biomarkers and targeted therapies for urothelial...

Biomarkers and Targeted

Therapies for Urothelial Cancer

Daniel P. Petrylak, MD

Professor of Medicine and Urology

Director, GU Translational Working Group

Co Director, Signal Transduction Program

Smilow Cancer Center, Yale University

Disclosure

• Consultant: Sanofi Aventis, Celgene, Pfizer,

Millineum, Dendreon, Johnson and Johnson,

Bayer, Medivation, Roche/Genetech,

Bellcium, Tyme

• Research Support: Roche, Merck, Dendreon,

Progenics, Lilly, Medivation, Agenysis, Astra

Zenca, GSK, Bayer

• Stock Tyme, Bellicum

Standard MVAC

Gem/Ci

s

Accelerated

MVAC

Vinflunin

Atezolizuma

b

2009:

Vinflunine

EMA Approved

1978: Cisplatin

US FDA

Approved

2016:

Atezolizumab

US FDA

Approved

Targeted Therapy in Urothelial Cancer

Vinflunin

2009:

Vinflunine

EMA Approved

Vinflunin

2009:

Vinflunine

EMA Approved

1.Immunotherapy is active only in a small subset of patients

2.Resistance to immunotherapy is often seen.

3.Significant percentage of patients are not fit enough to receive

Cisplatin-combination chemotherapy.

4.In this era of precision medicine, there is no FDA approved,

biomarker-selected targeted therapy for mUC.

UC is molecularly heterogeneous

• While multiple pathways are altered, the frequency of mutation in any one gene/ pathway is modest, at best

• Unselected trials with targeted agents unlikely to yield positive results

TCGA Network, Nature

2014

Multiple alterations in kinase signaling pathways

TCGA Network, Nature

2014

Multiple therapeutic targets within the cell cycle and RTK/Ras/PI3K pathways

Left box: mutation

Right box: copy

number

Red: activated or

amplified

Blue: inactivated or

deleted

PI3K/AKT/mTOR pathway in Urothelial Carcinoma

PI3K

Akt

mTORC

1

4E-

BP

p70S6

K

mTORC

2

TSC

1

Cell Growth,

Translation/Tumorigenesis

Cytoskeleton

Organization

TSC

2

Ching CB et al. Lab

Invest.2010

Wu Y et al. Cell Research 2007

PI3K/AKT/mTOR pathway in Urothelial Carcinoma

PI3K

Akt

mTORC

1

4E-

BP

p70S6

K

mTORC

2

TSC

1

Cell Growth,

Translation/Tumorigenesis

Cytoskeleton

Organization

TSC

2

Everolimus

Ching CB et al. Lab

Invest.2010

Wu Y et al. Cell Research 2007

TSC1 mutations in TCC

*

Sjödahl G et al. PLoS One. 2011

Knowles MA et al. Cancer Metastasis Rev

2009

Pymar LS et al. Hum Mol Genet 2008;

Frequency of TSC1 or TSC2 mutations: 8 to 15%.*

Personalized medicine in UC: mTOR/TSC1

• Whole genome sequencing revealed TSC1 and NF2 inactivating mutations

• In vitro evaluation shows TSC1 sensitizes urothelial cancer cells to mTOR inhibition

G Iyer et al. Science 2012;338:221

Personalized medicine in UC: mTOR/TSC1

• Patient treated on phase I study of everolimus/ pazopanib

• CR lasting 14 months

• WES showed activating mTOR mutations

Wagle, et al. Cancer Discovery

2014

Mutations are activating,

and can be inhibited by

rapamycin in vitro

MLN-0128 (aka. TAK228): NCI Protocol 9767

• Potent, highly selective ATP-competitive inhibitor of mTOR kinase that exhibits dual specificity against both TORC1 and TORC2 complexes.

• Dual TORC1/2 inhibition mitigates the feedback activation of AKT, known to cause resistance to TORC1 selective inhibitors.

• Displays cellular inhibition of TORC1 and TORC2 pathways with IC50 less than 10 nM.

• Potential of greater clinical activity than the currently available rapalogs.

