Overview of and current indications for the use of immune checkpoint inhibitors in urothelial carcinoma

Jonathan Rosenberg, MDAssociate Attending PhysicianSection Head, Non-prostate Genitourinary MalignanciesGenitourinary Oncology ServiceMemorial Sloan Kettering Cancer Center

Disclosures

AdvisoryCommittee

Astellas PharmaGlobalDevelopmentInc,AstraZenecaPharmaceuticalsLP,BayerHealthCarePharmaceuticals,Bristol-MyersSquibbCompany,EMDSerono Inc,GenentechBioOncology,InovioPharmaceuticalsInc,GritstoneOncology,Lilly,Merck,RocheLaboratoriesInc,SanofiGenzyme

ContractedResearch GenentechBioOncology,Incyte Corporation,Novartis

Current FDA approvals for bladder cancer

Agent Indication NOverall ResponseRate

(%)DOR(mos)

OverallSurvival(mos) Randomized

Atezolizumab 1st-linecis-ineligible

Priorplatinum

310

119

14.8%(11.1,19.3)

23.5%(16.0,31.0)

NR

NR

7.9(6.7,9.3)1

15.9(10.4,NR)2

No

No

Nivolumab Priorplatinum 270 19.6%(15.1,24.9)

NR 8.7(6, NR)3

No

Durvalumab Priorplatinum 182 17.0%(11.9,23.3)

NR Notreported

No

Avelumab Priorplatinum 242 16.1%(≥6mos follow-up)

Notestimable

Notreported

No

1. Rosenberg,etal.Lancet 20162. Balar,etal.Lancet 20173. Sharma,etal.LancetOncology20174. Avelumab packageinsert

NR:NotReached

Atezolizumab approved for prior platinum-treated patients

• SinglearmphaseIIstudy

• 310patients• Priorplatinum-

basedchemoformetastaticdiseaseorrelapsewithin12monthsofperiopchemotherapy

• 40%had2ormorepriorregimens

• ORR14.8%• MedianOS7.9mos• Modesttoxicity

Rosenberg,etal.TheLancet2016

Update on Phase III study of atezolizumab in patients with previously treated advanced bladder cancer

May 9, 2017The Phase III IMvigor211 study that evaluated atezolizumab in people with locally advanced or metastatic urothelial cancer whose disease progressed during or after treatment with a platinum-based chemotherapy (previously treated) did not meet its primary endpoint of overall survival compared to chemotherapy. The safety profile observed in IMvigor211 was consistent with what has been previously observed for atezolizumab.

https://www.gene.com/media/press-releases/14665/2017-05-09/genentech-provides-update-on-phase-iii-s

Atezolizumab:cisplatin-unfit(n=119)

IC1(n = 48)

IC0(n = 39)

21% (10, 35) 21% (9, 36)

8% 8%

13% 13%

IC2/3(n = 32)

IC1/2/3(n = 80)

All Patients(N = 119)

ORRa (95% CI) 28% (14, 47) 24% (15, 35) 23% (16, 31)

CR 12% 10% 9%

PR 16% 14% 14%

BalarAVetal.Lancet 2016

Mediandurationofresponsenotreached

USFDAapprovedApril2017

Checkmate 275: Activity of nivolumab in previously platinum-treated locally advanced or metastatic UC

Outcome,% AllN=265

ConfirmedORR 19.6

95%CI 15.0–24.9

Bestoverallresponse

Completeresponse 2.3

Partialresponse 17.4

Stabledisease 22.6

Progressivedisease 39.2

Unabletodetermine 18.5

PD-L1<1%n=143

PD-L1≥1%n=122

PD-L1≥5%n=81

16.1 23.8 28.4

10.5–23.1 16.5–32.3 18.9–39.5

<1 4.1 4.9

15.4 19.7 23.5

17.5 28.7 28.4

46.9 30.3 25.9

19.6 17.2 17.3

• PD-L1measuredontumorcells• Medianfollow-upwas7months(minimumof6months)

