Figure 1A. BAP1 inactivation, as determined by immunohistochemistry

Figure 1B. BAP1 mutations detected in MM patients The Cancer Genome Atlas

DEL, deletion; INS, insertion; SNV, single nucleotide variant.

Figure 2. BAP1 inactivation sensitizes to EZH2 inhibition in preclinical in vivo modelsa

aReprinted by permission from Springer Nature: Springer Nature Medicine “Loss of BAP1 function leads to EZH2-dependentTransformation” by Lindsay M LaFave, Wendy Béguelin, Richard Koche, Matt Teater, Barbara Spitzer et al., Copyright 2015.

Figure 4. EZH-203 study design

aAll patients will have completed at least the week 12 assessment, completed the final study visit, or terminated early from the study, whichever is sooner; bDisease Control: RECIST 1.1 or modified RECIST –confirmed objective response or stable disease at week 12.RECIST, Response Evaluation Criteria In Solid Tumors; R/R, relapsed or refractory.

Figure 5. Durability of disease control in patients with relapsed or refractory MM

Number in bars indicates lines of prior anti-cancer therapy excluding maintenance as its own line.Data as of Jan 16, 2018.*Dosing records incomplete.

Figure 6. 64 Year Old Male with Pleural MM Shows Slow Steady Reduction in Tumor Burden with 1st PR at Week 42

aBaseline as of February, 2017; bLast scan as of January 16, 2018.MM, malignant mesothelioma; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

Patient Vignette

Figure 3. EZH2-mediated repression of transcription

Phase 2 Multicenter Study of the EZH2 Inhibitor Tazemetostat as Monotherapy in Adults With Relapsed or Refractory Malignant Mesothelioma With BAP1 Inactivation (NCT02860286)

Marjorie G. Zauderer1, Peter Szlosarek2, Sylvestre Le Moulec3, Sanjay Popat4, Paul Taylor5, David Planchard6, Arnaud Scherpereel7, Thierry Jahan8, Marianna Koczywas9, Martin Forster10, Robert B. Cameron11, Tobias Peikert12, Carly Campbell13, Inbal Sapir13, Alice McDonald13, Coreen Oei13, Alicia Clawson13, Maria Roche13, Dean A. Fennell14

1Memorial Sloan Kettering Cancer Center, New York, NY; 2St. Bartholomew’s Hospital, London, UK, 3Institut Bergonie, Bordeaux, France; 4Royal Marsden Hospital, London, UK; 5Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK; 6Institut Gustave Roussy, Villejuif, France; 7Hospital of the University (CHU) de Lille, Lille, France; 8University of California, San Francisco, CA; 9City of Hope National Medical Center, Duarte, CA; 10University College Hospital, London, UK; 11University of California, Los Angeles, CA; 12Mayo Clinic, Rochester, MN; 13Epizyme, Inc., Cambridge, MA; 14University of Leicester and University Hospitals of Leicester, Leicester, UK

Presented at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1–5, 2018; Chicago, IL, USA

121

BACKGROUNDMesothelioma•Malignant mesothelioma (MM) is caused by occupational and environmental exposure to asbestos

fibers and other elongate mineral particles1

– The latency period from exposure to MM ranges from 20 to 40 years•Due to the location and characteristics of the malignancy, diagnosis is often at advanced stage of MM1,2

– Once diagnosed, patients have a median survival of approximately 1 year, experiencing rapid and aggressive progression with poor prognosis

•Available treatment for these patients is limited and in dire need of improvement both in efficacy and safety. All patients relapse on average 6 months following first-line treatment with chemotherapy2

•No drugs have been shown to improve survival as second-line therapy, and to date there is no standard of care or approved therapy in second-line1,2

•There is an urgent need for safe and effective targeted therapies for MM

BAP1•BRCA1-associated protein 1 (BAP1), a nuclear deubiquitinase, is commonly inactivated in MM tumors3,4

(Figure 1A-B)– Up to 66% of MM cases exhibit BAP1 inactivation, as measured by a loss of nuclear protein5

– Approximately 23% of MM cases harbor BAP1 genetic alterations3,4

– Inactivation is most common in epithelioid & biphasic subtypes compared with sarcomatoid5

EZH2•BAP1 inactivation is linked to a dependency on enhancer of zeste-homolog 2 (EZH2) activity6 (Figure 2)•EZH2 activity is implicated as an oncogenic driver and preclinical data suggest that elevated EZH2

activity may play a role in MM in the context of BAP1 loss6

Table 3. Patient demographics and baseline disease characteristics

Clinical CharacteristicsTotal Number of Patients

N=74Age (years), mean (SD) 65 (10)Male/Female, n (%) 49 (66)/25 (34)ECOG status PS 0/1, n (%) 19 (26)/55 (74)Prior lines of therapy, median (range) 2 (1–9) Therapy setting, n (%) Neoadjuvant 7 (9) Adjuvant 18 (24) Therapeutic for advanced/metastatic disease/Palliation 61 (83) Maintenance 5 (7) Unknown 6 (8)Time (months) from last PD to study entry, median (range) 1 (0–14)Primary tumor location; pleura/peritoneum, n (%) 68 (92)/6 (8)Histology, n (%) Epithelioid 65 (88) Sarcomatoid 1 (1) Biphasic 6 (8) Unknown 2 (3)Stage at diagnosis, n (%) I 3 (4) II 14 (19) III 13 (18) IV 28 (38) Unknown 16 (22)

ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PS, performance status.

