Approaches to the Treatment of Metastatic Bladder Cancer · IMVIGOR-130), the Data Monitoring Committees’ (DMC) found patients in the monotherapy arms of both trials with PD-L1

Approaches to the Treatment of

Metastatic Bladder 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

M-VAC vs Cisplatin Phase IIILong term survival

Cisplatin M-VAC

Evaluable 122 133

3 years 4 17

6 years* 2 9

*6 patients died of TCC, 1 2nd Ca, 2 other, 1 lost to F/U

Saxman, JCO, 15:2564, 1997

M-VAC: EORTC Dose Intensification

HD M-VAC: Methotrexate 30 mg/m2 Day 1; Vinblastine 3 mg /m2 Day 2Adriamycin 30 mg / m2

Cisplatin 70 mg/m2

G-CSF

Classic M-VAC:

Methotrexate 30 mg/m2 Day 1, 14, 21

Vinblastine 3 mg /m2 Day 1, 14, 21Adriamycin 30 mg / m2 Day 2Cisplatin 70 mg/m2 Day 2

Accrual :263 patients

Sternberg, C. N. et al. J Clin Oncol;

19:2638-2646 2001

Stromal PD-L1

modulation of T cells

Immune cell

modulation of T cells

PD-L1/PD-1-mediated

inhibition of

tumor cell killing

IFNg-mediated

upregulation of

tumor PD-L1

Priming and

activation of T cells

PD-L2-mediated

inhibition of TH2 T cells

B7.1

Herbst RS et al. J Clin Oncol . 2013;31(suppl; abstr 3000)

Key Attributes of

the Immune System

• Specificity

• Memory

• Adaptive

• Cancer cells develop many

mutations that can make them

appear foreign to the immune

system

• T cells can recognize, attack

and kill these “foreign” cancer

cells

• Cancer cells can evade

immune attack by expressing

PD-L1

• Adaptive tumor expression of

PD-L1 turns the immune

system OFF

• Clinically, we want to block

PD-1 or PD-L1 to reactivate

the immune system

• PD-L1 plays an important role

in dampening the anti-tumor

immune response

Mechanism of Immune Checkpoint Inhibitors

Checkpoint Inhibitors Approved for Use in Urothelial

Carcinoma7 US FDA Approvals May 2016-May 2017

Setting Antibody Approval Status

First-line

(cisplatin-

ineligible)

Atezolizumab • Accelerated approval granted in April 2017.

Pembrolizumab • Accelerated approval granted in May 2017.

Platinum-

pretreated

Atezolizumab • Accelerated approval granted in May 2016.

• In May 2017, the subsequent phase 3

IMvigor211 trial did not meet primary endpoint of

overall survival.

Nivolumab • Accelerated approval granted in February 2017.

Durvalumab • Accelerated approval granted in May 2017.

Avelumab • Accelerated approval granted in May 2017.

Pembrolizumab • Full approval granted in May 2017.

Approvals: First-line, Cisplatin-

Ineligible

Atezolizumab Pembrolizumab

Apr 2017 May 2017

Above agents are indicated in patients with locally advanced or

metastatic urothelial carcinoma not eligible for cisplatin-containing

chemotherapy.

Definition of the Medically Unfit

Patient

• Concurrent renal insufficiency limits the

administration of drugs such as cisplatin

• Cardiac dysfunction and third space

accumulation of fluids limit hydration of

patients

• Performance status predisposes to

neutropenia and dose adminstration

• No consisteentstandard definition of “unfit”

based on objective criteria

Treatment of the Medically Unfit

Patient

• Treatment goals shift to palliation of

symptoms rather than response/survival

• Single agent vs non cisplatin containing

doublets

• Immune therapy for first line treatment

IMvigor210 (Cohort 1)

Balar et al. Lancet. 2017;389:67

Key primary endpoint :

• Confirmed ORR: RECIST v1.1

(per central IRF)

Key secondary endpoints :

• DOR, PFS, OS, safety

Cohort 1 (N = 119):

1L cisplatin-ineligible

IMvigor210:

• Inoperable locally advanced

or metastatic urothelial

carcinoma

• Predominantly UC histology

• Tumor tissue evaluable for

PD-L1 testinga

Cohort 2 (N = 310):

Platinum-treated mUC

Atezolizumab 1200 mg IV q3w

until RECIST v1.1 progression


until loss of clinical benefit

Cohort 1–specific inclusion criteria

•No prior treatment for mUC (>12 mo since perioperative chemo)

•ECOG PS 0-2

•Cisplatin ineligibility1 based on ≥1 of the following:

