Andrea NecchiFondazione IRCCS Istitio azionale dei Ttmori, Milano, IialyEtropean Associaton of Urology – Research Fotndaton

Le nuove possibilità terapeutiche nella malattia localizzata

Disclosures

Consultnn or Advisory Role:

• Company: Roche, Bayer, Merck & Co. Inc., Astra Zeneca, Janssen, Astellas/Seatle Genetcs, Clovis

Oncology, BioClin Therapeutcs

Travel, Accommodatons, Expenses:

• Company: Roche, Merck & Co. Inc., Janssen, PeerVoice

Research Fundinn (Instiuton):

• Company: Merck & Co. Inc., Astra Zeneca

‹‹For their discovery of a revolutonary approach to cancer treatment›› Nobel Commitee, Stockholm, October 1 2018

The therapeutic area has evolved rapidly following the 2016 FDA/EMA approval of atezolizumab

TURB Radical cystectomy

• The point: cisplatnnbased NACT is the SoC for MIBC• Realnworld adherence to the SoC is poor• 50% of patents can receive cisplatn, many refuse NACT• Predictve biomarkers stll not ready for prime tme

ΔOS/RFS

Safety/toxicity issuesTiming from TURB>RC

++++++++

Forde PM, et al. N Engl J Med 2018

Urothelial Cancer Management: An Overview

Fai

Muscle

CISTaT1

T2

T3

T4

Connectve tssueBladder lininn

T2-T4: Muscle-Invasive Bladder

Cancer (MIBC)

Radical cysieciomy or Chemoradiaton

<25% nei adjuvani/ neoadjuvani (Gem/Cis)

Firsi-Line Meiasiatc

Gem/Cis or MVAC are SOC in US; Gem/Carbo for Cis-inelinible (50%)

AiezolizumabPembrolizumab

Second-Line Meiasiatc

AiezolizumabNivolumabAvelumab

DurvalumabPembrolizumabORR 15%-20%

mOS: 7.9-11.4 mo

Taxanes, nemciiabine,pemeirexed,

vinfunine (EU)ORR: 10%

mOS: 7-9 mo

10%-15%

10%-15%

70%-80%Ta/T1/Tis: Non‒Muscle-Invasive Bladder

Cancer (NMIBC)

TURBT/iniravesical BCG

Neoadjuvant IO before Radical Cystectomy

Immunoiherapy prior io RC in MIBC– PUREn01

• Pembrolizumab x 3 doses– ABACUS

• Atezolizumab x 2 doses– Immunotherapy +/n chemotherapy neoadjuvant studies onngoing

PURE-01 (NCT02736266): Neoadjuvant pembrolizumab before radical cystectomy for MIBC

• Fit and planned for cystectomy• Predominant (i.e. 50% at least) UC histology • cT≤3bN0 stage • Residual disease afer TURB (surgical opinion, cystoscopy or radiological presence) • GFR ≥20 ml/min (Cockcrof Gault formula)• ECOGnPS 0n1

3×3 weekly cycles of pembrolizumab 200 mn IV

• Cystectomy

• Postncystectomy management according to EAU guidelines

• Survival data collected untl 2ny post cystectomy

Prenpost treatment tssue/blood sample collecton for biomarker analyses

Prenpost treatment imaging: multparametric bladder MRI (mpMRI); 18FDGnPET/CT scan, T/A CT scan

Additonal DD-MVAC x 4 cycles in non-respondinn pis (investnaior choice)

Necchi A, et al. J Clin Oncol. 2018 Oct 20:JCO1801148 (Epub ahead of print)

Necchi A, et al. J Clin Oncol. 2018 Oct 20:JCO1801148

PURE-01 study: Prepping for cancer surgery with immunotherapy

Necchi A, et al. J Clin Oncol. 2018 Oct 20:JCO1801148

Significant biomarker changes in matched pre-post tumor samples

Necchi A, et al. AACR2018, AUA2018, ASCO2018, ESMO2018

Tumornstroma layer

Follicle

Tumor area

CD8+ T-cell infliraie in a pateni wiih ypT2 response

PURE-01: NGS and Immune-gene expression data identify predictive markers and additional therapeutic targets