Table 4. TEAEs occurring in ≥10% of patients, regardless of relationship to study drug

Patients (N=74)

Adverse EventsAll Grades ≥ 10%

n (%)Grade ≥3

n (%)Anemia 12 (16) 4 (5)Dyspnea 21 (28) 3 (4)Asthenia 9 (12) 2 (3)Cancer pain 19 (26) 2 (3)Fatigue 24 (32) 2 (3)Nausea 20 (27) 2 (3)Weight decreased 8 (11) 2 (3)Cough 16 (22) 1 (1)Decreased appetite 21 (28) 1 (1)Vomiting 16 (22) 1 (1)Diarrhea 11 (15) 0Lower respiratory tract infection 8 (11) 0

Table 5. Best response to tazemetostat treatment

Endpoint Category, n (%) Part 2a N=61 Total N=74PrimaryDCR (CR + PR + SD) at week 12 95% CIb

31 (51) 38-64%

35 (47) 36-59%

Secondary DCR (CR + PR + SD) at week 24 16 (26) 17 (23)Best Responsec Complete Response (CR) 0 0 Partial Response (PR)d 2 (3) 2 (3) Stable Disease (SD) 38 (62) 46 (62) Progressive Disease (PD) 16 (26) 21 (28) Non-evaluable 5 (8) 5 (7)

aSuccess at stage 2 was based on results from Part 2; bExact binomial; cBased on modified RECIST for thoracic disease and RECIST 1.1 elsewhere; dConfirmed responses.DCR, disease control rate.

Table 1. Patient key inclusion criteria

Inclusion

Age ≥18 years

ECOG performance status of 0 or 1

Life expectancy >3 months

MM of any histology that is relapsed or refractory after treatment with at least 1 pemetrexed-containing regimen

Documented and confirmed (CLIA/CAP) local diagnostic pathology of original biopsy

Evidence of BAP1 protein loss by local pathology (for part 2 of the study)

Measureable disease

CAP, College of American Pathologists; CLIA, certified through Clinical Laboratory Improvement Amendments; ECOG, Eastern Cooperative Oncology Group.

Table 2. Patient key exclusion criteria

ExclusionPrior exposure to tazemetostat or other inhibitor(s) of EZH2

History of known central nervous system metastasis

Prior malignancy other than the malignancies under studyException: A patient who has been disease-free for 5 years, or a patient with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible

Major surgery within 3 weeks prior to enrollment

Cardiovascular impairment, history of congestive heart failure greater than New York Heart Association Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment

Tazemetostat•EZH2 is an epigenetic regulator of gene expression and plays a critical role in multiple forms of cancer

(Figure 3)

•Tazemetostat is a potent, selective, oral EZH2 inhibitor that is generally well tolerated and has demonstrated preclinical and clinical activity in several tumor types

•Here, we report preliminary data from the phase 2 trial examining tazemetostat in patients with measurable relapsed or refractory MM

METHODS•Study EZH-203 (NCT02860286) is a phase 2, multicenter, open-label, 2-part study of tazemetostat

800 mg administered orally twice daily for relapsed or refractory MM (Figure 4)– Response assessment was evaluated after 6 weeks of treatment and every 6 weeks thereafter while

on study•Key inclusion and exclusion criteria are presented in Tables 1 and 2•Primary endpoint part 2: Disease control rate (DCR): CR+PR+SD at week 12•2-Stage Green Dahlberg Design; H0: DCR ≤25%, Ha: DCR ≥35%

RESULTS (JANUARy 16, 2018 DATA-CUT)Patient Characteristics•Enrollment of 74 patients to EZH-203 was completed in 10 months (Table 3)•A total of 70 of 74 tumor samples (95%) centrally confirmed BAP1-deficient

CONCLUSIONS AND NEXT STEPS•Tazemetostat was generally well tolerated in patients with relapsed refractory MM•Tazemetostat monotherapy showed promising anti-tumor activity in patients with

tumors harboring BAP1 inactivation, including confirmed responses and long-term disease control

•Studies to fully characterize patient tumor samples are ongoing – Exploratory prognostic indices– RNA-seq – Immune profiling by multiplex immunofluorescence

•Further clinical evaluation of tazemetostat in combination studies is warranted

REFERENCES1. Mazurek JM, Syamlal G, Wood JM et al. MMWR Morb

Mortal Wkly Rep. 2017;66:214–8.2. Baas P, Fennell D, Kerr KM et al. Ann Oncol. 2015;

26:v31–9.3. Bott M, Brevet M, Taylor BS et al. Nat Genet.