Sharma,etal.LancetOncology2017

Nivolumab 2nd-line: Overall survival

Alltreatedpatients

No.atRisk

AlltreatedpatientsPD-L1<1%

PD-L1≥1%

PD-L1≥1%

MedianOS,Months(95%CI)a

Alltreated 8.74(6.05-NR)

PD-L1<1% 5.95(4.30-8.08)PD-L1≥1% 11.30(8.74-NR)

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

OverallSurvival(P

roba

bility)

Months

PD-L1<1%

265 198 148 63 5 0143 101 69 26 2 0122 97 79 37 3 0

Galskyetal.ESMO2016

Sharma,etal.LancetOncology2017

Durvalumab approved for platinum-treated advanced UC

• Single-arm Phase I/II Study 1108

• 182 pts • Previously

treated UC w/ platinum-based chemo or relapse ≤1 y of (neo)adjuvant chemo

Allpatients(n=182)

PD-L1high(n=95)

PD-L1 low(n=73)

PD-L1unknown(n=14)

ORRbyblindedreview

31(17.0%) 25(26.3%) 3(4.1%) 3(21.4%)

CR 5(2.7%) 3(3.16%) 1(1.4%) 1(7.1%)PR 26(14.3%) 22(23.16%) 2(2.7%) 2(14.3%)

MedianDoR Notreached Notreached 12.3mo Notreached

Medianfollow-up=5.6mo

VENTANA(SP263)assayapprovedascomplementarydiagnostictest

PressRelease:May01,2017

Avelumab approved for platinum-treated advanced UC

• Single-arm JAVELIN Phase I study

• 242 pts • Previously

treated UC with platinum-based chemo or relapse ≤1 y of (neo)adjuvant chemo

Response Follow-up of≥13weeks(n=226)

Follow-up of≥6months(n=161)

ConfirmedORR 30(13.3%) 26(16.1%)CR 9(4%) 9(5.6%)PR 21(9.3%) 17(10.6%)

MedianDoR Not reached Notreached

Infusion-relatedreactionswerenotedin>20%ofpts,requiringpremedications(antihistaminesandacetaminophen)

AdverseEvents(AEs) N=242DeathsduetoAEs 6%OccurrenceofseriousAEs 41%

PressRelease:May09,2017

KEYNOTE045– Pembrolizumabimprovesoverallsurvivalvs.salvagechemotherapy

• Dealers choice chemotherapy– Docetaxel, paclitaxel, or

vinflunine

• Median OS 10.3 months for pembro vs. 7.4 for chemo (HR 0.73)

• PFS short, and not different between the two arms

Bellmunt Jetal.NEJM2017;376(11):1015-26.

OverallSurvival:PD-L1CombinedPositiveScore≥10%

Datacutoffdate:Sep7,2016.

0 2 4 6 8 10 12 14 16 18 20 22 240102030405060708090

100

Time,months

OS,

%

74 60 51 42 35 31 18 12 7 3 0 0 090 76 51 36 28 24 16 8 4 1 0 0 0

No.atrisk

Events,n HR(95%CI) PPembro 44 0.57(0.37-0.88) 0.0048Chemo 60

39.8%26.9%

Median(95%CI)8.0mo(5.0-12.3)5.2mo(4.0-7.4)

Bellmunt,etal.SITC2016

PD-L1statusisnegativeprognosticfactor,butpredictsbetterhazardratio

0

5

10

15

20

25

30

35

40O

RR

, % (9

5% C

I)

ConfirmedObjectiveResponseRate

21.1%

11.4%

Δ9.6%P =0.0011 PR

CR

TotalPopulation

21.6%

6.7%

CPS≥10%Population

7.0%

14.1%3.3%8.1%

6.8%

14.9%

2.2%4.4%

Pembrolizumab(N=270)

Chemotherapy(N=272)

Pembrolizumab(N=74)

Chemotherapy(N=90)

0

5

10

15

20

25

30

35

40

OR

R, %

(95%

CI)

CPS=combinedpositivescore

BellmuntJetal.,SITC2016

CheckMate 032: Ongoing Phase I/II trial of nivolumab+/- ipilimumab in advanced urothelial carcinoma

Primary endpoint: Objective response rate (ORR)

Sharma P et al. Proc ASCO 2016;Abstract 4501.

