Impatto dell’immunoterapia nei pazienti con tumore dell’urotelio

Milano, 17 Novembre 2017

Sergio Bracarda MD,

Head, Dept. of Oncology, Azienda USL Toscana Sud-Est

Istituto Toscano Tumori (ITT) Ospedale San Donato

Arezzo, Italy

My Disclosure

• Adv. Board Member for: Pfizer, BMS, Novartis, MSD, Roche, Genentech, Astellas, Janssen, Eusa Pharma, Ipsen, Exelixis.

• Travel Accomodation with: Pfizer, BMS, Roche, Astellas, Jannsen, Ipsen. Bayer

• Reasonable Honoraria (Talks) from: Pfizer, Roche, Astellas, Novartis,

BMS, Janssen

Bladder (Urothelial..) Cancer:

One of the most common GU malignancy worldwide ?

1SEER Stat database. 2013

Urothelial Tumors (UC): one or more Tumors ? (Urothelial Bladder Carcinoma)

Ta/T1/Tis: Non- muscle invasive TURBT/ intravesical BCG

T2-T4: Muscle Invasive:

radical cystectomy; <25%

get adjuvant/neoadjuvant (Gem/Cis)

1L Metastatic :

•Gem/Cis or MVAC are SOC in US;

•Gem/Carbo for Cis ineligible (50%);

2L Metastatic:

Pemetrexed, Vinfluinine (EU)

ORR: 10%; mOS: 7–9 mo Normal Urothelium

10-15%

10 -15%

70-80%

In US in 2013,

new 72,570 cases estimated &1

5,210 deaths in US (ACS, 2013 )

von der Maase H, et al. J Clin Oncol. 2005 23:4602-4608

OS with Gemcitabine/Cisplatin vs M-VAC in Metastatic UC

• N = 405 pts with locally advanced or metastatic UC 1.0

0.8 0.6 0.4 0.2

00 12 24 36 48 60 72 84 96

Median OS, Months:

GC 14.0 M-VAC 15.2

Proportion Surviving

Mos

Log-rank P = .44, Wald’s P = .66

GC M-VAC

UBC: What’s just behind the C(T) Corner and Why ?

1. Bellmunt. Ann Oncol. 2013; 2. TCGA. Nature. 2014; 3. Lawrence. Nature. 2013; 4. Kandoth. Nature. 2013; 5. Galsky. Clin Adv Hematol Oncol. 2013.

Overall survival in the eligible population*¹

Time (months) 1.0

0.8 0.6

0.0 0.2

Overall survival (probability)

VFL + BSC BSC

0.4

25

10 20 30 35

0 5 15

Overall survival in the ITT population¹

Time (months) 1.0

0.8 0.6

0.0 0.2

Overall survival (probability)

VFL + BSC BSC

0.4

25

10 20 30 35

0 5 15

M(+) UC Disease: OS rates for patients receiving second-line Vinflunine

*The eligible population excludes 13 patients who presented at least one major protocol violation at baseline 1. Belmunt, et al. 2009

2. Vinflunine (Javlor) SmPC Courtesy by Tom Powles

Median OS (ITT)

6.9 months with VFL + BSC (n=253) vs

4.6 months with BSC (n=117) HR 0.88 (log rank p=0.2868)

Median OS (eligible) 6.9 months with VFL + BSC (n=249) vs

4.3 months with BSC (n=108) HR 0.78 (log rank p=0.0403)

1 ^st & 2 ^nd Line mUBC, unmet need for new Rx Options, with:

• No efficacious alternatives to Cisplatin in 1

Line and no FDA- approved therapies in 2

Line after Platinum CT failure.

• Smart gain in PFS and OS (median OS≈ 7m

) in 2

Line with any possibility of a Cure.

• Significant complexity of UC treated Pts: mainly an Elderly

population, with frequent Comorbidities (cardiovascular problems,

impaired renal, function, polipharmacy) or frail cases: Need of

safer approaches .

