Tumori urologici

(1)

(2)

2

Susanne Baier

Oncologia medica Bolzano

Declinare il profilo molecolare nella pratica

clinica… Tumori urologici

(3)

Declinare il profilo molecolare nella pratica clinica… Tumori urologici

Carcinoma prostatica metastatico Carcinoma renale metastatico

Carcinoma uroteliale della vescica metastatico

(4)

Timeline - trattamento carcinoma prostatico

Uro News March 2019, Volume 23, Issue pp 50–57| Behandlungsmöglichkeiten in der Uroonkologie

(5)

mHSPC

Linee guida AIOM

(6)

mCRPC

Linee guida AIOM

(7)

Caratteristiche dei pazienti studi clinici

Rischio di malattia Tumour Burden Sede di Metastasi Sintomatologia

Trattamento precedenti

(8)

Considerazioni in ambulatorio per la scelta terapeutica

Tumour Burden

Estensione di malattia Sede di Metastasi

Sintomatologia

Trattamento precedenti PSA DT

Condizioni generali Patologie secondarie

Preferenze del paziente

Analisi

mutazionali ?

(9)

Highlights ASCO GU 19 mCRPC

Pembrolizumab plus olaparib in docetaxel- pretreated patients with metastatic-resistant prostate cancer

Yu EY, et alAbstract 145

Response to PARP inhibitor therapy in metastatic castrate- resistant prostate cancer (mCRPC) patients with BRCA1/2 versus ATM mutations

Handy Marshall C, et al.Abstract 154

Phase 2 study of niraparib in patients with metastatic

castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of

GALAHAD

Smith MR, et al.Abstract 202

(10)

Aims:

• To evaluate the efficacy, safety, and tolerability of pembrolizumab combined with olaparib in pts with Doc-pretreated mCRPC

Methods:

• KEYNOTE-365 is a non-randomised, multicentre, multi-cohort, open-label, phase 1b/2 study of pembrolizumab in combination with olaparib for pts with mCRPC

• Primary endpoints were to determine safety and PSA response rate

(confirmed PSA50)

145 – Yu EY, et al. KEYNOTE-365 cohort A: Pembrolizumab + olaparib in Doc-pretreated pts with mCRPC

Yu EY, et al. Poster presented at ASCO GU;

14–16 February 2019; San Francisco, CA, USA; abstract 145.

(11)

Results (cont.):

• Confirmed ORR per RECIST v1.1 was 7% among

RECIST-measurable-disease pts

• Median rPFS per PCWG3- modified RECIST v1.1 was 4.7 months

• Median OS was 13.5 months

Conclusions:

• Pembrolizumab + olaparib is generally well tolerated and shows promising activity in a molecularly unselected mCRPC pt population previously treated with CTx and second- generation hormonal Tx

• Median TTPP was 15.3 weeks for pts with RECIST-measurable disease

• In the total population, composite RR was 15%, median rPFS per PCWG3-modified RECIST v1.1 was 4.7 months, and median OS was 13.5 months

145 – Yu EY, et al. KEYNOTE-365 cohort A: Pembrolizumab +

olaparib in Doc-pretreated pts with mCRPC

(12)

154 – Handy Marshall C, et al. Response to PARP inhibitor Tx in mCRPC pts with BRCA1/2 vs ATM mutations

• Aim: To evaluate response to PARP inhibition Tx in pts with mCRPC with either ATM or BRCA1/2 mutations

• Methods: Retrospective analysis of 17 mCRPC patients treated with olaparib (of label)

• Primary endpoint: PSA₅₀response rates

• Secondary endpoint: Radiographic/clinical PFS and OS

Results: Pts with BRCA1/2 mutations appear to have better PSA responses to olaparib

• Longer time to clinical PFS or rPFS and OS was also observed for pts with BRCA1/2 mutations (PFS: HR 0.12 [95% CI 0.03–0.53]) (OS: HR 0.24 [95% CI 0.24–1.73])

Conclusions:

• Pts with mCRPC with BRCA1/2 mutations appear to have a better PSA response and longer PFS with olaparib compared with pts with ATM mutations similar to the

