molecular targets in bladder cancer: pd-1 and beyond … · imvigor 210 study design cohort 1 to be...

Molecular Targets in Bladder Cancer: PD-1 and Beyond

Sumanta Kumar Pal, M.D.

Assistant Professor,

Department of Medical Oncology &

Experimental Therapeutics

Co-Director, Kidney Cancer Program

City of Hope Comprehensive Cancer

Center

August 20, 2016

Disclosures

• Consulting: Pfizer, Novartis, Genentech, GSK, Astellas,

Medivation

• Honoraria: Genentech

Developments in Prostate Cancer

2005 2016

DocetaxelCabazitaxel Enzalutamide Abiraterone

Sipuleucel-T Radium-223

Developments in Renal Cell Carcinoma

2005 2016

Sorafenib Temsirolimus Bevacizumab Axitinib

Everolimus LenvatinibSunitinib NivolumabPazopanib

Cabozantinib

Developments in Bladder Cancer

1980 2016

Cisplatin

Atezolizumab

Overview

Topic

Nature of Treatment

Disease Bladder Cancer

Immune

MOAPD-1-

Directed Therapy

Targeted

MOAFGFR and

HER2 inhibition

BCG was FDA Approved in 1990

Adapted from: Redelman-Sidi G, et al. Nat Rev Urol. 2014;11:153-162.

Immune cell recruitment

Cytokine production

Immune-mediated cytotoxicity

Internalized BCG in tumor epithelial cell

Proposed BCG

mechanism

of action

PD-1 and PD-L1 inhibition: The next generation

T-cell

Antigen

Presenting

Cell

Adapted from: Pal SK et al Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling

Paradigm. Mol Cancer Ther 2012 Feb 17.

Genomic diversity in bladder cancer

Lawrence MS et al . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 07/11/print;499(7457):214-8.

FDA approved the use of atezolizumab

•Locally advanced or metastatic urothelialcarcinoma.•Predominantly urothelialhistology•Tumor tissue for PD-L1 testing

Cohort 1 (N=119)11 Cisplatin Ineligible

Cohort 2 (N-310)Platinum-treated nUC

Co-primary endpoints:

•ORR (confirmed) per RECIST v1.1 by central review

•ORR per immune-modified RECIST by investigator

Key secondary endpoints

•DOR, PFS, OS, safety

Key exploratory endpoints

•Intratumoral biomarkers

Imvigor 210 Study Design

Cohort 1 to be shown later

Atezolizumab 1200 mg IV q3w until

Loss of 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

Median follow-up: 17.5 months (range, 0.2 to 21.1+ mo)

Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated mUC. ASCO 2016

Atezolizumab Response Rates (by PD-L1 status)

IC2/3n = 100

IC1/2/3n = 207

Alla

N = 310

IC1n = 107

IC0n = 103

ORR: confirmed IRF RECIST v1.1 (95% CI)28%

(19, 38)

19%(14, 25)

16%(12, 20)

11%(6, 19)

9%(4, 16)

CR rate: confirmed IRF RECIST v1.1 (95% CI)15%(9, 24)

9%(6, 14)

7%(4, 10)

4%(1, 9)

2%(0, 7)

• Responses were seen in all IC subgroups, but ORR was enriched with higher

PD-L1 status

• Complete responses accounted for nearly half of the observed responses

– CRs were observed in all PD-L1 subgroups, with the highest rate in IC2/3

patients

a Includes 46 patients with missing/unevaluable responses. b CR + PR + SD ≥ 24-wk rate per IRF RECIST v1.1. Treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. Data cutoff: Mar. 14, 2016.


Duration of Response to Atezolizumab

• Responses were durable, with mDOR not reached in any PD-L1 subgroup

(range, 2.0+ to 13.7+ mo)

• Ongoing responses were seen in 38 of 45 responding patients (84%)

• Median follow-up time: 11.7 mo (range, 0.2+ to 15.2 mo)

50

0

‒100

0 9 18 27 36 45 54 63

Time on Study, weeks

SLD

Chan

ge

Fro

m B

aselin

e, %

0 9 18 27 36 45 54 63 0 9 18 27 36 45 54 63

IC2/3 IC0IC1

♦ Discontinued

▲ New lesion

Patients with CR or PR per IRF RECIST v1.1

Hoffman-Censits et al. GU ASCO 2016. Abstr 355.

Data cutoff: September 14, 2015.

Stable Disease with Atezolizumab

• Many non-responding patients experienced SD, suggesting that atezolizumab

may provide clinical benefit to these patients

– Disease control rate (CR + PR + SD ≥ 24-wk rate): 35% (IC2/3), 21% (IC1) and 19% (IC0)

Hoffman-Censits et al. GU ASCO 2016. Abstr 355.