− Renal impairment: GFR <60 and >30 mL/min

− Grade ≥2 hearing loss or peripheral neuropathy

− ECOG PS 2


Balar et al. Lancet. 2017;389:67

• N = 119

• ORR = 23% (9% CR) Overall Survival

Secondary Endpoints: DOR, PFS, OS, and ORR in all patients,

PD-L1‒positive and PD-L1–high-expressing patients; safety and

tolerability

Primary Endpoints:

• Planned interim analysis in first 100 patients

• Determine the PD-L1–high expression cutpoint

• ORR in all patients and PD-L1‒positive population

Pembrolizumab

200 mg Q3W

Primary Endpoints

• ORR in all patients

• ORR in patients with

PD-L1–positive

tumors

Patients (N = 350)

•Advanced urothelial cancer

•No prior chemotherapy for

metastatic disease

•ECOG PS 0-2

•Ineligible for cisplatin based

on ≥1 of the following:– CrCl <60 mL/min

– ECOG PS 2

– Grade ≥2 neuropathy or

hearing loss

– NYHA class III CHF

KEYNOTE-052: Pembrolizumab as 1st-Line

Therapy for Cisplatin-Ineligible Advanced

Urothelial Cancer

Balar et al. ESMO 2016; abstract LBA32_PR.

KEYNOTE-052 (ASCO17 Update)

O’Donnell et al. ASCO 2017; Abstract 4502.

N = 370

ORR: 29%

CR: 7%

Sequence of Therapy for Cisplatin-Eligible Patients

Cisplatin-based

chemotherapyPD-1 or PDL-1

Inhibitor

Single Agent

Chemotherapy

Sequence of Therapy for Cisplatin-Ineligible Patients

Carboplatin-

based

chemotherapy

Checkpoint

InhibitorSingle Agent

Chemotherapy

Carboplatin-

based

chemotherapy

Single Agent

Chemotherapy

Pembrolizumab/

atezolizumab

Comorbidity/patient

choice‒directed

(no validated

biomarkers)

Gem-Carbo (Ph III)1 Atezolizumab (Ph II)2 Pembrolizumab (Ph II)3

Number of patients 119 119 370

% with PS 2 44.5% 20% 42%

% CrCl <60 mL/min 55.5%a 70% 49%

% PS 2 + CrCl <60 mL/min 26.9%a 7% 9%

ORR 41.2% 23% 24%

Median PFS 5.8 mo 2.7 mo 2 mo; 3 mo on therapy

Median OS 9.3 mo 15.9 mo Not reported

Duration of response Not reported Not reached

(median f/u 17.2 mo)

Not reached

(78% ≥6 months)

aGFR 30-60 mL/min.

1. De Santis M, et al. J Clin Oncol. 2012;30(2):191-199; 2. Balar AV, et al. Lancet.

2017;389(10064):67-76; 3. Balar AV; et al. Lancet Oncol. 2017;18:1483-1492.

First-Line Therapy for Cisplatin-Ineligible Metastatic UC

PD-1/PD-L1 Inhibitor OR Gemcitabine-Carboplatin Based on Activity?

Use PD-L1 expression to select therapy for

cisplatin-ineligible patients?

5/18/2018

FDA Alert

•In two ongoing clinical trials (KEYNOTE-361 and

IMVIGOR-130), the Data Monitoring Committees’ (DMC)

found patients in the monotherapy arms of both trials

with PD-L1 low status had decreased survival

compared to patients who received cisplatin- or

carboplatin-based chemotherapy.

•Both trials have stopped enrolling patients whose

tumors have PD-L1 low status to the Keytruda or

Tecentriq monotherapy arms.

•The monotherapy arms remain open only to patients

whose tumors have PD-L1 high status.

Carboplatin-

based

chemotherapy

Pembrolizumab/

atezolizumab

PD-L1 (IHC)

Low High

First Line Chemotherapy +Checkpoint Therapy trials in

Metastatic Urothelial Cancer

CT ID Phase Target Experimental Arm(s) Standard Arm

NCT02807636

IMvigor130

III PD-L1 Atezo

OR

Atezo + Gem-Plat

Placebo + Gem-Plat

NCT02853305

KEYNOTE-361

III PD-1 Pembro

OR

Pembro + Gem-Plat

Gem-Plat

NCT02516241

DANUBE

III PD-L1 +/-

CTLA-4

Durvalumab

OR

Durva + Treme

Gem-Plat

NCT03036098

CM-901

III PD-1 + CTLA Nivo + Ipi* Gem-Plat

*This trial includes a substudy for cisplatin-eligible patients comparing

gemcitabine + cisplatin +/- nivolumab.