TRITON2 study

• This may be indicative of the role of BRCA1/2 as a mediator of DNA repair

a a a a

b

BRCA1/BRCA2 mutation ATM mutation 100

25 0

−50

−75 50

−100

−25 75

% best PSA response

BRCA1/BRCA2 mutation ATM mutation

aTruncated at 100%

bBRCA2 mutation with baseline PSA = 0 Best PSA response to olaparib

(by mutation status)

Radiographic or clinic PFS

1.00

0.25 0.50

0.00 0.75

0 5 10 15

Time (months) HR 0.12 (0.03−0.53)

OS

1.00

0.25 0.50

0.00 0.75

0 10 20 30

Time (months) HR 0.24 (0.31−1.73)

(13)

202 – Smith MR, et al. Phase 2 study of niraparib in pts with mCRPC and biallelic DRD: Preliminary results of GALAHAD

Aim:

Assess the efficacy and safety of niraparib in patients with mCRPC and biallelic DNA-repair gene defects

Methods:

Results:

• 50 patients with mCRPC and biallelic DRD with 78 % ECOG-PS 0 or 1 were recruited

• 94% of patients had bone metastases (47/50), 13 (26%) of patients with liver metastases and 5 (10%) with lung metastases

• 68% of patients had received enzalutamide, 62% abiraterone and 40% had 2 prior lines of taxane therapy

• 64% had received 3 or more prior therapies for prostate cancer

(14)

202 – Smith MR, et al. Phase 2 study of niraparib in pts with mCRPC and biallelic DRD: Preliminary results of GALAHAD

Smith MR, et al. Poster presented at ASCO GU;

14–16 February 2019; San Francisco, CA, USA; abstract 202.

Results (cont.):

Tumour response

• Patients with BRCA1/2 had higher composite and objective RR (62.1%

and 37.5%, respectively) compared to patients with non-BRCA DRD (23.8%

and 13.3%, respectively)

• 27% (3/11) of patients with visceral metastases showed objective RR

Duration of response

• The median total treatment duration was 6.0 months (2.0-19.0)

• Of the 23 biallelic responders the duration exceeded;

• 4 months in 17 patients

• 6 months in 11 patients

• Treatment was ongoing in 15 patients

Tumour response in patients with mCRPC and biallelic DRD treated with niraparib

Response All Biallelic DRD (N = 50) BRCA1/2

(N=29) Non-BRCA

(N=21)*

n/N

% (95% CI)

n/N

% (95% CI)

Composite RR 18/29

62.1% (42.3%, 79.3%)

5/21 23.8% (8.2%,

47.2%)

Objective RR 6/16

37.5% (15.2%, 64.6%)

2/15 13.3% (1.7%,

40.5%)

PSA50 15/29

51.7% (32.5%, 70.6%)

1/21 4.8% (0.1%,

23.8%) CTC Conversion

(<5/7.5 mL blood)

12/29 41.4% (23.5%,

61.1%)

4/21 19% (5.5%,

41.9%) Safety

• Grade 3/4 AEs were primarily hematologic

• Anaemia (26%), Neutropenia (8%), Nausea (11.7%), Thrombocytopenia (15%)

• The most common grade 3/4 non-hematological AEs were asthenia (6%) and back pain (5%)

Conclusions:

• Higher composite and objective RRs were observed in patients with BRCA1/2 biallelic DRD

• Treatment with niraparib showed durable clinical improvement, with duration of treatment of 6 or more months in third-line setting, where the time to progression is

typically <4 months

(15)

Genomic landscape carcinoma prostatico Highlights ASCO GU 2019

van Dessel LF, et al. The complete genomic landscape of mPC pinpoints clinically targetable subgroups

Methods:

WGS with average coverage of 114x for tumour and 38x for reference Calling of tumour-specific alterations

SNVs InDels CNAs

Structural variants

Biopsy sites of the metastatic lesions Lung

Bone Liver Soft tissue Lymph nodes

Median tumour cell percentage

Tumour cell percentage was 61% (95% CI: 57–64)

Van Dessel LF, et al. Poster presented at ASCO 2018; abstract 5014.