Necchi A, et al. J Clin Oncol. 2018 Oct 20:JCO1801148 (Epub ahead of print)

Posi Pembrolizumab x 3

pT0ADC 0.9 > 1.3Pre-pembrolizumab Posi-pembrolizumab

Necchi A, et al. SUO 2018

ABACUS: A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer

Castellano D, et al. Annals of Oncology (2018) 29 (suppl_8): viii303nviii331. 10.1093/annonc/mdy283

A Phase 1b/2 Multicenter Study of Neoadjuvant Pembrolizumab and Chemotherapy for Locally Advanced Urothelial Cancer (NCT02365766) 

Holmes C, et al. LBA33, ESMO 2018

CA209-9DJ 26 A pilot study to evaluate the safety of neoadjuvant nivolumab alone or in combination with ipilimumab for cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC) 

CA017-078: Peri-surgical Phase 3 trial of nivolumab ± BMS-986205 + chemotherapy in MIBC 

Clinicalirials.nov. NCT03661320. Accessed Ociober 5, 2018

Select ongoing bladder-sparing trials in MIBC: Trimodal therapy and other approaches

Is genomic classifcaton going to help in MIBC bladder cancer?

Can we predict response and survival after neoadjuvant chemotherapy?

Biomarker N Translatonal relevance Reference

ERCC2 mutaton 50 Associaton with pathologic response Van Allen EM et al, Cancer Discov 2014

ERCC2 mutaton 48+54 Associaton with improved OS in 2 independent cohorts of cisplatnntreated MIBC patents

Liu D et al. JAMA Oncol 2016Plimack ER et al, Eur Urol 2015

Plimack ER et al, ASCO 2014

ATM/RB1/FANCC mutatons 34 Associaton with improved pT<2 response and OS Plimack ER et al, Eur Urol 2015

ATM/RB1/FANCC mutatons 25 Associaton with improved pT<2 response Anari F et al, Eur Urol Oncol 2018

ERBB2 mutatons 71 Associaton with pT0 response Groenendijk FH et al, Eur Urol 2015

DNA damage response (DDR) gene alteratons 46 Associaton with pT<2 response and RFS with dosen

dense GC Iyer G et al, J Clin Oncol 2018

Singlensample genomic subtyping classifer 343 Basal tumors benefted the most from neoadjuvant

chemotherapy administraton Seiler R et al, Eur Urol 2017

A Phase II Trial of Risk Enabled Therapy After Initiating Neoadjuvant Chemotherapy for Bladder Cancer (RETAIN BLADDER) NCT02710734

Major Inclusion Criieria:• cT2nT3 N0M0• ECOG 0n1• Urothelial Predominant Histology

• MFS is defned as the absence of a recurrence of urothelial carcinoma that is >cN1 (more than one clinically suspicious pelvic lymph node) or surgically unresectable local recurrence (eg, cT4a) or M1 disease.

Sequencing(Caris)

Mutaton positvedefned as any alteratons in:

• ATM• RB1• FANCC• ERCC2

No residualiumor/ cT-0

ANDMuiaton Pos (+1)

cTa or cTis or cT1 or Pos (+)

cyiolony or cT0 muiaton Nen (-)

cT2

≥cT3

Pateni & Physician Choose

Primary Endpoint: Metastasisnfree survival (MFS) at 2 years.Nonninferiority design with a 14% margin between risknadapted design (MFS=78%) and standardnofncare (MFS=64%).Sample size=70 with an 82% power. Type I error=0.045