2011;43:668–72.4. Bueno R, Stawiski EW, Goldstein LD et al. Nat Genet.

2016;48:407–16.5. Cigognetti M, Lonardi S, Fisogni S et al. Mod Pathol.

2015;28:1043–57.6. LaFave LM, Béguelin W, Koche R et al. Nat Med.

2015;21:1344–9.

ACKNOWLEDGMENTSWe thank all of the physicians, study coordinators, site staff and most of all, the patients, caregivers, and families who have contributed to this studyThird-party writing assistance was provided by Ashfield Healthcare and funded by Epizyme, Inc.

Copies of this poster obtained through QR (Quick Response) code are for personal use only and may not be reproduced without written permission from the author of this poster.

Safety•A total of 71/74 (96%) patients had a treatment-emergent adverse event* (TEAE)

– The most frequent TEAEs included fatigue (32%), decreased appetite (28%), and dyspnea (28%), and were generally grade 1 or 2 in severity (Table 4)

•No patients discontinued the study due to treatment-related TEAEs•Five (7%) patients had a dose reduction due to TEAEs

– One patient experienced a dose reduction on 2 separate occasions•Ten (14%) patients died in this study; no deaths were related to tazemetostat as assessed by investigator *Any AE that occurred after patient initiated treatment

Patient Disposition•Overall, 67 of 74 patients discontinued study

– Disease progression: 61– Death caused by disease under study: 5– Refused further treatment: 1

•Seven patients are ongoing – Partial response (PR): 2– Stable disease (SD): 3– Progressive disease (PD): 2

•Continue on study per protocol

EfficacyObjective Response•Confirmed PRs were observed in 2 patients

– Both patients with a PR are ongoing treatment at 42 and 48 weeks – An example of clinical activity is shown in Figure 6A– Initial responses observed at weeks 36 and 42 (Figure 6B), consistent with emergence of late

responses noted across the tazemetostat clinical development program

Weeks since treatment initiation0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Patie

nts

Part 1Part 2Progressive diseasePartial response – confirmedOngoing

**

**

65232213132121321114134113125331132252111211213211132232111311112112213

73

On study scans

24 weeks 48 weeksbBaselinea

2016

Tazemetostat: week 48+ Pemetrexed cisplatin

2015 MarJuly

MayAug

Feb

2017PR SD

2018PR at week 42

DiagnosedES stage 3

Vinorelbine

PD

0% 1.3%

3.9%

-9.2%

-12.7%-14.9%

-16.2%

-33.3%-34.6%

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

5%

Baseline Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48

Chan

ge fr

om b

asel

ine

in su

m o

f les

ions

Time on tazemetostat treatment

PR criteria met per RECIST 1.1

Patientswith R/R

MM

STAGE 1 ANALYISTargeted enrollment = 30a

STAGE 2 ANALYISTargeted enrollment = 55

<5 patientswith Disease

Controlb

No further enrollment in cohortb

Pharmacokineticprofile of

tazemetostat and itsmetabolite

Response assessment evaluated after 6 weeks of treatment and then every 6 weeks thereafter

Enrollment continues to

n=55

≥5 patients with Disease

Controlb

PART 2BAP1 status: tumor loss of nuclear positivity

PART 1BAP1 status: undefined

Targeted enrollment = 12

≥17 patients with Disease

Controlb

<17 patientswith Disease

Controlb

BAP1 nuclear & cytoplasmic negative BAP1 nuclear negative, cytoplasmic positive BAP1 nuclear positive, cytoplasmic positive

Nuclear Loss Nuclear Positive

UCH

Freq

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mut

ation

HBM NLS BARD1 HCF-1

DEL SNV INS

BRCA1

1 250 363 656 717 729

p.W

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p.I4

7Lfs

*21

p.Q

280*

p.S1

0R

p.Q

85Sf

s*2

p.I2

10DE

L

p.X2

18_s

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p.C9

1G

p.X2

20_s

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p.IA

644E

fs*1

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IN64

5Kfs

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p.V6

54Q

fs*3

p.K6

51de

l

p.E2

84*

p.P2

93Gf

s*35

p.X2

18x

p.H1

69Tf

s*18

p.N

251T

fs*6

p.Q

392*

p.Q

456*

p.Y4

18W

fs*9

p.E1

82K

p.I7

2Cfs

*7

BAP1– BAP1 +

5 Vehicle

1 4 7 11 14

**

**

Time of EPZ011989 treatment (d)17 21 24

H226

500 mg/kgEPZ0119894

3

Tum

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hang

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1 4 7 11

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Time of EPZ011989 treatment (d)

H2452

500 mg/kgEPZ011989

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ns

Time of EPZ011989 treatment (d)14

Meso10

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Time of EPZ011989 treatment (d)

MSTO-211H

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4

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01 4 7 11 14 17 21 24

PRC2

EZH2

K27me3K27me3

K27me3

Compacted chromatin

Transcriptionalrepression

K27me3

A BOn study scans Tazemetostat treatment timeline