Nivolumab3 mg/kg IV Q2W

(N = 78)

Patients with locally advanced or metastatic urothelial carcinoma

Nivolumab 1 mg/kg +ipilimumab 3 mg/kg

IV Q3W for four cycles

(N = 26)

Nivolumab 3 mg/kg +ipilimumab 1 mg/kg

IV Q3W for four cycles

(N = 105)

Nivolumab 3 mg/kg IV Q2W

CheckMate 032: Response and survival

Sharma P et al. SITC 2016;Abstract 03.

Outcome

Nivo1mg/kg+Ipi 3mg/kg(n=26)

Nivo3mg/kg+Ipi 1mg/kg(n=104)

Diseasecontrolrate 57.7% 51%

ORR 38.5% 26%

CR 3.8% 2.9%

MedianPFS 4.3mo 2.6mo

MedianOS 10.2mo 7.3mo

CheckMate 032: Adverse events

Sharma P et al. SITC 2016;Abstract 03.

Grade≥3

Nivo 1mg/kg+Ipi 3mg/kg(n=26)

Nivo 3mg/kg+Ipi 1mg/kg(n=104)

All 30.8% 31.7%

Diarrhea 7.7% 4.8%

Pneumonitis 3.8% <1%

IncreasedALT NR 5.8%

IncreasedAST NR 3.8%

Colitis NR 3.8%

NR = not reported

PowlesTetal.ProcASCO2016;AbstractTPS4574.

Primaryendpoint:Progression-freesurvival

Durvalumab+tremelimumabn=175

Standardchemotherapyn=175

N=525

R

1:1:1

Durvalumabmonotherapyn=175

Treatment-naïve,unresectableStageIVUBC

DANUBE: Phase III trial of first-line durvalumab±tremelimumab in unresectable metastatic urothelial bladder cancer

www.clinicaltrials.gov (Accessed May 2017).

Ongoing Phase III Trials of Immune Checkpoint Inhibitor Combinations in Urothelial Cancer

Trialname Phase N Treatment

NCT02516241 III 1,005

• Durvalumab

• Durvalumab+tremelimumab

• SOC chemotherapy

CheckMate901

(NCT03036098)III 690

• Nivolumab +ipilimumab

• SOCchemotherapy

SOC = standard of care

Current Status of Systemic Therapy for Bladder Cancer

Muscleinvasive Metastaticpriorchemotherapy

Metastaticpriorimmunotherapy

PembrolizumabClinicaltrialswithnovelapproaches

Maintenance:Avelumab

Metastaticchemotherapy

naive

AtezolizumabNivolumabDurvalumabAvelumab

Platinum-basedorsingle-agentchemotherapyAtezolizumab

TaxanesVinfluninePemetrexed

Perioperativecisplatin-basedchemotherapy

Cisplatinineligible:PembrolizumabDurvalumab

Cisplatineligible:Durvalumab±TremelimumabNivolumab+ipilimumabAtezolizumab

Adjuvant:PembrolizumabAtezolizumabNivolumab

• 4 agents approved for locally advanced or metastatic patients previously treated with platinum-based chemotherapy

– Nivolumab (anti-PD1)– Atezolizumab (anti-PD-L1)– Durvalumab (anti-PD-L1)

– Avelumab (anti-PD-L1)• 1 agent approved for cisplatin-ineligible first-line therapy

– Atezolizumab (anti-PD-L1)

• Responses often occur quickly and are frequently durable• Only a minority of patients respond, and new approaches are

warranted.

Immune checkpoint blockade in urothelial carcinoma