Outline of patient inclusion workflow

mPC pts included for biopsy n = 238

Non-metastatic biopsy site (i.e. prostate)

n = 2

No biopsy taken n = 12

Fresh-frozen biopsy and blood control taken

n = 224

Succesful biopsy (TC% ≥ 30%)

n = 149

Failed biopsy (TC% < 30%)

n = 75

Failed WGS due to poor quantity or quality

n = 4

WGS biopsy (90x) and blood control (30x)

n = 145

(16)

Results:

Complete genomic landscape

Median tumour mutational burden: 2.86 per Mbp genome-wide. SNVs and InDels were not enriched in coding regions

C > T substitutions at CpG dinucleotides were enriched

Structural variants were common (except for insertions)

8q and Xq (including AR) were frequently amplified. 8p and Y were frequently deleted

Genomic landscape carcinoma prostatico Highlights ASCO GU 2019

van Dessel LF, et al. The complete genomic landscape of mPC pinpoints clinically targetable subgroups

***

** ***

*** *** ***

200,00 50,000 10,000 1,000 100 10

Mutational type SNVInDels

10,000

1,000

100

10

C > A C > T T > A T > G C > G C > T (CpG) T > C

10,000

10 100 500 250

Type DUP INSINV DELBND

0 0.2 0.4 0.6 0.8 1.0

The complete genomic landscape of mPC

(A)Mutational burden expressed as number of SNVs (blue) and InDels (green) for genomic, intragenic and coding regions (B)Frequency of DNA transitions (AG or CT) and transversions (AC/T or GC/T). In orange, C→T substitution in the

CpG context are indicated.

(C)Frequency of structural variants. Significant differences are indicated by an asterisk (** p ≤ 0.001; p ≤ 0.001).

(D)Frequency of CAN. Chromosomes are plotted on the x axis. Amplifications (CNA ≥ 3) are indicated in red. Deep amplifications (CNA ≥5) are indicated in yellow.

Deletions are indicated in dark blue (heterozygous deletions, CNA ≤ 1) and light blue (homozygous deletions, CNA ≤0) . Key aberrant genes are indicated.

FANCA

Amplifications ≥ 3, deep amplifications ≥ 5 chr1 chr2 chr3 chr4 chr5 chr6 chr7 chr8 chr9 chr10 chr11 chr12 chr13 chr14 chr15 chr16 chr17 chr18 chr19 chr20 chr21 chr22 chrX chrY

NCOA2 PABPC1 MYC NDRG1 AMER1 MSN AR

1.0 0.8 0.6 0.4 0.2 0

Deletion ≤ 1, Nom. deletion ≤ 0 LRP1B RAD17 APC CCNC PRDM1 ARHGEF10 LEPROTL1 PTEN SUFU MGMT BRCA2 RB1 GPC5 SOX21 RFWD3 MAP2K4 SMAD4 DCC

A B C

D

***

(17)

Results:

Clinically targetable subgroups

• 12 pts with high tumour mutational burden

(10/Mbps) were identified, of whom 11 had

microsatellite instability/

mismatch repair deficiency signatures and enriched somatic mutations in DNA repair genes

• Signature 3 was identified in 27 pts with > 20%

contribution, of whom 17 had a somatic BRCA1/2 alteration

•

AR and MYC were

frequently amplified; PTEN and RB1 were frequently deleted

• In 66 pts the TMPRSS2-

ERG fusion was identified

Genomic landscape carcinoma prostatico Highlights ASCO GU 2019

van Dessel LF, et al. The complete genomic landscape of mPC pinpoints clinically targetable subgroups

TMB > 10/Mbp 0

5 10 20 30 80

0 25 50 75 100 Mutational burden (per 1 Mb)

Signatures (relative contribution)

ATM (20) ATR (4) BAP1 (6) BARD1 (7) BRCA1 (9) BRCA2 (33) BRIP1 (6) CDK12 (11) CHEK2 (17) FANCA (46) GEN1 (8) MLH1 (10) MRE11 (2) MSH2 (14) MSH3 (10) MSH6 (13) NBN (8) AR (91) MYC (30) RB1 (56) TP53 (74) PTEN (74)