Schema (NCI Protocol 9767)

TSC1 /

TSC2

mutation

sequencing

to be done

at

Yale

Profiling

Lab by Dr.

Jeff Sklar Primary

Endpoint: ORR

N=25

Epidermal Growth Factor

EGF family

– Her-2/neu: 25 % of primary and metastases

– EGF expressed in 70-80% of primary and

metastatic lesions

Treatment Plan

AUC=area under the curve; IV=intravenous

Agent Dose Route Days

Treatment

Interval

Trastuzumab 4-mg/kg

loading dose

2 mg/kg

subsequent

infusions

IV 1, 8, 15 21 days

Paclitaxel 200 mg/m2 3-hour IV

infusion

1 21 days

Carboplatin AUC=5 15-minute

IV infusion

1 21 days

Gemcitabine 800 mg/m2 30-minute

IV infusion

1, 8 21 days

HER-2 Status

N=109

Method Number of Positive

Patients

Percentage

Positive

Any Method 57 52.3%

IHC (2+ or 3+) 53 48.6%

FISH (>2.0) 15 13.8%

Serum (>16.0) 13 11.9%

Any 2 out of 3 21 19.3%

All 3 criteria 3 2.8%

Distribution of Disease by HER-2 Status

*Non-parametric Wilcoxon rank-sum test

.

Her-2/neu

Positive

Her-2/neu

Negative

P-

Value

Median number of metastases 2 1 0.014*

Incidence of 2 or more

Metastases

50.9% 30.8% 0.051

Worst metastatic site 0.311

Liver or bone 40.4% 26.9%

Lung 14.0% 23.1%

Soft Tissue 43.9% 48.1%

Best Response (n=44)

Overall Response Rate 31 (CI 55-83%) 70%

Complete Response 5 11%

Partial Response 26 * # 59%

Response by IHC of 2+ 14/21 67%

Response by IHC of 3+ 15/20 75%

Stable Disease 5 11%

Progressive Disease 3 7%

No Response Assessment 5 11%

* 2 patients had a pathologic CR

# 31% of patients with PR had also bone mets. RR: 82% FISH+ ve, 67% FISH -ve

UMCC 9955

Time To Events in Months

7.195%CI:

4.8-8.0

9.3 95%CI:

6.7-10.2

14.1

95%CI:

11.5-17.1

Median Survival by HER2 Status

–HER2 IHC 2+ patients:

» 15.8 months

–HER2 IHC 3+ patients:

»13.3 months.

–FISH positive patients:

» 11.9 months

–FISH negative patients:

»15.5 months

S0031: ZD1839 in Transitional Cell

Carcinoma of the Bladder

EGF-R 3+

Staining

Her-2/Neu 3+

Staining

30 patients who failed 1 prior

chemotherapeutic treatment for

metastatic disease were treated with ZD

1839 500mg PO QD

17 patients had a pretreatment biopsy ,

immunohistochemistiry performed using

antibodies to EGF-R, Her-2/Neu, p53

EGF-R Expression and Best Response

EGF

Staining

0 1+ 2+ 3+

PROG 4 3 1 7

STAB 0 1 0 0

PR 0 1 0 0

R

Lapatinib 1500mg PO OD

Placebo

Endpoints

Primary: Progression free survival (PFS)

Secondary: Overall survival/adverse events.

Exploratory: subset analysis

Stratification: Chemotherapy response/PS

Chemotherapy

Screening

phase

(n=446)

(LaMB) Trial design

Eligibility criteria

• Metastatic transitional

cell carcinoma

• HER1/2 positive

• Clinical benefit with

first line chemotherapy

• Normal ejection

fraction

Treatment

phase

(n=232)

PFS 4.6 mos, OS 12.6 mos

PFS 5.3 mos, OS 11.6 mos

Centralized IHC

70% cisplatin based

Statistics: 30% difference!

HR 0.96

(95%CI: 0.7-1.3)

P=0.79

Median PFS

lapatinib

12.6 months

(95%CI: 9-16.2)

Placebo

12.0 months

(95%CI:10.6-15.8)

.

Randomised population:

OS for lapatinib vs. placebo

Further Therapy: Lapatinib = 58 (50%), Placebo = 64 (55%)

Exploratory analysis:

PFS and OS in the HER 1/2 strongly positive (3+) population.