Approvals: Previously-treated

Disease

Atezolizumab Nivolumab Durvalumab Avelumab Pembrolizumab

May 2016 Feb 2017 May 2017

Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma who

have disease progression during or following platinum-containing chemotherapy or within 12 months of

neoadjuvant or adjuvant treatment with (platinum-containing) chemotherapy.


Rosenberg et al. Lancet. 2016; 387:1909.

IMvigor210:

• Inoperable locally advanced

or metastatic urothelial

carcinoma

• Predominantly UC histology

• Tumor tissue evaluable for

PD-L1 testinga

Cohort 1 (N = 119):

1L cisplatin-ineligible

Cohort 2 (N = 310):

Platinum-treated mUC


until RECIST v1.1 progression


until loss of clinical benefit

Cohort 2-Specific Inclusion Criteria

• Progression during/following platinum

(no restrictions on # prior lines of therapy)

• ECOG PS 0-1

• CrCl ≥ 30 mL/min

Key primary endpoint :

•Confirmed ORR: RECIST v1.1

(per central IRF)

Key secondary endpoints :

•DOR, PFS, OS, safety


Rosenberg et al. Lancet. 2016; 387:1909.

All patients:

• ORR = 15% (5% CR)

• mOS = 7.9 months

Phase Ia Trial of Atezolizumab in Pretreated Bladder Cancer

Petrylak et al. ASCO 2015; Abstract 4501.

• N = 92

• 72% with ≥2 prior

systemic therapies

• ORR 50% in PD-L1 high

(IC2/3)

• ORR 17% in PD-L1 low

(IC0/1)

OS by PD-L1 Status


Median Survival by Baseline

Characteristics


Patterns of AE Occurrence


IMvigor211 Phase III Trial in

Previously-treated Urothelial Cancer

• Primary endpoint: OS in IHC 2/31/2/3ITT

• Secondary endpoints: PFS, ORR, DOR

• FPI: Q4 2014

Atezolizumab

1200 mg IV q3w

Patients with previously treated

relapsed UBC

(n = 767 [230 PD-L1+])

Vinflunine, paclitaxel, or docetaxel

IV q3w until progression

FPI=first patient in; ITT=intent-to-treat.

http://www.clinicaltrials.gov/ct2/show/NCT02108652.

.

Key Eligibility Criteriaa

• 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

27 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. b Defined by time from prior

chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. c Confirmed response was not required

for secondary efficacy endpoints. This analysis reports exploratory confirmed responses.

IMvigor211 Study Design

27

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 factorsb (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 DORc

– Safety

– PROs: EORTC QLQ-C30

Chemotherapy

(investigator’s choice)

• Vinflunine q3w

• Docetaxel q3w

• Paclitaxel q3w

Key secondary endpoints:

ORR, then PFS

Primary endpoint:

OS

OS: IC2/3

OS: IC1/2/3

OS: ITT

PFS: IC2/3

PFS: IC1/2/3

PFS: ITT

ORR: IC2/3

ORR: IC1/2/3

ORR: ITT

2-sided = 0.05

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

OS Analysis: IC2/3 Population

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

P = 0.41

Events/

PatientsMedian 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 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months


OS Analysis: IC1/2/3 Population

Events/

PatientsMedian OS

(95% CI)


Atezolizumab 220/316 8.9 mo (8.2, 10.9) 40% (35, 46)

Chemotherapy 232/309 8.2 mo (7.4, 9.5) 33% (28, 39)

HR = 0.87 (95% CI: 0.71, 1.05)

P = 0.14

No. at Risk

Atezolizumab 316 274 232 198 175 141 122 97 64 41 23 9 1

Chemotherapy 309 273 228 188 153 121 95 66 46 31 15 7 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

▪ Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo)


OS Analysis: ITT Population

Events/

PatientsMedian OS

(95% CI)


Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37)80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

HR = 0.85 (95% CI: 0.73, 0.99)

P = 0.038

No. at Risk

Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1

Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

▪ OS was also examined in

subgroups based on chemotherapy

type at randomization

– Improved OS was observed

with atezolizumab vs. taxanes


OS by Chemotherapy Type

ITT With Taxane

No. at Risk

Atezolizumab 215 186 153 125 106 89 81 66 45 34 19 7 0

Taxane 214 179 147 122 94 74 58 35 20 16 4 3 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Su

rviv

al

100

Months

HR = 0.73 (95% CI: 0.58, 0.92)

SubgroupMedian OS

(95% CI)

Atezolizumab 8.3 mo (6.6, 9.8)

Taxane 7.5 mo (6.7, 8.6)