TURBT #1 AMVAC x 3 TURBT #2

ActveSurveillance

Iniravesicle Tx

OR

Chemo-RT

OR

Cysieciomy

Chemo-RT

OR

Cysieciomy

Cysieciomy

Pateni & Physician Choose

Study NCT02710734. ClinicalTrials.gov website. Accessed May 25, 2018

Systemic Therapy: Gem Cis NivolumabBiomarker: ATM, FANCC, ERCC2, or High TMB

HCRN 16-257: Neoadjuvani nemciiabine, cisplatn, plus nivolumab in patenis wiih muscle-invasive bladder cancer wiih selectve bladder

sparinn

Systemic Therapy: ddGem Gem CisBiomarker: DDR panel from the literature

Reni

sira

ton

Gemciiabine cisplatn plus nivolumab for 4 cycles

Genomic Sequencinn of TURBT Specimens

Nivolumab

Cysieciomy

Cysieciomy

Prospectvely validaie DDR panel wiih “benefi”

ddGC in all patenis 6 cycles over 12 weeks

Gemcitabine 2500 mg/m2

Cisplatn 35mg/m2 D1.2D1 Every 14

days

MSK-IMPACTsequencinn

T2nT4Bladder sample

Modifed DDRGene Panel

ERCC2ERCC5BRCA1BRCA2RAD51CATRRECQL4ATMFANCC

DDR delalteraton

68 patents

RadicalCysieciomy

RadicalCysieciomy

Bladder sparinn

Deleterious alteratons in one or more of these genes will allow patents to be potentally eligible for the bladdernsparing arm of the study

DDR wt

187 patents

AO31701: A phase II siudy of dose-dense Gemciiabine plus Cisplatn in patenis wiih muscle-invasive bladder cancer wiih bladder preservaton for ihose

patenis whose iumors harbor deleierious DNA damane response (DDR) nene alieratons

PresianinnImaninnCysiec +TURBT

≥T1Responses

≤pT2N0Responses

Other risk adapted neoadjuvant studies in development

Plimack E, AACR 2018 Oral presentaton

ctDN

A

ctDN

A

PI: Mat Galsky Gupta I, et al. J Clin Oncol 2018; 10.1200/JCO.2017.75.0158. [Epub ahead of print]

My personal view on neoadjuvant IO developments in MIBC

• Singlenagent IO have demonstrated actvity in biomarkernselected (PDnL1+) pts

• (Efcacy daia and ihe impaci of ypT response posi-IO are pending)

• Cisnbased chemotherapy provides actvity and efficacy in genomicallynaltered pts

• Most of the genomic biomarkers are suitable for both IO and chemo optons

• Cisnbased chemotherapy is a suboptmal backbone for combinaton therapy in unselected pts

• IO versts chemotherapy is ready for prime tme in PDnL1+ pts

IO Therapy/Siudy Phase/N Siudy Arms Primary Endpoinis Secondary Endpoinis

Estmaied Primary

Completon Daie

Nivolumab1

CheckMate 274(NCT02632409)

Phase 3N=640

• Nivolumab (adjuvant)• Placebo • Diseasenfree survival

• Nonnurothelial track recurrencenfree survival

• Diseasenspecifc survival• OS

April 2020

Pembrolizumab2

AMBASSADOR(NCT03244384)

Phase 3N=739

• Pembrolizumab (adjuvant)• Observaton

• Diseasenfree survival• OS (up to 5 years)

• Diseasenfree survival and OS in PDnL1+ and PDnL1n patents

February 2019

Atezolizumab3

IMvigor010(NCT02450331)

Phase 3N=700

• Atezolizumab (adjuvant)• Observaton • Diseasenfree survival

• Diseasenspecifc survival • OS• Distant metastasisnfree

survival• Nonnurinary tract

recurrencenfree survival• Safety, QoL• PK, immunogenicity

October 2019

1. Study NCT02632409. ClinicalTrials.gov website. Accessed July 24, 2017. 2. Study NCT03244384. ClinicalTrials.gov website. Accessed July 24, 2017 3. Study NCT02450331. ClinicalTrials.gov website. Accessed July 24, 2017.