Slide 11

Presented By Seth Lerner at 2017 ASCO Annual Meeting

A new Paradigm in UBC ?

Molecular Subtypes and Outcome

Presented By Seth Lerner at 2017 ASCO Annual Meeting

1. Bellmunt. Ann Oncol. 2013; 2. TCGA. Nature. 2014; 3. Lawrence. Nature. 2013; 4. Kandoth. Nature. 2013; 5. Galsky. Clin Adv Hematol Oncol. 2013.

Somatic mutation frequencies observed in exomes from 3083 tumor-normal pairs

Reprinted pending permission from Macmillan Publishers Ltd: Nature, Lawrence MS, et al. Jul 11;499(7457):214-8, 2013.

•Patients with UBC have a high rate of somatic mutations

• High mutational complexity rates similar to tobacco/environmental carcinogen exposure^2-4

• Potential for many neo-antigens to be seen as foreign by host immune system^2-4

But also…: High rate of Somatic Mutations in UBC

Somatic mutations and response to immunotherapy

Presented By Bishoy Faltas at 2017 ASCO Annual Meeting

Slide 2

Presented By David Liu and David McConkey

at 2017 ASCO Annual Meeting

The winning NAC Model

(..going back to Enrico

Presentation…)

Tumor heterogeneity correlates with worse OS

Presented By Bishoy Faltas at 2017 ASCO Annual Meeting

The New Treatment Options Data:

..Started with MPDL3280A (Atezolizumab) in Adv. UBC

2014 ASCO & ESMO Meetings

IMvigor 210: Study Design

§ Single-arm phase II study with 2 cohorts ^[1]

§ Cohort 2 study

– Primary endpoints: confirmed ORR by RECIST v1.1 (per central review), ORR per immune-modified RECIST (per investigator)

– Secondary endpoints: DoR, PFS, OS, safety

1. ClinicalTrials.gov. NCT02108652. 2. Balar AV, et al. ASCO 2016. Abstract LBA4500. 3. Dreicer R, et al.

ASCO 2016. Abstract 4515. 4. Rosenberg JE, et al. Lancet. 2016;387:1909-1920.

Pts with inoperable advanced or metastatic UC, predominantly TCC

histology,

evaluable tumor tissue for PD-L1 testing

(N = 429)

Cohort 1

Previously untreated, cisplatin ineligible

(n = 119)

Cohort 2

Prior platinum treatment

(n = 310)

Atezolizumab 1200 mg IV Q3W

until PD

Atezolizumab

1200 mg IV Q3W

until loss of benefit

Phase II IMvigor210 (Cohort 1): First-line Atezolizumab Efficacy Data

§ N = 123 patients with previously untreated, cisplatin-ineligible, inoperable advanced or

metastatic UC

§ Median follow-up: 17.2 mos

§ ORR: 23%

– CR rate: 9%

– No difference by PD-L1 status

§ mOS: 15.9 mos

– Shorter in PD-L1 high vs low – 57% alive at 12 mos

Balar AV, et al. Lancet. 2017;389:67-76.

0 20 40 60 80 100

OS ( % )

0 4 8 12 16 20 24

Mos Censored

All patients (N = 119) IC2/3 (n = 32)

IC0/1 (n = 87)

15.9 (10.4-NE) 12.3 (6.0-NE) 19.1 (9.8-NE) Median OS, Mos (95% CI)

Note: Pt cohort colors were switched in original publication, and has been corrected in this slideset

§ N = 370 patients with previously untreated, cisplatin ineligible, inoperable advanced or

metastatic UC

§ Median follow-up: 5 mos

§ ORR: 24%

– CR rate: 5%

– PD-L1 positive did better (ORR: 39% to 48%)

§ OS data not mature

Phase II KEYNOTE-052: First-line

Pembrolizumab for Pts With Cisplatin-Ineligible Advanced UC

Balar AV, et al. ASCO GU 2017. Abstract 284.