Phase Ib JAVELIN Solid Tumor Trial of

Avelumab: Trial Schema

• Open-label, multicenter phase Ib study in pts with confirmed solid tumors

▪ Primary endpoint: ORR, safety

▪ Secondary endpoints: PFS, OS, and association of PD-L1 expression on tumor cells with clinical activity of avelumab

Advanced UC Cohort: Pts with

histology or cytology confirmed

metastatic UC after progression on

or ineligible for platinum-based

chemotherapy for metastatic

disease; ECOG PS 0-1

(N = 241)

Avelumab

10 mg/kg IV Q2W

Treated until PD, unacceptable

AE, or investigator decision

Patel M, et al. ASCO GU 2017. Abstract 330.

Phase Ib JAVELIN Solid Tumor Trial of Avelumab (ASCO17 Update)

ORR in patients with ≥6 months follow-up (N = 161): 17% (6% CR)

Apolo, et al. ASCO17; Abstract 4528.

N = 242

mOS 7.4 mo

mPFS1.5 mo

(6.6 wk)

KEYNOTE-045: Phase III Study Design

CPS, combined positive score; PD, progressive disease.

Bellmunt et al. SITC 2016; Abstract 02.

Bajorin et al. ASCO 2017, Abstract 4501.

Pembrolizumab Chemotherapy

ORR

CR

21%

8%

11%

3%

Median OS HR P Value

Pembro 10.3 mo0.70 .0004

Chemo 7.4 mo

Data cutoff: Jan 18, 2017

Median follow-up: 18.5 mo

Median PFS HR P Value

Pembro 2.1 mo0.96 .32

Chemo 3.3 mo

Future Directions

Non Muscle Invasive Disease

Combinations

Adjuvant therapy

Biomarkers

Addition of Ipilimumab to Nivolumab at

Progression

• 10 patients who evidenced progression of

disease on nivolumab.

• 1 PR, 4 SD after addition of ipilimumab.

• Modest increase in grade 3/4 toxicities.

Callahan et al. ASCO GU 2017; Abstract 384.

Checkmate 032

Checkmate 032

Ipilimumab(Ipi) +Nivolumab(N)

ORR PFS OS

N 3 mg/kg 26% 2.8 9.9

N+ Ipi 3 mg/kg 27% 2.6 7.4

N+ Ipi 1 mg/kg 38% 4.9 15.3

PDL-1 Expression and ORR

Adjuvant PD-1/PD-L1 Inhibitor Phase

III Trials

PI Population Control

Arm

Experimental

Arm

Primary

Endpoint

Industry All-comers MIUC

Prior NAC- ≥pT2

No AC ≥pT3

No therapy Atezolizumab PFS

Industry All-comers MIUC

Prior NAC- ≥pT2

No AC ≥pT3

Placebo Nivolumab PFS

Intergroupa All-comers MIUC

Prior NAC- ≥pT2

No AC ≥pT3

No therapy Pembrolizumab PFS/OS

aPI: Apolo; SWOG PI: Sonpavde; ECOG PI: Srinivas.

Neoadjuvant Therapy With IO Agents

Selected Phase I-II Trials

Trial ID Phase Regimen Primary Endpoint

NCT03294304 II GC-Nivolumab pCR

NCT02690558 II GC-Pembrolizumab pCR

NCT02365766 I/II G/GC-Pembrolizumab Feasibility, pCR

NCT02451423 II Atezolizumab pCR, immune response

NCT02736266 II Pembrolizumab pCR

NCT02812420 II Durvalumab + Tremelimumab Feasibility

NCT02845323 II Nivolumab +/- Urelumab Immune response

Pending I Durvalumab +/- CD73i Feasibility, Immune response

Chemo-IO

IO

IO-IO

Planned Phase III Trial by NRG, SWOG

ChemoRT +/- Concurrent Adjuvant Atezolizumab

RT +

Chemotherapy

(5-FU-MMC,

Cisplatin +/- 5-FU)

ATEZOLIZUMAB x 1 year

OBSERVE

Survival

PFS

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

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

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

54

~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.

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

EV-101: Disposition of Patients With Metastatic Urothelial Cancer

Patients With mUC

All Doses

(N=155)

Patients with mUC

1.25 mg/kg EV

(N=112 )

Subjects continuing treatment, n (%) 29 (19) 27 (24)

Treatment discontinuations, n (%) 126 (81) 85 (76)

Disease progression (radiographic) 83 (53.5) 56 (50)

Disease progression (clinical symptoms) 11 (7) 7 (6)

Adverse event 18 (12) 12 (11)

Subject withdrew consent 5 (3) 3 (3)

Investigator’s decision 7 (4.5) 5 (4)

Other 2 (1) 2 (2)

Median time on treatment, weeks (range)22.6

(1.1, 89)

23.7

(1.1, 78)

Data presented as n (%).

mUC, metastatic urothelial cancer. Data cut-off date is April 9, 2018.