FGFR-3(Fibroblast Growth Factor

Receptor)• A membrane based tyrosine kinase receptor involved in cellular

proliferation, differentiation, and steroid biosynthesis.17

FGFR-3(Fibroblast Growth Factor

Receptor)

• In addition to activating mutations, FGFR over-expression has been implicated in bladder cancer with Turo et al. noting up-regulated FGFR expression via IHC in 53 and 56 of 106 matched pairs of primary tumors and metastases. 18

• FGFR inhibitors and anti-FGFR antibody-drug conjugates are in ongoing and upcoming trials in advanced urothelial carcinoma.

BISCAY – Umbrella StudyA biomarker-directed study in patients with muscle-invasive bladder cancer

Module A: Durvalumab* +AZD4547 OR

AZD4547

Module D: Durvalumab*

Module B: Durvalumab* + Lynparza

Module C: Durvalumab* + AZD1775

Dx sample

analysed

FGFR

inhibitor

PD-L1

only

PARP

inhibitor

WEE1

inhibitor

Treatment option MOA

*PD-L1

FGFR3 mutations/

fusions

None

ATM, BRCA1/2,

HRR gene trunc or

missense mut/del

CDKN2A loss

RB1 loss

CCNE1 ampl

MYC ampl

Biomarkers

Assignment to module dependent on presence of biomarker

Module B2: Durvalumab + Treme + Lynparza

Module C2: Durvalumab + Treme + AZD1775

28

~11%

~22%

~46%

~19%

Adjusted

Prev

Binding of Ramucirumab to VEGFR-2 and Icrucumab to

VEGFR-1 Inhibits Subsequent Signaling

Rationale for VEGF Blockade in Bladder Cancer

• Antiangiogenic agents, particularly anti-VEGFR-2 monoclonal

antibodies (MAbs), may be capable of acting as chemosensitizing

agents when given in combination with docetaxel, since this effect was

demonstrated in mice when an anti-VEGFR-2 MAb, DC101, was

combined with paclitaxel.

• Anti-VEGFR-1 MAbs may inhibit metastasis, based on the observed

impact of the anti-VEGFR-1 MAb, MF1, on VEGFR-1-positive circulating

hematopoietic progenitor cells in mice.

Expression of VEGFR-2 in bladder

cancer but not in normal urothelium

Key trials of angiogenesis inhibitors in metastatic UC

DRUG SETTING N ORR mPFS mOS REF

GC+BEVA 1L 43 72% 8.2 19.1 Hahn, 2011

Carbo+GEM+BEVA

1LUnfit

51 49% 6.5 13.9 Balar, 2013

GC + sunitinib 1L 63 64% 6 12 Geldart, 2015

GC + sunitinib 1L 33 49% 8 13.8 Galsky, 2013

Sunitinib 1LUnfit

38 8% 4.8 8.1 Bellmunt, 2011

GC + sorafenib 1L 89 52.5% 6.3 11.3 Krege, 2014

• No striking data except for the combo with bevacizumab• Toxicity is a key issue in this population of patients with comorbidities

Key trials of angiogenesis inhibitors in metastatic UC

DRUG SETTING N ORR mPFS mOS REF

Aflibercept 2L 22 45% 2.8 NR Twardowski, 2010

Pazopanib + paclitaxel

2L 28 54% 6.2 10 Srinivas, 2015

Docetaxel+vandetanib

2L 145 7% 2.56 5.85 Choueiri, 2012

Docetaxel+ramucirumab

2L 46 24% 5.4 10.4 Petrylak, 2016

Docetaxel + icrucumab

2L 49 12% 1.6 8.1 Petrylak,2016

Randomized Phase III Study Of Gemcitabine And Cisplatin With Or Without Bevacizumab In Patients With

Advanced Transitional Cell Carcinoma

Decreased hazard rate for death by 24%

Increase OS from 13.8 to 18.63 months

87% power, two-sided alpha = 0.05

RANGE: a randomized, double-blind, placebo-controlled phase 3 study of docetaxel with or without ramucirumab in platinum-refractory advanced or metastatic urothelial carcinoma

