, open-label, phase 3 trial

NivopostIpi:Phase3CA209-037

Nivolumab 1stline:Phase 3:CA209-066:

Treatuntilprogression*orunacceptabletoxicity

Primaryendpoint:

• OS

Secondaryendpoints:

• PFS

• ORR

• PD-L1correlates

R1:1

Nivolumab3mg/kgIV

Q2W+

PlaceboIVQ3W

N=210(206treated)

PlaceboIVQ2W

+Dacarbazine

1000mg/m2 IVQ3W

N=208(205treated)

Double-

blind

EligiblepatientswithunresectablestageIIIorIVmelanoma(N=418)

• BRAFwild-type

• Treatment-naïve

Stratifiedby:

• PD-L1status(≥5%cell-surfacestainingcutoff)

• M-stage

SMR2014

RobertCetal.NEngl .JMed 2014

CA209-066TimetoandDurabilityofResponse

Nivolumab Dacarbazine

Timetoresponse,median(range),mo

2.1(1.6–7.6)

2.1(1.8–3.6)

Durationofresponse,median(range),mo NR 6.0

(3.0–NR)

Ongoingresponseamongrespondersa 72/84(86%) 15/29(52%)

aAtthetimeofthelastfollow-up;NR=Notreached

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78

Time(Week)

Nivolum

ab(84/21

0)Da

carbazine

(29/20

8)

Patie

nts

(no.ofrespo

nders/no

.ran

domize

d)

OntreatmentOfftreatmentFirstresponseOngoingresponseDeath

SMR2014

Table4.CheckMate 066safetyresults3

Results(cont)

Nivolumab(n=206)

Dacarbazine(n=205)

Anygrade

Grade3–4

Anygrade

Grade3–4

Treatment-relatedAEs,n(%) 153(74.3) 24(11.7) 155(75.6) 36(17.6)AEsleadingtodiscontinuationoftreatment,n(%) 14(6.8) 12(5.8) 24(11.7) 19(9.3)Serioustreatment-relatedAEs,n(%) 19(9.2) 12(5.8) 18(8.8) 12(5.9)

3.RobertC,etal.NEngl JMed2015;372:320-30.

CheckMate 066QoL results:TimetofirstdeclineofEORTCQLQ-C30globalhealthstatus/QoL

aTherateofdeteriorationofEORTCQLQ-C30globalhealthstatus/QoLreached50%at276daysforNIVOand179daysforDTIC.bEORTCQLQ-C30MID:≥10points.CI=confidenceinterval;DTIC=dacarbazine;HR=hazardratio;MID=minimalimportantdifference;NIVO=nivolumab.4.LongGV,etal.PresentedattheAmericanSocietyofClinicalOncology2015AnnualMeeting;May29–June2,2015;Chicago,IL, USA.Poster270.

Number ofPts at Risk

1.00

0.8

0.6

0.4

0.2

0.0

Time to First MID Decline (days)b

0 50 100 150 200 250 300 350 400 450

NIVO 147 115 92 68 48 40 29 20 10135 84 56 41 24 13 4 0 0DTIC

HR = 0.66 (95% CI: 0.47, 0.94); P = 0.021Prob

abili

ty o

f Det

erio

ratio

na

Conclusion

Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who

had metastatic melanoma without a BRAF mutation.

CA209-066 Phase IIItrialofnivolumab 3mg/kg

RobertC,etal.NEngl JMed2015;372:320-30.

Study Overview

Cutaneous melanoma: ESMO ClinicalPracticeGuidelinesfordiagnosis,treatmentandfollow-up.

Dummer Retal.AnnOncol 2015Sep;26Suppl 5

• Inthecontextofnewdevelopmentsandmedicalprogress,therearecontinuouslynewexperimentaltreatmentoptionsforpatientswithadvancedmetastaticmelanoma,includingcombinedtherapieswithanti-CTLA4andanti-PD1antibodies,withintralesionaltherapiesandsmallmolecules.

• Patientsshouldpreferentiallybereferredtocentres ofexcellencethatprovideacomprehensiveclinicaltrialprogramme.

Summary• CTL4andPD-1blockageinmetastaticmelanomapatientsachieves:

• Longtermdiseasecontrolinasubsetofpatientsand• Survivalimprovement.

• TheAntiPD-1approvedagents,Pembrolizumab andNivolumab,aremoreactivethantheAntiCTL4approvedagent,Ipilimumab,inadvancedmelanoma.

• Toxicityseemstobemostfrequentinpatientswhoachieveresponse,butisnota“must”.• Nospecificbiomarkersoflongtermresultshavebeenidentifiedsofar,butstudiesonthismatterareongoing.

• Therearealsoanumberofissuespending:• Optimaldose• Durationoftreatment• SequenceandCombinations• Primaryrefractorinessandresistance• Reinduction• ….

Thankyouforyourattention