6

0

Jonathan E. Rosenberg

Patients With mUC

1.25 mg/kg

(N=112)

Primary tumor site bladder, n (%) 86 (77)

Site of metastases at baseline, n (%)

Liver 33 (29)

Lung 54 (48)

Lymph node only 21 (19)

≥2 prior therapies in the metastatic

setting, n (%)71 (63)

Prior platinum-based therapy, n (%) 105 (94)

Prior taxane treatment, n (%) 32 (29)

Prior CPI treatment, n (%) 89 (79)

CPI was most recent therapy 65 (73*)

Data cut-off date is April 9, 2018.

*Percentage based on number of patients with prior CPI.

CPI, checkpoint inhibitors; mUC, metastatic urothelial cancer.

Patients With mUC

1.25 mg/kg

(N=112)

Median age, years (range) 67 (24–86)

Male, n (%) 82 (73)

Race, n (%)

Caucasian 103 (92)

Asian 5 (5)

Other 3 (3)

ECOG Score

0 36 (32)

1 76 (68)

Hemoglobin levels <10 g/dL, n (%) 23 (21)

GFR <60 mL/min 56 (50)


ECOG, Eastern Cooperative Oncology Group; GFR, Glomerular filtration rate;

mUC, metastatic urothelial cancer.

EV–101: Demographics and Disease Characteristics

6

1


Enfortumab Vedotin Toxicity Profile

Patients With mUC

1.25 mg/kg

(N=112)

Treatment-Related Adverse Events in ≥25% of Patients With

mUC

All Grade Grade ≥3

Fatigue 60 (54) 1 (1)

Alopecia 50 (45) 0

Decreased appetite 45 (40) 1 (1)

Dysgeusia 43 (38) 0

Nausea 40 (36) 1 (1)

Pruritus 39 (35) 1 (1)

Peripheral neuropathy 39 (35) 0

Diarrhea 36 (32) 1 (1)

Maculo-papular rash 28 (25) 3 (3)


Data presented as n (%). Adverse events listed are individual preferred terms.

mUC, metastatic urothelial cancer.

• Consistent with previous reports, EV

was generally well tolerated1

6

2

1Petrylak DP et al. J Clin Oncol. 2017;35:106–106.

• The majority of adverse events considered at least possibly related to EV were mild-to-moderate in severity


Grade ≥3 Adverse Events Regardless of Treatment Attribution

6

3

Patients With mUC

1.25 mg/kg

(N=112)

Grade ≥3 Adverse Events in ≥5% Patients with mUC Regardless of Treatment Attribution

Anemia 9 (8)

Hyponatremia 8 (7)

Urinary tract infection 8 (7)

Hyperglycemia 7 (6)

Grade 5 Adverse Events Regardless of Treatment Attribution

Diabetic ketoacidosis* 1 (0.9)

Dyspnea 1 (0.9)

Multiple organ dysfunction syndrome* 1 (0.9)

Progressive disease 1 (0.9)

Sepsis 1 (0.9)

Small intestinal perforation 1 (0.9)

Respiratory failure* 1 (0.9)

Urinary tract obstruction* 1 (0.9)

Data cut-off date is April 9, 2018. Data presented as n (%). Adverse events listed are individual preferred terms.

*Fatal AEs that were considered at least possibly related to enfortumab vedotin. mUC, metastatic urothelial cancer.


Investigator-Assessed Response in Patients With mUC on Enfortumab Vedotin

1

0

1.25 mg/kg

(N=112)a

Confirmed CR 4%

Confirmed PR 37%

Confirmed ORRb (95% CI) 41% (31.9, 50.8)

SD 30%

DCRb (95% CI) 71% (62.1, 79.6)

Data cut-off date is April 9, 2018. CR, complete response; DCR, disease control rate

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

disease. aPatients must have at least one post-baseline assessment; responses assessed per

RECIST 1.1. b95% CI based on the Clopper-Pearson method.