Mutational burden Signatures

InDels SNVs

50 60 70 80 Signature 1

Signature 2 Signature 3 Signature 4 Signature 5

Signature 6 Signature 8 Signature 9 Signature 11 Signature 12

Signature 30 Filtered

Categories Frameshift variant (Disruptive) inframe InDel

Amplification Deep amplification

Missense variant Multiple mutations

Deletions Hom. deletions

Start/stop alteration Splicing variant

Structural variant Bone

Lymph node

Liver Lung

Soft tissue 0 2 4 6 −log10 (q value (dN/dS))

WGS analysis pinpoints clinically actionable subgroups.

Columns represent individual pts, who are sorted by mutational burden.

The panel below provides additional clinical information for each pt.

(A)Mutational burden per pt.

(B)Mutational signatures.

(C)Altered genes (SNVs and CNAs) and ETS fusions.

(xx) indicate number of pts A

B

C

(18)

Results:

Recurrent mutations in mPC

WGS analysis identified recurrently mutated genes in mPC including

• Well-known genes: AR, TP53, PTEN, and FOXA1

• Novel genes: NKX3-1, TBC1D4

Genomic landscape carcinoma prostatico Highlights ASCO GU 2019

van Dessel LF, et al. The complete genomic landscape of mPC pinpoints clinically targetable subgroups

Conclusions:

• mPC genomes are highly unstable and heterogeneous, with frequent somatic alterations, including SNVs, CNAs, and structural variants

• WGS analysis distinguishes subgroups with targetable mutational signatures and

genomic alterations, who might be eligible for targeted therapies, either established or experimental

Overview of the mutational landscape of mPC.

Mean mutational burden per MB. Chromosomes are plotted on the x axis. Genes with relatively more non-synonymous than synonymous mutations are indicated in green (COSMIC cancer gene census) and black (no COSMIC cancer gene census).

15

0 2.5 5 7.5 10 12.5

(19)

. Genomic correlates of clinical outcome in advanced prostate cancer

Wassim Abidaa, et al.PNAS first published May 6, 2019

Contributed by Charles L. Sawyers, March 27, 2019 (sent for review February 19, 2019; reviewed by Samuel Aparicio, John T. Isaacs, and Nandita Mitra)

Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study.

J.Clin.Onc. 2019 May 1;37(13):1120-1129. doi: 10.1200/JCO.18.01731. Epub 2019 Mar 13 Conferma di < PFS e OS in pazienti trattati con ABI/ENZA

Oh M, et al. The association of BRCA1 and BRCA2

mutations on PC risk, frequency, and mortality: systematic review and meta-analysis

Rischio di malattia aumentato di 1,9 nei portatori di BRCA ( 2,64 in BRCA2 e 1,34 in BRCA 1) OS < in BRCA 2

Mateo J, et al. Genomic profiling of primary prostate tumours from pts who develop mCRPC

>Difetti genomici in DDR e geni del ciclo cellulare in popolazione con prognosi sfavorevole

= difetti genomici di DDR (ATM, BRCA1, BRCA2, CHEK1, CHEK2, FANCA, PALB2) in malattia localizzata

DDR status stabile durante evoluzione di m CRPC

> Mutazioni + amplificazioni AR in mCRPC rispetto m HSPC

(20)

Applicabili nella pratica clinica ?

Variante splicing 7 (AR-V7) Resistenza a trattamento endocrino , sensibilità a CHT –tassani, impatto sulla OS

BRCA1 /BRCA2 aumentato rischio di sviluppare mPCa, resistenza a trattamento endocrino, sensibili e PARP inibitori

PTEN mTor pathway

MSI sensibilità a immunoterapia

TP53/RB 1 loss alterazioni tipicamente presente nei istotipi con differenziazione

neuroendocrina e comportamento più aggressivo, > presenti in pazienti pretrattati con ABI/ENZA, sensibilità a trattamento CHT platino

RB1 loss –significativa correlazione fra OS e durata di trattamento endocrino

ATM DNA damage repair (DDR) sensibilità per PARP inibitori e CHT platino

NKX3-1 prostatic tumor suppressor gene localizzato su cromosoma 8p

TBC1D4 GTPase-activating protein –implicazioni in metabolismo glucidico

(21)

Immunoterapia carcinoma prostatico

Studi clinci con ipilimumab hanno dimostrato minimo efficacia in CRPC.

