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• ….
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