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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)
[email protected]@AndreaNecchi