Treatment Exposure and Response Duration in Confirmed Responders (n = 89)

0 8 1 Wks 6

2 4

3 2

4

0 4

8 5 6

6 4

7 2

*

*

* *

*

***

**

* *

**

* **

* * *

* *

* * *

* **

** *

***

* *

*

CR/PR PD

Last dose

On treatment

IMvigor 210 (Cohort 2): OS associated with PD-L1 Expression on IC (Immune Cells)

Dreicer R, et al. ASCO 2016. Abstract 4515.

Rosenberg JE, et al. Lancet. 2016;387:1909-1920.

Median OS,

Mos (95% CI) 12-Mo OS, % (95% CI) 100

90 80 70 60 50 40 30 20 10 0

OS (% )

Censored

IC2/3 (n = 100) IC1 (n = 107) IC0 (n = 103)

11.4 (9.0-NE) 6.7 (5.1-8.8) 6.5 (4.4-8.3)

48 (38-58) 30 (20-39) 29 (20-39)

0 2 4 6 8 10 12 14 16

Pts at Risk, n Mos IC2/3

IC1 IC0

100 107 103

92 89 84

74 68 60

67 58 49

58 47 40

50 32 32

23 10 14

2

1

1

Key Eligibility Criteria^a

• mUC with progression during or following platinum-based chemotherapy – ≤ 2 prior lines of therapy

• Measurable disease per RECIST v1.1

• ECOG PS 0-1

• Evaluable sample for PD-L1 testing

• TCC histology as primary component (N = 931)

§Primary endpoint – OS, tested hierarchically

in pre-specified populations

10 Powles T, et al. EAS 2017, IMvigor211.

DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT02302807. bDefined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. cConfirmed response was not required for secondary efficacy endpoints. This analysis reports exploratory confirmed responses.

IMvigor211 Study Design

10

Atezolizumab 1200 mg q3w R

1:1

No crossover permitted per protocol

Survival follow-up Loss of

clinical benefit

RECIST v1.1 progression Stratification Factors

• No. of risk factors^b(0 vs. 1/2/3)

• Liver metastases (yes vs. no)

• PD-L1 status (0/1 vs. 2/3)

• Chemotherapy (vinflunine vs. taxanes)

§ Additional endpoints

– Efficacy: RECIST v1.1 ORR, PFS and DOR^c – Safety

– PROs: EORTC QLQ-C30 Chemotherapy (investigator’s choice)

• Vinflunine q3w

• Docetaxel q3w

• Paclitaxel q3w

10 HR, hazard ratio. Powles T, et al. EAS 2017, IMvigor211.

OS Analysis: IC2/3 Population

HR = 0.87 (95% CI: 0.63, 1.21) P = 0.41

Events/

Patients Median OS (95% CI)

12-mo OS Rate (95% CI) Atezolizumab 72/116 11.1 mo(8.6, 15.5) 46% (37, 56) Chemotherapy 88/118 10.6 mo(8.4, 12.2) 41% (32, 50)

No. at Risk

Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80 60

0

10 12 14 16 18 20

2 4 6 8

0 22 24

20 40

Overall Survival

100

Months

80 60

0

10 12 14 16 18 20

2 4 6 8

0 22

20 40

Overall Survival

100

Months

24

No. at Risk

Atezolizumab 111 111 111 111 108 105 101 82 57 39 24 11 1

Chemotherapy 129 129 129 129 119 108 94 67 41 33 16 7 1

§Disease control was also observed across arms – DCR is defined by

patients with confirmed CR/PR or SD ≥ 24 weeks per RECIST v1.1

§OS analysis suggests improved survival in patients with disease control in the

atezolizumab arm

10 DCR, disease control rate; PD, progressive disease; SD, stable disease. Powles T, et al. EAS 2017, IMvigor211.

aNote: Analysis includes patients who survived long enough to be evaluated for disease control.