Data cutoff: September 14, 2015.

100

0

‒100

0 9 18 27 36 45 54 63

Time on study, weeks

0 9 18 27 36 45 54 63 0 9 18 27 36 45 54 63

IC2/3 IC0IC1

Patients with stable disease per IRF RECIST v1.1

♦ Discontinued

▲ New lesion

SL

D C

ha

ng

e

Fro

m

Ba

se

line, %

Overall Survival with Atezolizumab

• Longer OS observed in patients with higher PD-L1 IC status

• mPFS (2.1 mo per RECIST v1.1; 2.6 mo per imRECIST)

underscores a disconnect between PFS and OS

Subgroup

Median OS(95% CI)

IC2/3 IC0/1 All

All pts

(N = 310)

11.9 mo

(9.0, 17.9)

6.7 mo

(5.4, 8.0)

7.9 mo

(6.7, 9.3)

Subgroup

12-mo OS(95% CI)

IC2/3 IC0/1 All

All pts

(N = 310)

50% (40, 60)

31% (24, 37)

37% (31, 42)

Median follow-up (range): All Pts: 17.5 mo (0.2 to 21.1+ mo)


NE, not estimable. Data cutoff: Mar. 14, 2016.

Immune-mediated Adverse Events

AE (N = 310)a All Grade Grade 3-4

Pneumonitis 2% 1%

AST increased 2% 1%

Dyspnea 1% 1%

ALT increased 1% < 1%

Blood bilirubin

increased1% < 1%

Rash 1% < 1%

Hyperglycemia 1% 0%

Colitis 1% 1%

Diarrhea 1% < 1%

Transaminases

increased1% < 1%

Dry skin 1% 0%

Pruritus 1% 0%

Pyrexia 1% 0%

• 30% of patients received

steroids for any purpose

• Immune-mediated AEs

(imAEs) were observed at

frequencies of 10% (all

Grade) and 6% (G3-4)

• No patients were treated with

non-corticosteroids

immunomodulatory agents

for imAEs (e.g. infliximab,

tocilizumab, rituximab, IL-2)

a Occurring in ≥ 2 patients (all Grade). Additional G3-4 events (n = 1 each): Autoimmune hepatitis, Cytokine release syndrome, hepatitis, paraplegia, pericardial effusion, blood alkaline phosphatase increased, chronic kidney disease, hypotension, musculoskeletal pain, sepsis. Data cutoff: March 14, 2016.


Overall Response Rates of PD-1/PD-L1 Antibodies in Post-

Platinum Setting

Slide courtesy of Betsy Plimack from ASCO 2016 Discussion

Genomic diversity in bladder cancer

Lawrence MS et al . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 07/11/print;499(7457):214-8.

Atezolizumab in bladder cancer

Rosenberg JE et al Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm,

multicentre, phase 2 trial. The Lancet.

PD-L1 status as a Biomarker for Metastatic Urothelial Cancer

Slide courtesy of Betsy Plimack from ASCO 2016 Discussion

Author Phase Drug SettingTotal

n

Definition of

PDL1 +

% of patients

PDL1 "high"

or "positive"

ORR in

favorable

biomarker

group

ORR - all

Balar

ASCO 16II Atezolizumab First line cis ineligible 119 IC 2/3 27% 28% 24%

Dreicer

ASCO 16II Atezolizumab Post platinum 310 IC 2/3 32% 28% 16%

Sharma

ASCO 16I basket Nivolumab Post platinum 78 >=1% TC 37% 24% 24%

Massard

ASCO 16I basket Durvalumab Post platinum 42

>25% in TC or

IC67% 46% 31%

Plimack

ASCO 15I basket Pembrolizumab Post platinum 29

≥1% tumor or

stroma100% 28% 28%

Apolo

GUASCO

2016

I basket Avelumab Post platinum 44≥5% tumor

cells*16% 40% 16%

Petrylak

ASCO 15I basket Atezolizumab pre/post platinum 87 IC 2/3 45% 50% 34%

•Locally advanced or metastatic urothelialcarcinoma.•Predominantly urothelialhistology•Tumor tissue for PD-L1 testing

Cohort 1 (N=119)11 Cisplatin Ineligible

Cohort 2 (N-310)Platinum-treated nUC

Co-primary endpoints:

•ORR (confirmed) per RECIST v1.1 by central review

•ORR per immune-modified RECIST by investigator

Key secondary endpoints

•DOR, PFS, OS, safety

Key exploratory endpoints

•Intratumoral biomarkers

Imvigor 210 Study Design

Cohort 1 to be shown later

Atezolizumab 1200 mg IV q3w until

Loss of 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

Median follow-up: 17.5 months (range, 0.2 to 21.1+ mo)