Duration of Response in Patients With Metastatic Urothelial Carcinoma

6

5

Median duration of confirmed

response, months (range)

5.75

(1.8, 12.9)


Prior CPI Treatmenta CPI-Naïvea Liver Metastasesa

1.25 mg/kg

(n=89)

1.25 mg/kg

(n=23)

1.25 mg/kg

(n=33)

Confirmed CR 3.4% 9% 0

Confirmed PR 37% 35% 39%

Confirmed ORRb (95% CI)40%

(30.2, 51.4)

44%

(23.2, 65.5)

39%

(22.9, 57.9)

SD 34% 17% 21%

DCRb (95% CI)74%

(63.8, 82.9)

61%

(38.5, 80.3)

60%

(42.1, 77.1)


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

CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); PR, partial response; ORR, overall response rate (ORR=CR+PR);

SD, stable disease. aEvaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1.bData presented as % (95% CI); 95% CI based on the Clopper-Pearson method.

Clinical Response With Enfortumab Vedotin in mUC Patients With or Without Prior CPI or Liver Metastases

6

6


Clinical Response With Enfortumab Vedotin in mUC Patients With or Without Prior CPI or Liver Metastases

6

7

Prior CPI Treatmenta CPI-Naïvea Liver Metastasesa

1.25 mg/kg

(n=89)

1.25 mg/kg

(n=23)

1.25 mg/kg

(n=33)

Confirmed CR 3.4% 9% 0

Confirmed PR 37% 35% 39%

Confirmed ORRb (95% CI)40%

(30.2, 51.4)

44%

(23.2, 65.5)

39%

(22.9, 57.9)

SD 34% 17% 21%

DCRb (95% CI)74%

(63.8, 82.9)

61%

(38.5, 80.3)

60%

(42.1, 77.1)


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

CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); PR, partial response; ORR, overall response rate (ORR=CR+PR);

SD, stable disease. aEvaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1.bData presented as % (95% CI); 95% CI based on the Clopper-Pearson method.


Progression-Free Survival in Patients With mUC Treated With Enfortumab Vedotin 1.25 mg/kg

6

8


Median PFS, Months (95% CI)

All patients with mUC 5.4 (5.1, 6.2)

Patients with prior

CPI5.4 (5.1, 6.2)

Preliminary Overall Survival in Patients With mUC Treated With Enfortumab Vedotin 1.25 mg/kg

6

9


Overall Survival

OS at 6 Months, %

All patients with mUC 74.4

Patients with prior

CPI75.6

OS at 12 Months, %

All patients with mUC 56.3

Patients with prior

CPI54.2


Trials in Progress

• Phase II trial of Enfortumab Vedotin

– Platinum treated cohort: 100 patients closed to accrual

– Cisplatin ineligible, carboplatin naïve: Accruing, targeting 100 patients

• Phase I trial of Enfortumab Vedotin +pembrolizumab

• Phase III trial of Enfortumab Vedotin vs chemotherapy

(paclitaxel, docetaxel, vinflunine)in checkpoint failures

Sacituzumab Govitecan (IMMU- 132)

in Patients With Previously Treated Metastatic

Urothelial Cancer (mUC):

Results From a Phase I/II Study

Scott T. Tagawa1, Bishoy Faltas1, Elaine T. Lam2, Philip Saylor3, Aditya Bardia3, Julio J. Hajdenberg4, Alicia K.

Morgans5, Emerson Lim6, Kevin Kalinsky6, Pamela Simpson7, Matthew D. Galsky8, Robert M. Sharkey9,

David M. Goldenberg9†, Trishna Goswami9, William A. Wegener9, Daniel Petrylak10

1Weill Cornell Medicine, New York, NY; 2University of Colorado Cancer Center, Aurora, CO; 3Massachusetts General Hospital Cancer

Center, Harvard Medical School, Boston, MA; 4University of Florida Health Cancer Center, Orlando, FL; 5Vanderbilt Ingram Cancer Center,

Nashville, TN; 6Columbia University Irving Medical Center-Herbert Irving Comprehensive Cancer Center, New York, NY; 7Helen F. Graham

Cancer Center, Christiana Care Health System, Newark, DE; 8Icahn School of Medicine Mount Sinai, Tisch Cancer Institute, New York, NY; 9Immunomedics, Inc., Morris Plains, NJ; 10Yale School of Medicine, Yale Cancer Center, New Haven, CT.

*Work done while Chairman and Chief Scientific Officer of Immunomedics, Inc.

View Poster Board #B5; Feb 15th 5:15 PM

mUC results in IMMU-132-01 Study

Trop-2: trophoblast cell surface antigen 2; 1. Avellini et al. Oncotarget 2017;8:58642.. 2. Starodub et al. Clin Cancer Res 2015;21:3870. 3. Cardillo et al. Clin Cancer Res. 2011;17:3157-3169. 4. Sharkey et al. Clin Cancer Res. 2015;21:5131-

5138. 5. Cardillo et al. Bioconjugate Chem. 2015;26:919-931. 6.Govindan et al. Mol Cancer Ther. 2013;12:968-978. 7. Faltas et al. Nat Genet. 2016;48:1490-1499. 8. Bardia et al. J Clin Oncol. 2017;35:2141-2148

• Trop-2 is an epithelial cell surface antigen

highly expressed in UC1.