Ph3 Adjuvant/ Registrational Studies in MIBC

Expandinn ihe role of immunoiherapy io NMIBC:Firsi resulis from Keynoie-057 irial

KEYNOTE-057: Single-Arm, Open-Label Phase 2 Study (NCT02625961)

Patenis

• HR NMIBC patenis unresponsive io BCG who refuse or are inelinible for cysieciomy

• Patenis wiih papillary disease musi have fully resecied disease ai siudy eniry

• Two cohoris

• Cohori A (n = 130): CIS wiih or wiih oui papillary disease (hinh-nrade Ta or T1)

• Cohori B (n = 130): papillary disease (hinh-nrade Ta or any T1) wiihoui CIS

Patenis

• HR NMIBC patenis unresponsive io BCG who refuse or are inelinible for cysieciomy

• Patenis wiih papillary disease musi have fully resecied disease ai siudy eniry

• Two cohoris

• Cohori A (n = 130): CIS wiih or wiih oui papillary disease (hinh-nrade Ta or T1)

• Cohori B (n = 130): papillary disease (hinh-nrade Ta or any T1) wiihoui CIS

Pembrolizumab200 mn Q3W

Pembrolizumab200 mn Q3W

Evaluatons wiih cysioscopy, cyiolony, ±

biopsy Q12W × 2 y, ihen Q24W × 2 y and once

yearly ihereaferand

CT uronram Q24W × 2 y or more frequenily as clinically indicaied

Evaluatons wiih cysioscopy, cyiolony, ±

biopsy Q12W × 2 y, ihen Q24W × 2 y and once

yearly ihereaferand

CT uronram Q24W × 2 y or more frequenily as clinically indicaied

If HR NMIBC preseni ai any assessmeni Discontnue ireaimeni; enier survival follow-up

If no persisience or recurrence of HR NMIBC ai any assessmeni

Contnue assessmenis and pembrolizumab untl

recurrence of hinh-risk NMIBC, PD, or

24 monihs of ireaimeni compleie

Primary End Poinis• CR (absence of HR NMIBC) in Cohort A

• DFS in Cohort B

Primary End Poinis• CR (absence of HR NMIBC) in Cohort A

• DFS in Cohort B

Secondary End Poinis• CR (absence of any disease ‒ highnrisk or lownrisk NMIBC) in cohort A

• DOR in cohort A• Safety/tolerability

Secondary End Poinis• CR (absence of any disease ‒ highnrisk or lownrisk NMIBC) in cohort A

• DOR in cohort A• Safety/tolerability

Results from Keynote-057

de Wit R, et al. Annals of Oncology (2018) 29 (suppl_8): viii303nviii331. 10.1093/annonc/mdy283

Targeting the pre-BCG refractory space

POTOMAC (NCT03528694): A Phase 3, Randomised, OpennLabel, MultnCenter, Global Study of Durvalumab and BCG Administered as Combinaton Therapy Versus BCG Alone in HighnRisk, BCGnNaïve NMIBC Patents

Checkmaie 9UT (NCT03519256): Phase 2 Trial of Nivolumab ±BCG ±IDOi in HighnRisk, BCGnUnresponsive NMIBC

Efficacy and Safety of Pembrolizumab (MKn3475) in Combinaton With Bacillus CalmetenGuerin (BCG) in HighnRisk NonnMuscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676, NCT03711032)

Urothelial Cancer Management: An Overview

Fai

Muscle

CISTaT1

T2

T3

T4

Connectve tssueBladder lininn

T2-T4: Muscle-Invasive Bladder

Cancer (MIBC)

Radical cysieciomy or Chemoradiaton

<25% nei adjuvani/ neoadjuvani (Gem/Cis)

Firsi-Line Meiasiatc

Gem/Cis or MVAC are SOC in US; Gem/Carbo for Cis-inelinible (50%)

AiezolizumabPembrolizumab

Second-Line Meiasiatc

AiezolizumabNivolumabAvelumab

DurvalumabPembrolizumabORR 15%-20%

mOS: 7.9-11.4 mo

Taxanes, nemciiabine,pemeirexed,

vinfunine (EU)ORR: 10%

mOS: 7-9 mo

10%-15%

10%-15%

70%-80%Ta/T1/Tis: Non‒Muscle-Invasive Bladder

Cancer (NMIBC)

TURBT/iniravesical BCG

Sinnle-aneni IO siraieny’Highnrisk localized’ UBC(HG/CIS postnBCG >> T3)

andrea.necchi@istiuioiumori.mi.ii@AndreaNecchi