Daniel P. Petrylak1, Kim N. Chi2, Alexandra Drakaki3, Cora N. Sternberg4, Ronald De Wit5, Hiroyuki Nishiyama6, Evan Y. Yu7, Daniel Castellano8, Syed Hussain9, Ivor J. Percent10, Aude Fléchon11, Aristotelis Bamias12, Michiel S. van der Heijden13, Nobuaki Matsubara14, Boris Alekseev15, Richard A. Walgren16, Oday Hamid16, Annamaria H. Zimmermann16, Katherine M. Bell-McGuinn16, Thomas Powles17

1Yale University School of Medicine, New Haven, CT, USA; 2British Columbia Cancer Agency, Vancouver, British Columbia, Canada 3UCLA Medical Center, Los Angeles, CA, USA; 4San Camillo and Forlanini Hospitals, Rome, Italy; 5Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 6University of Tsukuba, Tsukuba, Ibaraki, Japan; 7University of Washington, Seattle, Washington, USA; 8Hospital Universitario 12 de Octubre, Madrid, Spain; 9University of Liverpool, Liverpool, UK; 10Florida Cancer Specialists, Port Charlotte, Florida, USA; 11Centre Léon Bérard, Lyon, France; 12National and Kapodistrian University of Athens, Athens, Greece; 13Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 14National Cancer Center Hospital East, Chiba, Japan; 15P.A. Herzen Moscow Oncological Research Institute, Moscow, Russia; 16Eli Lilly and Company, Indianapolis, IN, USA; 17Barts Cancer Institute, Queen Mary University of London, United Kingdom

Funded by: Eli Lilly and Company

35

Background

• Ramucirumab is a human IgG1 monoclonal antibody VEGFR-2 antagonist.

1Petrylak DP, et al. J Clin Oncol 2016

• Ramucirumab plus docetaxel improved median progression-free survival (PFS) and trended toward an improvement in ORR (24% vs 9%) compared to docetaxel in a randomized phase 2 study in platinum-refractory UC.1

• To confirm these results, we conducted a randomized phase 3 trial (RANGE).

Phase 2 Trial (NCT01282463) Results1

RANGE (NCT02426125) Trial Design

IDMC with two safety interims (≥100 and ≥250 evaluable patients)*Docetaxel 60 mg/m2 in East Asia #Docetaxel was limited to 6 cycles; up to 4 additional cycles could be given after sponsor approval.

1:1

Placebo 10 mg/kg + Docetaxel 75 mg/m2 IV *#

Day 1 of a 21-day cycle, N =267

Ramucirumab 10 mg/kg + Docetaxel 75 mg/m2 IV *#

Day 1 of a 21-day cycle, N =263Key Inclusion Criteria: • Locally advanced, unresectable or metastatic UC• Progression ≤14 mo after platinum regimen • Prior immune CPI allowed • ECOG PS 0 or 1

Disease progression or

other withdrawal criteria met

R

A

N

D

O

M

I

Z

E

Stratification factors:• Geography (North America vs. East Asia vs. Europe/other) • ECOG PS at baseline (0 vs. 1)• Visceral metastasis (yes vs. no), defined as liver, lung or

bone.

Primary Endpoint: Progression-free survival (investigator assessment)

Secondary Endpoints: OS, ORR, disease control rate, duration of response, safety, patient-reported outcomes, PK and immunogenicity

Baseline Demographics and Characteristics (ITT; N=530)

Ramucirumab + docetaxel (n=263) Placebo + docetaxel (n=267)

Median age, years (range) 65 (34-86) 66 (32-83)Male 81% 81%Race: White | Asian 78% | 21% 76% | 23%ECOG PS: 0 | 1 46% | 52% 47% | 53%Pure transitional cell histology 76% 78%Primary tumor site:

Lower tract: bladder | urethra 64% | 3% 64% | 2%Upper tract: renal pelvis | ureter | other 14% | 13% | 5% 15% | 13% | 7%

Sites of metastases:Lymph node only | visceral | liver 20% | 69% | 30% 17% | 70% | 26%