Parliamo di una malattia poco immunogenico – cold tumors

Mutational burden aumenta dopo diverse linee di trattamenti

Biomarker per targeting si possono sviluppare tramite selezione da trattamento

Forse più efficace in qualche sottogruppo-instabilità

dei microsatelliti (MSI) e CDK12

(22)

Declinare il profilo molecolare nella pratica clinica… Tumori urologici

Carcinoma prostatica metastatico

Carcinoma renale metastatico

Carcinoma uroteliale della vescica

(23)

Trattamento carcinoma renale Linee Guida AIOM 11/2018

*Non autorizzati da AIFA al momento della stesura di questa LG 1 Solo dopo Sunitinib

(24)

Considerazioni in ambulatorio per la scelta terapeutica

Rischio prognostico Tumor Burden

Istotipo

Estensione di malattia Sede di Metastasi

Sintomatologia

Trattamento precedenti Condizioni generali

Patologie secondarie Tossicità

Analisi

molecolari?

(25)

Scelta di prima linea

1. NCCN:

https://www.nccn.org/professionals/physician_gls/pdf/kidney .pdf(Accessed September 2018), modified according to label; 2. EAU:

http://uroweb.org/guideline/renal-cell-carcinoma/

(Accessed September 2018).

Strength Recommendations

Strong Use ipilimumab plus nivolumab in treatment-naïve

patients with ccmRCC of IMDC intermediate and poor risk

Use cabozantinib in treatment-naïve patients with Weak ccmRCC of IMDC intermediate and poor risk

Weak Do not use bevacizumab plus IFN-α in treatment-

naïve favourable- and intermediate-risk ccRCC patients

Weak Do not use temsirolimus in treatment-naïve

poor-risk ccRCC patients

NCCN Guidelines Version 1.2019

¹

ccmRCC, clear-cell metastatic renal cell carcinoma; EAU, European Association of Urology; IFN, interferon; IL,

interleukin; NCCN, National Comprehensive Cancer Network.

EAU Guidelines

²

Clinical trial

Pazopanib (category 1, preferred) Sunitinib (category 1, preferred)

Ipilimumab + nivolumab (category 1, preferred for intermediate- and poor- prognosis risk groups; category 2B

for favourable-risk group)

Bevacizumab + IFN-α2b (category 1)

Temsirolimus (category 1 for poor group;

category 2B for selected patients -r isk of other risk groups)

Cabozantinib (for poor- and intermediate-risk groups)

High-dose IL-2 for selected patients

Active surveillance for select, asymptomatic

patients

(26)

(27)

Checkmate 214 ESMO 2017

(28)

Checkmate 214 ASCO GU 2019

(29)

Approvazione EMA IPI/NIVO 01/19

Nivo +Ipi con tasso di risposta obiettiva del

41,6% versus 26,5% con sunitinib nei pazienti a rischio intermedio o sfavorevole (endpoint co- primario)

La PFS mediana nel gruppo di combinazione è

stata di 11,6 mesi (IC 95%: 8,71 - 15,51) vs 8,4

mesi (IC 95%: 7,0 - 10,8) nel braccio con sunitinib

(30)

ASCO GU 2019

Terapie di combinazione

(31)

ASCO GU 2019

Terapie di combinazione

(32)

A13 A15

A16

A17

A18 A14

Intratumoral heterogeneity (ITH)

(33)

Dornbusch et al. PLoS One 2013

(34)

HIF CD31 CAIX

Dornbusch et al. PLoS One 2013

(35)