Imvigor 210 Cohort 1 Data from ASCO

IC2/3

(n = 32)

IC1/2/3

(n = 80)

All Patients

(N = 119)

IC1

(n = 48)

IC0

(n = 39)

ORRa (95% CI) 28% (14, 47) 25% (16, 36) 24% (16, 32) 23% (12, 37) 21% (9, 36)

CR 6% 6% 7% 6% 8%

PR 22% 19% 17% 17% 13%

Subgroup ORRa 95% CI

Demographics and prior treatment

Age ≥ 80 years (n = 25) 28% 12, 49

Perioperative chemob (n = 22) 36% 17, 59

Primary tumor sites

Bladder/urethra (n = 85) 17% 9, 26

Upper tract (n = 33) 42% 25, 61

Metastatic sites at baseline

Lymph node only (n = 31) 32% 17, 51

Visceralc (n = 78) 15% 8, 25

Liver (n = 25) 12% 3, 31

Cisplatin ineligibility criteria

Impaired renal function (n = 83) 27% 17, 37

ECOG PS2 (n = 24) 25% 10, 47

Renal impairment and ECOG PS2 (n = 8) 25% 3, 65 Balar AV et al. ASCO 2016; LBA4500.

Key Demographics

• 28% with upper tract disease

• 70% with Cr Cl 30-60

• 20% ECOG 2

PD-1/PD-L1 inhibition in earlier settings?

Courtesy of Peter Black, MD.

Bladder Cancer Diagnostics: The Pre-Metastatic Niche

There is an environment in the lymph nodes around the bladder that cultivates the

spread of cancer.

Diagnostic: Features of the pre-metastatic niche could serve as a personalized

prognostic factor


Pal SK, Pham A, Vuong W, Liu X, Lin Y, Ruel N, Yuh BE, Chan K, Wilson T, Lerner SP, McConkey D, Jove R, Liang W. Prognostic

Significance of Neutrophilic Infiltration in Benign Lymph Nodes in Patients with Muscle-invasive Bladder Cancer. Euroepan Urology

Focus. 2016;16:S2405-4569.

Neutrophil infiltration and pSTAT3 in benign lymph nodes predict OS


SWOG Coltman Award: Validation of findings in S1011

• Tissues will be send to the Lee lab at City of Hope

Overview

Topic

Nature of Treatment

Disease Bladder Cancer

Immune

MOAPD-1-

Directed Therapy

Targeted

MOAFGFR and

HER2 inhibition

Bladder Cancer Diagnostics: Defining Landscape

Characterizing Frequent Mutations in Advanced Bladder Cancer

Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, Nazeer T, Elvin JA, Palma N, Yelensky R, Lipson D, Miller VA, Stephens PJ,

Subbiah V, Pal SK. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder

reveals a high frequency of clinically relevant genomic alterations. Cancer. 2015 Dec 9.

• More advanced population

than TCGA

• High frequency of FGFR3

alterations

• High frequency of HER2

alterations


Upper Tract versus Lower Tract Disease

Pal SK, Ali SM, Elvin JA, Frampton GM, Vergilio J-A, Suh J, Gunuganti V, Mian B, Fisher HAG, Nazeer T, Miller VA, Stephens PJ,

Ross JS. Comparison of upper tract urothelial carcinoma and urothelial carcinoma of the bladder to reveal key differences in mutational

profile and load. ASCO Meeting Abstracts. 2016;34(15_suppl):4522.

Parameter UCB UTUC

Number of Patients 295 195

Genomic Alterations/sample 6.4 6.4

Short Variants 61% 76%

Copy Number Changes 22% 37%

Rearrangements 2% 2%

Clinically Relevant GA/sample 2.6 2.0

Most Frequent Clinically

Relevant GA

FGFR3 (21%)

PIK3CA (20%)

ERBB2 (16%)

FGFR3 (28%)

PIK3CA(16%)

CCND1 (12%)

MDM2 (11%)

TSC1 (11%)

ERBB2 (11%)

ERBB2 short variant mutation

frequency in micropapillary

variant of UC

40% 43%


Smoking vs Non-Smoking

Joshi M, Vasekar M, Grivas P, Emamekhoo H, Hsu J, Miller VA, Stephens PJ, Ali SM, Ross JS, Zhu J, Warrick J, Drabick JJ, Holder

SL, Kaag M, Li M, Pal SK. Relationship of smoking status to genomic profile, chemotherapy response and clinical outcome in patients

with advanced urothelial carcinoma. Oncotarget. 2016 May 18.