Hemoglobin < 10 g/dL 14% 13%Time since previous chemotherapy < 3 mo 44% 46%Bellmunt of risk factors: 0 | 1 | 2 | 3 | 4 23% | 32% | 26% | 18% | <1% 20% | 36% | 31% | 12% | 1% Prior neo-adjuvant or adjuvant therapy 30% 37%Prior platinum-based therapy:

cisplatin | carboplatin 60% | 36% 68% | 29%Prior immune checkpoint inhibitor 7% 10%

Bellmunt risk factors1,2: liver metastases, hemoglobin <10 g/dL, ECOG PS >0, and time since previous therapy <3 months. 1Bellmunt J, et al. J Clin Oncol 2010; 2Sonpavde G, et al. Eur Urol 2013

Progression-free Survival

Median follow-up duration in the full ITT population was 5.0 months (interquartile range [IQR], 2.3–8.9)

0 2 4 6 8 10 12 14 16 18

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 IIIIIIIIIIIIIIII

IIIII

IIIII

I

IIII I I I

IIIIIIIII

II I

I I II I II I I I II

IIIIIIII IIII

II

I

I

I I

IIIII

III III I I III I

I I I

0 2 4 6 8 10 12 14 16 18

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 IIIIIIIIIIIIIIIIIIIIIIIIIIIIII

I IIIII

I IIIIIIIII III II

IIIIIII

I

III II

I II II

IIIIIIIII

II

II

II

IIII

II

II

IIII

II

II

III I I II I

Pro

gres

sio

n-f

ree

Su

rviv

al P

rob

abili

ty Ramucirumab + docetaxel (n=216); median, 4.07 monthsPlacebo + docetaxel (n=221); median, 2.76 months

HR, 0.757 (95% CI, 0.607 to 0.943)Log-rank P=0.0118

Ramucirumab + docetaxel (n=216); median, 4.04 months

Placebo + docetaxel (n=221); median, 2.46 months

HR, 0.672 (95% CI, 0.536 to 0.842)Log-rank P=0.0005

Progression-free Survival (Month) Progression-free Survival (Month)

216

221

132

124

96

77

40

34

28

19

19

7

12

3

4

2

1

2

0

0

216

221

117

102

87

67

34

28

21

14

10

4

7

3

2

2

0

1

0

0

Investigator assessment Independent blinded assessment

28.5 %18.9 %

11.9 %4.5 %

28.6 %16.7 %

8.3%5.1 %

PFS (Investigator Assessment) Subgroup Analyses

Best Overall Response

24.5%

14.0%

Treatment-emergent Adverse Events (Grade ≥ 3 TEAEs that occurred in ≥5% of patients or of special interest)

Consolidated: Fatigue, neutropenia, leukopenia, bleeding or hemorrhage, hypertension, renal failure, venous and arterial thromboembolic, fistula, congestive heart failure, GI perforation

Ramucirumab + docetaxel (n=258) Placebo + docetaxel (n=265)Any Grade Grade ≥3 Any Grade Grade ≥3

Any 244 (95%) 156 (60%) 251 (95%) 163 (62%)Fatigue 110 (43) 20 (8) 121 (46) 25 (9)Neutropenia 51 (20) 39 (15) 44 (17) 36 (14)Febrile neutropenia 25 (10) 25 (10) 17 (6) 17 (6)Anemia 40 (16) 7 (3) 64 (24) 28 (11)Leukopenia 26 (10) 17 (7) 24 (9) 21 (8)

AEs of special interestBleeding or hemorrhage 67 (26) 8 (3) 46 (17) 12 (5)

Epistaxis 36 (14) 0 13 (5) 0 Hematuria 27 (10) 5 (2) 17 (6) 5 (2)GI hemorrhage 10 (4) 2 (<1) 10 (4) 3 (1)Pulmonary hemorrhage 1 (<1) 0 0 0