• Sacituzumab govitecan is distinct from

other ADCs:2-6

− High drug-to-antibody ratio5

− Hydrolysis of the linker releases the

SN-38 cytotoxic intracellularly and in

the tumor microenvironment. Thus,

Sacituzumab govitecan-bound tumor

cells are killed by intracellular uptake

of SN-38, and adjacent tumor cells are

killed by SN-38 released

extracellularly6

• Sacituzumab govitecan has shown

preclinical and clinical activity.3,7,8

Humanized anti-Trop-2

antibody

• Directed towards Trop-

2, an epithelial antigen

expressed on many

solid cancers

Linker for SN-38

• Hydrolysable linker for

payload release

• High drug-to-antibody

ratio (7.5:1)5

SN-38 payload

• SN-38 more potent than

parent compound,

irinotecan

• In xenograft models,

ADC delivers up to 136-

fold more SN-38 than

irinotecan

Sacituzumab Govitecan is a Trop-2-Directed

Antibody-Drug Conjugate (ADC)

72


Demographic and Baseline Characteristics

Characteristic N=45

Age (y), median (range) 67 (49, 90)

Male, n (%) 41 (91)

Race, n (%)

White 39 (87)

Black 2 (4)

Asian 1 (2)

Other 2 (4)

Not reported 1 (2)

ECOG PS, n (%)

0 14 (31)

1 31 (69)

Visceral metastatic sites, n (%) 33 (73)

Lung 27 (60)

Liver 15 (33)

Other 5 (11)

Nonvisceral metastatic sites, n (%) 12 (27) *Placeholder for Bellmunt risk groups description.

Characteristic N=45

Median prior anticancer regimens, range 2 (1-6)

Median prior anticancer regimens in CPI-treated

pts (n=17), range

3 (1-6)

Lines of prior therapies, n, (%)

≤2 prior lines 28 (62)

≥3 prior lines 17 (38)

Bellmunt risk groups*, n, (%)

Low 25 (56)

Intermediate 16 (36)

High 4 (9)

73

*Risk factors are ECOG PS >0, presence of liver metastases, and hemoglobin <10 g/dL


Adverse Events (Worst Grade CTCAE) ≥20% or 5% grade

≥3 (Regardless of Causality; N=45)

• Most frequent SAEs included:

– Febrile neutropenia, diarrhea and

neutrophil count decreased in 2 pts each

– 24% of pts used GCSF

• No treatment-related deaths

• 6/45 pts discontinued due to AE not related to

progressive disease

– No patient discontinued due to

neutropenia

– And one patient discontinued due to

diarrhea

GCSF, granulocyte colony-stimulating factor; SAE, serious adverse event.

74

Event All Grades (%) Grades 3 (%) Grade 4 (%)

Diarrhea 69 9 0

Nausea 67 2 0

Fatigue 58 9 0

Neutropenia* 51 22 16

Constipation 44 0 0

Alopecia 40 0 0

Decreased appetite 38 0 0

Anemia 33 13 0

Cough 31 0 0

Vomiting 31 2 0

Pyrexia 24 0 0

Back pain 22 0 0

Dizziness 22 0 0

Rash 22 0 0

Hypophosphatemia 20 11 0

Febrile neutropenia 7 7 0

*Combined terms of Neutropenia' or 'Neutrophil count decrease'.


Objective Response Rate by Subgroup

75

Objective Response Rate, % (n/N) [95% CI]

Overall cohort 31.1 (14/45) [18.2, 46.6]

Lines of prior therapies

≤2 prior lines 39.3 (11/28) [21.50, 59.42]

≥3 prior lines 17.6 (3/17) [3.80, 43.43]

Prior checkpoint inhibitors

(median of 3 prior lines of therapy)23.5 (4/17) [6.81, 49.90]

Prior platinum and checkpoint

inhibitors26.7 (4/15) [7.79, 55.10]

Visceral involvement at study entry

Yes 27.3 (9/33) [13.30, 45.52]

Liver 33.3 (5/15) [11.82, 61.62]

No 41.7 (5/12) [15.17, 72.33]


Best Percent Change From Baseline in Tumor Size*

76

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. *Based on the sum of the diameters of the target lesions (longest for non-nodal, short axis for nodal

lesions); †pt had % change of 0 with best overall response of PD; ‡qualified for CR based on lymph node target lesion shrinkage to <10 mm. **One subject had 100% reduction of target lesions, but

limited response in non-target lesions, hence classified as PR.