• Never, current and ex-smokers have a distinct

genomic profile

• GAs in NSD1 were more frequent in CS as

compared to other groups (P < 0.001)

Bladder Cancer Diagnostics: Setting Guidelines

Pal SK, Agarwal N, Boorjian SA, Hahn NM, Siefker-Radtke AO, Clark PE, Plimack ER. National Comprehensive Cancer Network

Recommendations on Molecular Profiling of Advanced Bladder Cancer. J Clin Oncol. 2016 Jul 25.

• There is a dearth of available therapies

• Even immunotherapy approaches are non-curative

• Broader use of genomic profiling will facilitate studies of targeted

therapy in this disease

Everolimus: Retrospectively Assessing Extreme Responders

Iyer G Science 2012

Everolimus: Applying FM Results to an Individual Case

Ali S (Submitted)

AuthorTiming of Genomic

Profiling

mTOR Pathway

Alternations

Other Genomic

Alterations

Iyer et al Retrospective after

treatment

TSC1/NF2 Unknown

Wagle et al Retrospective after

treatment

MTOR E2014k,

E2419K

CTNNB1, TP53

Ali et al Prospective and

guided treatment

NF2 TP53, ATRX,

ATM

Targets To Explore …

Pal SK, Milowsky MI, Plimack ER. Optimizing systemic therapy for bladder cancer. Journal of the National

Comprehensive Cancer Network : JNCCN 2013 Jul 1;11(7):793-804.

Dovitinib

Milowsky ASCO GU 2013

FGFR3 mut

Group 1: FGFR3 mut

~20 patients

Group 1: FGFR3 mut

~ 20 patients

FGFR3 WT

Group 2: FGFR3 WT

~20 patients

Group 2: FGFR3 WT

~ 20 patients

Stratification / Study Entry

Treatment with Dovitinib500 mg p.o. 5 days on / 2 days off, cycle: 28 days

Study EndpointsPrimary: ORR (CR, PR)

Secondary: PFS, DCR, Safety, PK Profile

Stage 1

Stage 2

Dovitinib

Milowsky ASCO GU 2013

BGJ398: A more potent dovitinib?

Sequist AACR 2014

FGFR3 inhibition in bladder cancer

Bladder Cancer Therapeutics: Targeted Therapies

Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, Nazeer T, Elvin JA, Palma N, Yelensky R, Lipson D, Miller VA, Stephens PJ,

Subbiah V, Pal SK. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder

reveals a high frequency of clinically relevant genomic alterations. Cancer. 2015 Dec 9.

FGFR3 inhibition in bladder cancer


Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, Hoffman-Censits JH, Quinn D, van der Noll R, Burris HA, Galsky MD,

Gravis G, Lee J-L, Medioni J, Mortazavi A, Maroto P, Parker K, Chen X, Isaacs R, Bajorin DF. Efficacy of BGJ398, a fibroblast growth

factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (mUC) with

FGFR3 alterations. ASCO Meeting Abstracts. 2016;34(15_suppl):4517.

FGFR3 inhibition with BGJ398


Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, Hoffman-Censits JH, Quinn D, van der Noll R, Burris HA, Galsky MD,

Gravis G, Lee J-L, Medioni J, Mortazavi A, Maroto P, Parker K, Chen X, Isaacs R, Bajorin DF. Efficacy of BGJ398, a fibroblast growth

factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (mUC) with

FGFR3 alterations. ASCO Meeting Abstracts. 2016;34(15_suppl):4517.


DNA Repair Pathways Remain Essential in Bladder Cancer

• VX-970 is a first-in-class ATR inhibitor and may synergize with cisplatin

Adapted from Jackson SP, Bartek J. The DNA- damage response in human biology and disease Nature (2009) 461, 1071


NCI Project Team Member: VX-970

• First-in-class ATR inhibitor

Metastatic urothelial

carcinoma

• No prior systemic therapy

for metastatic disease

• At least 12 months elapsed

since platinum-based

perioperative treatment

• KPS≥70

• CrCl > 50 mL/min

CG

CG + VX-

970*

1:1

R

andom

iza

tion

Primary Endpoint:

• Progression-free survival

Secondary Endpoints:

• Overall survival

• Response rate

• Safety

• Biomarker assessments

Total Enrollment:

• N=90

Bladder Cancer Therapeutics: Chemo as targeted therapy?


Muscle-invasive bladder

cancer

• No prior systemic therapy f

• Candidates for platinum-

based chemotherapy

• KPS≥70

• CrCl > 60 mL/min

CG

ddMVAC

1:1

R

andom

ization

Primary Endpoint:

• To characterize the

relationship of DDMVAC-

and Gemcitabine-Cisplatin

(GC)-specific COXEN

scores by pT0 rate at

cystectomy in patients

treated with neoadjuvant

chemotherapy

COXEN

• Led by Tom Flaig, MD (U. Colorado)

molecular targets in bladder cancer: pd-1 and beyond … · imvigor 210 study design cohort 1 to be...

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