Clone 405.9A11

Clone SP142

Clone 405.9A11

(36)

esmo.org

Molecular correlates differentiate response to atezolizumab + bevacizumab vs sunitinib:

results from a Phase III study (IMmotion151) in untreated metastatic renal cell carcinoma

Brian I. Rini,

¹

Mahrukh Huseni,

²

Michael B. Atkins,

³

David F. McDermott,

⁴

Thomas Powles,

⁵

Bernard Escudier,

⁶

Romain Banchereau,

²

Li-Fen Liu,

²

Ning Leng,

²

Jinzhen Fan,

²

Jennifer Doss,

²

Stefani Nalle,

²

Susheela Carroll,

²

Shi Li,

²

Christina Schiff,

²

Marjorie Green,

²

Robert J. Motzer

⁷

1

Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA;

²

Genentech, Inc., South San Francisco, CA, USA;

3

Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA;

⁴

Beth Israel Deaconess Medical Center, Boston, MA, USA;

⁵

Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK;

6

Gustave Roussy, Villejuif, France;

⁷

Memorial Sloan Kettering Cancer Center, New York, NY, USA

(37)

IC, tumour-infiltrating immune cell; IHC, immunohistochemistry; ITT, intent-to-treat; IV, intravenous; KPS, Karnofsky performance status;

MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival;

PO, by mouth; q3w, every 3 weeks; QD, once a day; R, randomised; RCC, renal cell carcinoma; TME, tumour microenvironment.

a≥ 1% IC: 40% prevalence using SP142 IHC assay. ^bNo dose reduction for atezolizumab or bevacizumab. ^cInvestigator assessed PFS per RECIST v1.1.

Key eligibility

• Treatment-naive advanced or metastatic RCC

• Clear cell and/or sarcomatoid histology

• KPS ≥ 70

• Tumour tissue available for PD-L1 staining

R 1:1

Atezolizumab 1200 mg IV q3w

^b

+

Bevacizumab 15 mg/kg IV q3w

^b

Sunitinib 50 mg PO qd (4 weeks on, 2 weeks off) N = 915

Stratification

• MSKCC risk score

• Liver metastases

• PD-L1 IC IHC status (< 1% vs ≥ 1%)

^a

Co-primary endpoints

• PFS

^c

in PD-L1+

• OS in ITT

Exploratory endpoints include:

• Validation of gene signatures from IMmotion150 and their association with PFS

• Biomarker characterisation in MSKCC risk subgroups and sarcomatoid tumours

Rini B, et al. IMmotion151 Biomarkers.

ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI

IMmotion151: Study Design

(38)

Angiogenesis

^High

Angiogenesis

^Low

PFS

Months

PFS

Months

0 2 4 6 8 10 12 14 16 18 20 22 24

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1 Sunitinib (n = 151)

Atezo + bev (n = 177)

0 2 4 6 8 10 12 14 16 18 20 22 24

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1 Sunitinib (n = 265)

Atezo + bev (n = 230)

5.95 8.94 10.12 12.45

HR (95% CI)

Angiogenesis

^Low

Angiogenesis

^High

Atezo + bev vs

sunitinib 0.68 (0.52, 0.88) 0.95 (0.76, 1.19)

Atezolizumab + Bevacizumab Improved PFS vs Sunitinib in the Angiogenesis ^Low Subset

Angiogenesis

(39)

T-effector

^High

T-effector

^Low

Immune

T-effector gene signature did not differentiate PFS within the sunitinib or atezolizumab + bevacizumab treatment arms

8.41 9.72 8.34 12.45

Sunitinib (n = 234) Atezo + bev (n = 243)

Sunitinib (n = 182) Atezo + bev (n = 164)

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

PFS PFS

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Months Months

0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24

HR (95% CI)

T-effector

^Low

T-effector

^High

Atezo + bev vs

sunitinib 0.91 (0.73, 1.14) 0.76 (0.59, 0.99)

Atezolizumab + Bevacizumab Demonstrated

Improved PFS vs Sunitinib in T _eff ^High Subset

(40)

aBiomarker-evaluable population.