Hypertension 29 (11) 15 (6) 12 (5) 5 (2)Renal failure 15 (6) 8 (3) 19 (7) 2 (<1)Proteinuria 23 (9) 2 (<1) 8 (3) 1 (<1)Venous thromboembolic 6 (2) 1 (<1) 13 (5) 5 (2)Arterial thromboembolic 8 (3) 6 (2) 2 (<1) 0Fistula 5 (2) 3 (1) 2 (<1) 2 (<1)Congestive heart failure 3 (1) 2 (<1) 1 (<1) 1 (<1)GI perforation 3 (1) 2 (<1) 1 (<1) 1 (<1)

Conclusions

• RANGE is the first phase 3 study to demonstrate a PFS advantage over chemotherapy alone in platinum-refractory advanced or metastatic UC (HR 0.757, P=0.0118)

– PFS outcomes were consistent across most patient subgroups

– OS data will be reported when maturity has been achieved

• ORR was higher in the ramucirumab plus docetaxel arm (24.5% vs 14.0%)

• The combination of ramucirumab and docetaxel did not result in significant additive toxicity or compromise quality of life when compared to placebo plus docetaxel

• The combination of ramucirumab and docetaxel is a new treatment option for patients with platinum-refractory advanced UC.

Figure 2. Decreased Tumor Burden in Urothelial Carcinoma Patients (RECIST 1.1)

ITT Population

Cohort D

N = 24

Objective response rate 3 (13)a

Disease control rateb 12 (50)

Median duration of response, mo (95% CI) NR (4.6-NR)

Median time to response, mo (95% CI) 2.8 ( 1.3-5.5)

Duration of stable disease 2.8 (1.9-NR)

Best overall response, n (%)

Complete response (CR) -

Partial response (PR) 3 (13)

Stable disease (SD) 9 (38)

Progressive disease (PD) 11 (46)

Not evaluable 1 (4)

aAll responders were PD-L1 positive.bPatients with best response of CR, PR, or SD.

NR= not reached.

Presented by Petrylak DP et al.

48% of evaluable

patients

experienced a

decrease in target

lesion

Enfortumab Vedotin: Proposed Mechanism of Action

Presented by: Daniel P.

Petrylak

Enfortumab Vedotin is being co-developed by Seattle Genetics, Inc. and Astellas Pharma Inc.

Study Design

• This phase 1, 3-part study (NCT02091999) enrolled patients with

metastatic malignant solid tumors treated with ≥1 prior chemotherapy

regimen

• IV administration over 30 minutes on Days 1, 8, and 15 every 28 days

• Study enrollment in Parts B and C ongoing


Petrylak

Part A (closed) Dose escalation/expansion, adaptive trial

design utilizing a Continual Reassessment

Method, to determine RP2D

• Cohort 1: 0.5 mg/kg


• Cohort 3: 1 mg/kg


Nectin-4 expressing tumors, including mUC

RP2D1.25

mg/kg

Part B (enrolling)Dose expansion: 3 cohorts (n=15/cohort)• Cohort 1: Urothelial Cancer-Cis-ineligible

(1 mg/kg escalating to 1.25 mg/kg)

• Cohort 2: NSCLC (1.25 mg/kg)

• Cohort 3: Ovarian Cancer (1.25 mg/kg)

Part C (enrolling) Dose expansion: 1 cohort (n=60)

• CPI-treated mUC patients (1.25 mg/kg)

https://www.clinicaltrials.gov. Accessed 12 May 2017.

https://www.clinicaltrials.gov/

Screening of Nectin-4 Expression in mUC

• At screening, patients with mUC had

samples that were centrally assessed

by immunohistochemistry (IHC) for

Nectin-4

– Almost all patient (97%) samples

showed Nectin-4 expression

– Expression of Nectin-4 was high

(median H-score 280 out of a 300

maximum score)

• Due to the above findings, pre-

screening for Nectin-4 is no longer an

eligibility requirement for subjects with

mUC


Petrylak

0

50

100

150

200

250

300

H-s

core

PatientsGray bars indicate patients with Nectin-4 H-score <150

Blue bars indicate patients with H-scores of ≥150Note: data cutoff November 2016, N=186

Disposition of Patients with Metastatic Urothelial

Cancer

• As of 28 April 2017, 81

patients with mUC have

been treated at sites across

the United States and

Canada

– 21 patients in dose-

escalation cohorts

– 60 in dose-expansion

cohorts


Petrylak

Patients with mUC (N=81)