†

‡

Be

st P

erc

en

t C

ha

nge

Fro

m B

ase

line

Ta

rge

t L

esio

ns

• Excludes 5 pts with no post-baseline scans

**


Patients With Objective Responses (n=14/45)

77

EndpointOverall

(N=45)

ORR (CR or PR), n (%) [95% CI]14 (31)

[18.2, 46.6]

CR, n (%) 2 (4)

PR, n (%) 12 (27)

Time to onset of response (mo),

Median

(Range)

1.9

(1.7, 7.4)

Duration of response (mo),

Median

(Range)

12.9

(1.3, 29.4+)

Censored: subjects whose duration of responses are censored due to missing 2 tumor assessments or

discontinuation

Three patients have ongoing response with durations of 16.9+, 18.7+, and 29.4+ months and all three of

them are still on treatment

and all three of them are still on treatment

• 50% of responders demonstrated

a DoR of ≥ 12 mo


Progression-Free and Overall Survival*

78

At risk:P

rob

ab

ility

of O

S

Pro

ba

bili

ty o

f P

FS

Progression-Free Survival Overall Survival

45 29 19 13 8 6 5 3 2 2 1 0 45 40 32 30 25 23 17 12 9 7 6 3 2 1 0

Median PFS

7.3 months

(95% CI: 5.0, 10.7)

39 42 450 3 6 9 12 15 18 21 24 27 30 33 36

Time (months) Time (months)

Median PFS

7.3 months

(95% CI: 5.0, 10.7)

0 3 6 9 12 15 18 21 24 27 30 33 36

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Median OS

16.3 months

(95% CI: 9.0,

31.0)

*Data as of Sept 1, 2018; PFS: 3 progression-free pts have an ongoing response and on treatment; OS: 5 live pts still on treatment. OS, overall survival; PFS,

progression-free survival.


Summary

• Sacituzumab govitecan, a novel Trop-2-directed ADC, demonstrated clinically significant activity in pts with heavily pre-treated relapsed/refractory mUC

– ORR: 31% (2 CR, 12 PR) overall with an ORR of 39% in those with ≤2 prior lines of treatment• 26.7% in CPI- and platinum-treated pts

• 33.3% in pts with liver metastases

– Median duration of response: 12.9 months

– Median PFS: 7.3 months

– Median OS: 16.3 months

• Sacituzumab govitecan was well tolerated, with a predictable safety profile

– Most common treatment-emergent AEs were neutropenia and diarrhea, which were manageable

– Low rate of patient discontinuation due to AEs• No patients discontinued due to neutropenia and 1 patient discontinued due to diarrhea

– No treatment-related deaths

• In conclusion, sacituzumab govitecan demonstrated significant clinical activity in pts with relapsed/refractory mUC, including pts with prior CPI + platinum treatment and visceral disease

79


TROPHY-U-01 (IMMU-132-06) StudyA Phase II Open Label, Study of IMMU-132 in Metastatic Urothelial Cancer After Failure of

Platinum-based Regimen or Anti-PD-1/ PD-L1 Based Immunotherapy

• Results from the Study-01 basket trial warranted further investigation in a dedicated phase 2 trial.

• TROPHY-U-01 (NCT03547973) is an international, single-arm, open-label, phase 2 trial evaluating

the antitumor activity and safety of sacituzumab govitecan in 140 pts with advanced UC.

80

View TROPHY-U-01 Poster on Feb 15th TPS #495; Poster Board #N5

NCT Trial Number: 03547973

PD-1, programmed cell death-1; PD-L1, programmed death ligand-1.

Continue

treatment in the

absence of

unacceptable

toxicity or PD

Sacituzumab Govitecan 10 mg/kg

Days 1 and 8, every 21 days

Objectives:

• Overall response rate

(ORR) will be centrally

reviewed

• Duration of response

(DOR)

• Progression-free survival

(PFS)

• Overall survival (OS)

Cohort 1 (100 patients): pts who

progressed after prior platinum-

based and anti PD-1/anti PD-L1

based therapies.

Cohort 2 (40 patients): pts ineligible

for platinum-based therapy and who

progressed after prior anti PD-1/anti

PD-L1 based therapies.

Documents

Approaches to the Treatment of Metastatic Bladder Cancer · IMVIGOR-130), the Data Monitoring Committees’ (DMC) found patients in the monotherapy arms of both trials with PD-L1