0.92 0.86 0.48 0.74 0.70

0.94 0.82 0.57 HR

0,2 2

Favours Sunitinib Favours Atezo + bev

Hazard Ratio 1.0

n 61 291

84 267

156 667 134 688 Baseline Factor

MSKCC Intermediate/Poor MSKCC Favourable

PD-L1+

Non-Sarcomatoid Sarcomatoid

All evaluable patients

MSKCC Intermediate/Poor MSKCC Favourable

Non-Sarcomatoid Sarcomatoid

Subgroup PFS Analyses in PD-L1+ and

All Evaluable Patients ^a

(41)

Declinare il profilo molecolare nella pratica clinica… Tumori urologici

Carcinoma prostatica metastatico Carcinoma renale metastatico

Carcinoma uroteliale della vescica

(42)

5-year survival rate of metastatic UBC is 6%

*Rates are adjusted for normal life expectancy and are based on cases diagnosed from 2004–2010 in the SEER 18 areas, followed through 2011.

‡Includes renal pelvis.

§Includes intrahepatic bile duct.

Howlader N, et al. (eds). SEER Cancer Statistics Review, 1975–2011

**5-year survival rates* (%) for patients diagnosed at metastatic stage**

5 -y ear surv iv al rate (% )

(43)

Linee Guida AIOM 2018

(44)

Timeline

Terapia sistemica in carcinoma uroteliale

Vogelzang N, ASCO 2015

(45)

52 KPS<80

Visceral mets: lung, bone, liver

Prognostic factors: MSKCC data with MVAC

Bajorin DF, JCO 1999

(46)

Improved 5-factor prognostic classification of patients receiving salvage systemic therapy for advanced urothelial carcinoma

Sonpavde G, Pond GR, Rosenberg JE, Bajorin DF, Regazzi AM, Mullane S, Niegisch G, Albers P, Necchi A, Di Lorenzo G, Fougeray R, Ko Y-J, Rozzi A, Matsumoto K, Lee JL, Kitamura H, Kume H,

Milowsky MI, Choueiri TK, Bellmunt J

Discovery (n=491) Validation (n=167)

Factor HR (95% CI) p-value HR (95% CI) p-value TFPC <3

months

1.49 (1.19, 1.87) <0.001 1.35 (0.87, 2.08) 0.18

ECOG PS>0 1.39 (1.16, 1.67) <0.001 1.58 (1.06, 2.35) 0.023 Liver

Metastases

1.45 (1.16, 1.81) <0.001 1.26 (0.83, 1.90) 0.27

Hb <10 g/dl 1.73 (1.27, 2.35) <0.001 1.35 (0.94, 1.96) 0.10 Alb <LLN 1.61 (1.20, 2.15) 0.002 1.90 (1.27, 2.85) 0.002

Sonpavde G et al, J Urol 2015

(47)

Timeline –studi clinci

(48)

Considerazioni in ambulatorio per la scelta terapeutica

Rischio prognostico Fit for cisplatino

Analisi

molecolari?

(49)

Cisplatin ineligibility

Galsky MD, Rosenberg JE, Hahn N, Sonpavde G, Bellmunt J, JCO 2011

Clearance creatinine <60 ml/min

(<50 in qualche studio clinico phase II trials) – sembra che la formula di

calcolo CrCl sono inadequate (Raj GV, JCO 2006)

(50)

▪ eterogeneicità del del tumore

▪ Eterogeniceità dei pazienti

▪ Inaccuratezza di staging e conseguente rischio di malattia

▪ Analisi, quantificazione e integrazione dei dati su biomarkers di diverse piattaforme

▪ Accesso ai materiali in patologia

▪ early trials - costo studi clinici e competizione

Nonstante timeline degli studi promettenti -nessun biomarker applicabile nella clinica ?