Disease Control

Disease Control

IC2/3 IC1/2/3 ITT

Atezo

(n = 113)

Chemo

(n = 116)

Atezo

(n = 312)

Chemo

(n = 306)

Atezo

(n = 462)

Chemo

(n = 461)

DCR, % 34% 33% 26% 28% 24% 28%

95% CI, % 25, 43 24, 42 21, 31 23, 34 20, 28 24, 32

OS in ITT Population With Disease Control^a

Atezolizumab Chemotherapy

esmo.org

EFFICACY AND SAFETY OF NIVOLUMAB

MONOTHERAPY IN PATIENTS WITH METASTATIC UROTHELIAL CANCER (mUC) WHO HAVE

RECEIVED PRIOR TREATMENT Results from the phase II CheckMate 275 study

LBA31_PR

Matthew D. Galsky,

Margitta Retz,

Arlene Siefker-Radtke,

Ari Baron,

Andrea Necchi,

Jens Bedke,

Elizabeth R.

Plimack,

Daniel Vaena,

Marc-Oliver Grimm,

Sergio Bracarda,

José Ángel Arranz,

Sumanta Pal,

Chikara Ohyama,

Abdel Saci,

Alexandre Lambert,

Suba Krishnan,

Alex Azrilevich,

Padmanee Sharma

1Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA; ²Klinikum Rechts der Isar, Munich, Germany; ³MD Anderson Cancer Center, University of Texas, Houston, TX, USA; ⁴California Pacific Medical Center, San Francisco, CA, USA; ⁵Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; ⁶University of Tübingen, Tübingen, Germany; ⁷Fox Chase Cancer Center, Philadelphia, PA, USA; ⁸Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA; ⁹Jena University Hospital, Jena, Germany; ¹⁰Ospedale San Donato, Azienda USL Toscana Sud-Est, Istituto Toscano Tumori, Arezzo, Italy; ¹¹Hospital General Universitario Gregorio Marañón, Madrid, Spain; ¹²City of Hope Comprehensive Cancer Center, Duarte, CA, USA; ¹³Hirosaki University, Hirosaki, Aomori, Japan;¹⁴Bristol-Myers Squibb, Princeton, NJ, USA

15Bristol-Myers Squibb, Braine-l’Alleud, Belgium

1 CheckMate 275: Open label single-arm Phase II

Study of Nivolumab in UC Study design

aPatients were required to have an evaluable tumor PD-L1 sample at screening, however patients were not excluded based on PD-L1 status.

The primary analysis was to occur 6 months after approximately 70 patients with tumor PD-L1 expression of ≥5% were treated bVerified PD-L1 assay with 5% expression level was used to determine tumor PD-L1 expression status

cPatients could have been treated beyond progression under protocol-defined circumstances

Treat until progression^c

or unacceptable

toxicity All treated patients

N=270^a

Nivolumab 3 mg/kg IV

Q2W PD-L1 ≥5%^b

n=81

PD-L1 <5%^b n=184 Cohort Assignment

Blinded independent review committee assessment of response (BIRC) using RECIST v1.1

Patients with locally advanced

or metastatic urothelial carcinoma progressing despite platinum-

based chemotherapy

Treatment

CheckMate 275: Antitumor activity to nivolumab

Outcome, % All

N=265

Confirmed ORR by BIRC

19.6

95% CI 15.0–24.9

Best overall response

Complete response 2.3

Partial response 17.4

Stable disease 22.6

Progressive disease 39.2

Unable to determine 18.5

aBy RECIST v1.1

b265 of 270 patients were evaluated for efficacy, as 5 patients had insufficient follow-up

• Confirmed ORR in patients with PD-L1 <5% was 15.8% (95% CI, 10.8–21.8)

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

8

• Median follow-up was 7 months (minimum of 6 months)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Months Progression-Free Survival (Probability)

0 3 6 9 12

CheckMate 275: Progression-Free Survival

No. at Risk All treated patients

aSimilar results were seen using the 5% PD-L1 tumor expression cutoff

265 110 48 17 0

Median PFS, Months (95% CI)^a All treated 2.00 (1.87–2.63)

All treated patients PD-L1 <1%

PD-L1 <1% 1.87 (1.77–2.04)