Subjects continuing treatment 21 (26)

Treatment discontinuations 60 (74)

Disease Progression (radiographic) 37 (46)

Disease Progression (clinical symptoms) 5 (6)

Adverse Event 10 (12)

Subject Withdrew Consent 4 (5)

Investigator’s Decision 3 (4)

Other 1 (1)

Median time on treatment, weeks (range) 15.1 (1.1, 64.6)

Data presented as n (%).

mUC, metastatic urothelial cancer. Data cut-off date is April 28, 2017

Demographics and Baseline Characteristics of

Patients with Metastatic Urothelial Cancer


Petrylak

Patients with mUC (N=81)

Median age, years (range) 67 (41–84)

Male, n (%) 57 (70)

Site of Primary Tumor, n (%)

Bladder 51 (63)

Upper Tract 30 (37)

Site of metastases at baseline, n (%)

Visceral 49 (61)

Lung 39 (48)

Liver 23 (28)

Prior CPI treatment, n (%) 37 (46)

Prior Platinum-based therapy, n (%) 77 (95)

Prior taxane treatment, n (%) 35 (43)CPI, checkpoint inhibitors; mUC, metastatic urothelial cancer. Data cut-off date is April 28, 2017

Treatment-Related Adverse Events in ≥10% of Patients with Metastatic Urothelial Cancer

0.5 mg/kg(n=2)

0.75 mg/kg(n=14)

1.0 mg/kg(n=27)

1.25 mg/kg(n=38)

Total(N=81)

Nausea 0 3 (21) 12 (44) 14 (37) 29 (36)

Pruritus 0 2 (14) 11 (41) 12 (32) 25 (31)

Fatigue 0 3 (21) 9 (33) 12 (32) 24 (30)

Diarrhea 1 (50) 3 (21) 7 (26) 12 (32) 23 (28)

Alopecia 0 2 (14) 6 (22) 12 (32) 20 (25)

Decreased appetite 0 1 (7) 6 (22) 11 (29) 18 (22)

Dysgeusia 0 2 (14) 7 (26) 8 (21) 17 (21)

Anemia 1 (50) 0 7 (26) 7 (18) 15 (19)

Vomiting 1 (50) 2 (14) 3 (11) 6 (16) 12 (15)

Drug eruption 0 0 5 (19) 6 (16) 11 (14)

Peripheral neuropathy 0 2 (14) 1 (4) 7 (18) 10 (12)

Weight decreased 0 1 (7) 3 (11) 6 (16) 10 (12)

Hypophosphatemia 0 1 (7) 7 (26) 2 (5) 10 (12)

AST Increased 0 0 5 (19) 4 (11) 9 (11)

Data presented as n (%); orange box indicates recommended phase 2 dose. Bold font indicates most commonly reported AE related to enfortumab vedotin.

Adverse events listed are individual preferred terms.

• Treatment-emergent and

treatment-related

adverse events were

consistent– Treatment-related diarrhea

was grade ≤2 in severity

– Ongoing ophthalmologic

assessments show corneal

findings to be infrequent

and mostly incidental in

nature

(≤ grade 1)

– RP2D was 1.25 mg/kg with

the best balance of activity

and tolerability; MTD was

not reached


Petrylak

0.5 mg/kg(n=2)

0.75 mg/kg(n=14)

1.0 mg/kg(n=27)

1.25 mg/kg(n=38)

Total(N=81)

Urinary tract infection 0 2 (14) 4 (15) 3 (8) 9 (11)

Hypophosphatemia 0 1 (7) 5 (19) 1 (3) 7 (9)

Hyponatremia 0 1 (7) 2 (7) 2 (5) 5 (6)

Anemia 0 0 4 (15) 3 (8) 7 (9)

Hyperglycemia 0 3 (21) 1 (4) 0 4 (5)

Hyperuricemia 0 0 2 (7) 2 (5) 4 (5)

Data presented as n (%). Orange box indicates recommended phase 2 dose. mUC, metastatic urothelial cancer.