Difficoltà nella traslazione

(51)

Sistema di classificazione -

sottotipi molecolari

(52)

Meta-analisi di Tan 2018

espressione genica in 2411 casi di neoplasia muscolo invasivo e non

Sono stati identificato 6 sottotipi e correlati al outcome

• neural-like OS 87 mesi

• HER2-like OS 107,7 mesi

• papillary-like OS135 mesi

• luminal-like OS 91,7 mesi

• squamous cell carcinoma-like OS 20 mesi

• mesenchymal-like OS 86,6 mesi

(53)

Mutations in 131 T2-T4 Tumors

TCGA Network, Nature 2014

(54)

Knowles & Hurst, Nat Rev Cancer 2015

(55)

Risultati deludenti con target therapy

(56)

Necchi A, Lancet Oncol 2012

Gallagher DJ, J Clin Oncol 2010

Pazopanib

Sunitinib

(57)

Srinivas SS et al, GU ASCO 2015

(58)

A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects with Metastatic or Surgically

Unresectable Urothelial Cancer with FGFR Genomic Alterations

“… Tumors must have at least 1 of the following translocations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or

One of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C”

Bahleda R, ASCO 2014 Sequist LV, AACR 2014

BGJ-398 in FGFR3-mutated UBC

JNJ-42756493 at ≥6mg dose in UBC with

FGFR aberrations

(59)

Nature Reviews Urology 10, 184 (2013); published online 5 March 2013;

doi:10.1038/nrurol.2013.35

(60)

PD-L1 IHC staining in urothelial bladder cancer ?

(61)

Rationale for the development of immunotherapy in early stage urothelial bladder carcinoma-3

PD1/PD-L1 Pathway

Mullane SA, ASCO 2014

aPD-L1

Indication

PD-L1+

Tumor-Infiltrating Immune Cells (ICs)

UBC (n = 205) 27%

RCC (n = 88) 25%

NSCLC (n = 184) 26%

Melanoma (n = 59) 36%

Based on staining of archival tumor tissue from patients prescreened in MPDL3280A Phase Ia study.

PD-L1+: IHC 3 (≥ 10% of ICs PD-L1+) or IHC 2 (≥ 5% but <

10% of ICs PD-L1+).

PD-L1‒: IHC 1 (≥ 1% but < 5% ICs PD-L1+) or IHC 0 (<1% ICs PD-L1+).

Powles T, et al. ASCO, 2014.

Bellmunt J, et al. ESMO, 2014

(62)

Association of PDL-1 expression by TIMC and OS in urothelial carcinoma

Bellmunt J, Ann Oncol 2015

(63)

A myriad of next generation I-O trials with mono- or

combination therapy are underway in almost all clinical settings

• Pembrolizumab

• Everolimus+intra

vesical GEM (NCT01259063)

Pembrolizumab+RT (NCT02560636)

PURE01:

Pembrolizumab>Cystectomy (EudraCT: 2015-002055-10)

MIRTOS:

Atezolizumab>Cystectomy

Phase III: Atezolizumab (NCT02450331) Phase III: Pembrolizumab

(AMBASSADOR) Phase III: Avelumab (EudraCT 2015-003262-86)

Phase III: Nivolumab (CA209-274)

Phase III: Avelumab (EudraCT 2015-003262-86)

Phase II: Regorafenib (NCT02459119) NEOADJUVANT ADJUVANT

BCG Refractory

Phase II: KEYNOTE-052, Pembrolizumab

(NCT02335424)

Phase III: KEYNOTE-045, Pembrolizumab

(NCT02256436) Phase III: Atezolizumab (GO29294), NCT02302807 Phase III: MEDI4736 vs MEDI4736+Tremelimumab vs ChemoTx (DANUBE,

NCT02516241)

MAINTENANCE Tx

REFRACTORY Atezo+Bevacizumab

Atezo+Rad223 AD4547/MEDI4736 AZD8186/MEDI4736

Olaparib/MEDI4736 Wee1/MEDI4736

Olaparib/MEDI4736/Tremelimuma b

Etc.

Sources: http://ClinicalTrials.gov; http://www.bcan.org

(64)

Prognostic Factor

Hb < 10 g/dL Liver Mets ECOG PS > 1

Risk Group

0 No PF

1 1 PF

2 2 PF

3 3 PF

Bellmunt J et al. J Clin Oncol. 2010

(65)

72

(66)