143 49 21 9 0

PD-L1 <1%

PD-L1 ≥1% 3.55 (1.94–3.71)

122 61 27 8 0

PD-L1 ≥1%

PD-L1 ≥1%

CheckMate 275: Overall Survival

All treated patients

No. at Risk All treated patients PD-L1 <1%

PD-L1 ≥1%

PD-L1 ≥1%

Median OS, Months (95% CI)^a All treated 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

Overall Survival (Probability)

Months

PD-L1 <1%

aSimilar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached

265 198 148 63 5 0

143 101 69 26 2 0

122 97 79 37 3 0

KEYNOTE-045 Study Design (NCT02256436)

Presented By Dean Bajorin at 2017 ASCO Annual Meeting

Overall Survival: Total

Presented By Dean Bajorin at 2017 ASCO Annual Meeting

Overall Survival: Subgroups

Presented By Dean Bajorin at 2017 ASCO Annual Meeting

Efficacy: PD-L1 CPS ≥10%

Presented By Dean Bajorin at 2017 ASCO Annual Meeting

Epacadostat Plus Pembrolizumab in Patients With Advanced Urothelial Carcinoma:<br />Preliminary Phase 1/2 Results of ECHO-202/KEYNOTE-037

Presented By David Smith at 2017

ASCO Annual Meeting

Immunotherapy in Platinum failing Advanced UC:

Safety Data (March 2017)

Agent Phase N

(Evaluable)

Median Follow-up,

Mos

Grade 3-5 Tx- Related AE,

%

Tx-Related Deaths,

n (%)

Any Grade Tx- Related AE,

%

No Tx- Related AE,

%

Atezolizumab

(IMvigor210) II 310 21.0 18.0 0 71.0 29.0

Pembrolizumab

(KEYNOTE-045) III 270 14.1 15.0 4 (1.5) 60.9 39.1

Durvalumab

PD-L1+ enriched I/II 191 5.6 6.8 2 (1.0) 60.7 39.3

Nivolumab

(CheckMate-275) II 270 7.0 18.0 3 (1.1) 64.0 36.0

Avelumab

(JAVELIN) Ib 241 7.3 7.4 1 (0.4) 62.2 37.8

Ipilimumab +

nivolumab

I/II 130 7.8-16.7 31.5 1 (0.8) 83.1 16.9

1. Loriot Y, et al. ESMO 2016. Abstract 783P. 2. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. 3. Powles T, et al.

ASCO GU 2017. Abstract 286. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 5. Patel M, et al. ASCO GU 2017.

Abstract 330. 6. Sharma P, et al. 2016 SITC Annual Meeting.

But, only Immuno-Oncology Options in the Future of UC ? Or, other possible Rx Options will move the Scenario

toward a “Lung AdenoCarcinoma Model”

16

Oncogenic Drivers with effective treatments in NonSquamous vs Squamous NSCLC

ALK, anaplastic lymphoma kinase;

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer 1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014:e353–65;

2. Pao W, Girard N. Lancet Oncol 2011;12:175–80;

3. Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51

Unknown oncogenic drivers or oncogenic drivers without proven

treatments Unknown oncogenic

drivers or oncogenic drivers without proven

treatments EGFR M+

15–20%

Squamous NSCLC^2,3 Nonsquamous* NSCLC¹

EML4-ALK+

3–7%

EGFR M+ or EML4-ALK+

<5%

*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell, and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped together into a category (non-small cell carcinoma or nonsquamous non-small cell

carcinoma) when it is necessary, or useful, to considered them in the same way, even although the tumors may be different

9

Squamous cell carcinomas frequently have genetic mutations in multiple pathways

CDKN2A, cyclin-dependent kinase inhibitor 2A; HLA-A, human leukocyte antigen A; KEAP1, kelch-like ECH-associated protein 1;

MLL2, mixed lineage leukemia 2; NFE2L2, nuclear factor (erythroid derived 2)-like 2; NOTCH1, neurogenic locus notch homolog protein 1; NSCLC, non-small cell lung cancer; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit;

PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; TP53, tumor protein 53 1. Cancer Genome Atlas Research Network. Nature 2012;489:519–25 Samples with

mutations, %

Significantly mutated genes in squamous NSCLC¹

Statistically significant recurrent mutations found in 10 genes, including mutation of TP53 in nearly all specimens

Synonymous Splice site Missense Nonsense

Frame shift Inframe indel Other non- synonymous

132100

80 6040 200 Overall no.mutations permegabase Synonymous Non- synonymous

70503010 81%

15%

8%

16%

12%

20%

3%

15%

8%

7%

TP53 CDKN2A PTEN PIK3CA KEAP1 MLL2 HLA-A NFE2L2 NOTCH1 RB1

0.5 2.0 3.5 –log10 (Q value) Reprinted by permission from Macmillan Publishers Ltd

Available New Data for New possible Agents in UC and:

ü FGF Pathway ü ERBB Pathway ü Angiogenic

Pathway

Efficacy

• Responses observed at the 9 mg QD and 10 mg intermittent levels (as of 06 Jun 2016)

- 11 PR out of 24 FGFR+ pts, ORR of 45.8%

(95% CI 25.6%, 67.2%)

▪ 9 mg QD: 7/11 PR. ORR: 63.6%

▪ 10 mg intermittent: 4/13 PR. ORR: 30.8%

• Median duration of response: 7.2 mo (1.6+

to 15.3 mo), (95% CI 3.3 to 15.3 mo)

• Median PFS: 5.1 mo (95% CI 2.8 to 5.9 mo) - 6-mo PFS of 24%; 12-mo PFS of 12%

ESMO 2016 Abstract EDI1001 FTIH Study -Soria et al: Safety and Activity of the Pan–Fibroblast Growth Factor Receptor (FGFR) Inhibitor Erdafitinib in Phase 1 Study Patients with Advanced Urothelial Carcinoma (UC)

• AEs of special interest (AESI):

– No Grade 4 AESI

– Hyperphosphatemia; Skin/Nail toxicity; Eye toxicity:

Phase II Data:Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma Pts

With ERBB Alterations.

• Results: 5/23 pts (21.7%) achieved 3m PFS (primary end point).

• The study did not meet the criterion of ≧7 pts reaching 3m PFS necessary to proceed to the 2° stage of enrollment. Median PFS for the entire cohort was 1.4 months.

• EGFR amplifications (11%), HER2 amplifications (7%), and ERBB3 somatic mutations (11%) relatively frequent in UC.

• Possible role for dual inhibition in pts with HER2/EGFR overexpression.

Choudhury N, et Al. J Clin Oncol. 2016 Jun 20;34(18).

• 5/6 pts (83%) with ERBB molecular alterations consisting of HER2 copy number amplification and/or ERBB3somatic mutations achieved 3m PFS, whereas 0/15 pts (0%) without alterations reached PFS3 (P < .001, Fisher’s exact test (Fig 1).

• median PFS in the 6 pts with HER2 /

ERBB3 alterations: 6.6 months versus 1.4 mos

in pts without alterations (Fig 2); P <.001, log-

rank test).

My CONCLUSIONS

• Rx Options in Medical Oncology are quickly moving from “General Approaches”

(e.g. CG Chemotherapy for UBC) to “Taylored Approaches” (I-O Options, Target Agents, but why not still a Chemo in some cases ..!)

• Consequent Rapid Evolution of Treatment Scenarios from classical “GU, GI, Lung, eg, Tumors” to (also?) Target Expressing Tumors (e.g: going toward I-O Optimal candidates or Target expressing Tumors, also considering expression timelines ..)

• Not still the moment of a “Silver Bullet” for UC, but we are moving to identify Cohorts of Pts to be treated with different Classes of Agents, with I-O quickly becoming the preferred Treatment Option in 2° L. setting after Platinum failure.

• This may be also due to a new, TCGA- based, Tumor Classification .

end