Grade ≥3 Adverse Events Occurring in ≥5% Patients

with mUC Regardless of Attribution to Treatment

• Serious AEs were observed in 32 (40%) patients; urinary tract infection (n=4, 5%), acute renal failure (n=3,

4%), and dehydration (n=4, 4%) were reported in >2 patients

• Treatment-related serious AEs were observed in 7 (9%) patients; only pulmonary embolism (n=2) was

reported by >1 patient

• Three patients with mUC experienced a grade 5 AE cardiac arrest (n=1), small intestinal perforation and

sepsis (n=1), acute renal failure (n=1); none of these were considered related to enfortumab vedotin


Petrylak

Maximum Reduction from Baseline in Total Tumor

Burden in Patients with mUC on Enfortumab Vedotin


Petrylak

Investigator-Assessed Response in Patients with

mUC on Enfortumab Vedotin


Petrylak

0.5 mg/kg(n=2)

0.75 mg/kg(n=12)

1.0 mg/kg(n=27)

1.25 mg/kg(n=30)

Total(N=71)a

CR, n (%) 0 0 2 (7) 1 (3) 3 (4)

PR, n (%) 1 (50) 4 (33) 6 (22) 15 (50) 26 (37)

SD, n (%) 1 (50) 6 (50) 9 (33) 6 (20) 22 (31)

PD, n (%) 0 2 (17) 6 (22) 6 (20) 14 (20)

NE, n (%) 0 0 4 (15) 2 (7) 6 (9)

ORRb (95% CI)

(unconfirmed)

50(1.3, 98.7)

33(9.9, 65.1)

30(13.8, 50.2)

53(34.3, 71.7)

41(29.3, 53.2)

DCRb (95% CI)100

(15.8, 100)83

(51.6, 97.9)63

(42.4, 80.6)73

(54.1, 87.7)72

(59.9, 81.9)

Orange box indicates recommended phase 2 dose.

CR, complete response; SD, stable disease; PR, partial response; DCR, disease control rate (DCR=CR+PR+SD); ORR (unconfirmed), overall

response rate (ORR=CR+PR).aPatients must have at least one post-baseline assessment; responses assessed per RECIST 1.1.b95% CI based on the Clopper-Pearson method.

Response in mUC Patients with Prior CPI, Taxane

Treatment, or Liver Metastases on Enfortumab Vedotin


Petrylak

Prior CPI Treatmenta Prior Taxane Treatment Liver Metastases

1.25 mg/kg(n=17)

All Dosesb

(N=32)1.25 mg/kg

(n=10)All Dosesb

(N=29)1.25 mg/kg

(n=5)All Dosesb

(N=19)

CR, n (%) 0 1 (3) 1 (10) 1 (3) 0 1 (5)

PR, n (%) 8 (47) 13 (41) 5 (50) 11 (38) 3 (60) 8 (42)

SD, n (%) 5 (29) 9 (28) 0 (0) 8 (28) 1(20) 4 (21)

ORRc (95% CI)

(unconfirmed)47

(23.0, 72.2)44

(26.4, 62.3)60

(26.2, 87.8)41

(23.5, 61.1)60

(14.7, 94.7)47

(24.4, 71.1)

DCRc (95% CI)77

(50.1, 93.2)72

(53.3, 86.3)60

(26.2, 87.8)69

(49.2, 84.7)80

(28.4, 99.5)68

(43.4, 87.4)

Data cut-off date April 28, 2017.

Data presented as n (%), unless otherwise indicated.

CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); NE, not evaluable; PD, progressive disease; PR, partial

response; ORR (unconfirmed), overall response rate (ORR=CR+PR); SD, stable disease. aNo patients with prior CPI treatment received 0.5 mg/kg enfortumab vedotin.bEvaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1.cData presented as % (95% confidence interval [CI]); 95% CI based on the Clopper-Pearson method.

Conclusions

• Multiple targets are being evaluated for the treatment

of metastatic urothelial carcinoma including EGF,

Her-2/neu, AKT/PI3Kinase, and FGF-R

• Antiangiogensis therapy combined with docetaxel

improves PFS in second line patients with metastatic

urothelial cancer

• Enfortumab Vedotin has activity in second line

urothelial carcinoma

biomarkers and targeted therapies for urothelial...

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