INTERIMREPORTFROM’APHASE2’ … … · interimreportfrom’aphase2’ multicenter’study’of...
Transcript of INTERIMREPORTFROM’APHASE2’ … … · interimreportfrom’aphase2’ multicenter’study’of...
INTERIM REPORT FROM A PHASE 2 MULTICENTER STUDY OF TAZEMETOSTAT, AN EZH2 INHIBITOR: CLINICAL ACTIVITY AND FAVORABLE SAFETY IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA
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Franck Morschhauser, Gilles Salles, Pamela McKay, Hervé Tilly, Anna Schmitt,John Gerecitano, Peter Johnson, Steven Le Gouill, Michael J. Dickinson,Christophe Fruchart, Thierry Lamy, Aristeidis Chaidos, Wojciech Jurczak, Stephen Opat,John Radford, Pier Luigi Zinzani, Sarit Assouline, Guillaume Cartron, Alicia Clawson,Natasha Picazio, Scott Ribich, Stephen J. Blakemore, John Larus, Harry Miao,Mark Woodruff, Peter T. Ho, Vincent Ribrag
International Conference on Malignant Lymphoma (ICML)June 14-17, 2017
TAZEMETOSTAT FOR THE TREATMENT OF B-CELL NHL
• EZH2 is an epigenetic regulator of gene expression and plays a critical role in multiple forms of cancer
‒ Activating mutations of EZH2 can act as an oncogenic driver for cancers, especially in FL and GCB-DLBCL, present in ~20% of patients
• Tazemetostat
‒ First-in-class, potent and selective oral inhibitor of mutated and wild-type EZH2
‒ Preclinical activity in DLBCL cells lines, with greater activity in EZH2 mutant models
‒ Monotherapy activity and favorable safety in phase 1 studies in patients with relapsed or refractory (R/R) NHL, as well as certain genetically defined solid tumors
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K27me3K27me3
K27me3K27me3
Transcriptional Repression
Compacted Chromatin
EZH2
PRC2
Y646F/N/H/S/CA682GA692V
Tazemetostat
TAZEMETOSTAT PHASE 2 NHL STUDY DESIGN
• Global, multi-center, open-label study in 6 cohorts of patients with R/R DLBCL or FL‒ Patients prospectively stratified by EZH2 mutational status and cell of origin‒ ≥2 prior therapies
• Primary endpoint: overall response rate 1 (ORR)‒ Secondary efficacy endpoints: progression-free survival (PFS) and duration of response
• Study initiated with 5 monotherapy cohorts (n=270)‒ 3 cohorts of DLBCL (n=60 each) and 2 cohorts of FL (n=45 each)‒ Cohort of tazemetostat + prednisolone (n=70) in DLBCL added in 2017
31 Objective response assessed by IWG-NHL criteria (Cheson 2007)Restaging every 8 weeks for 6 cycles, then every 12 weeks thereafter
PRE-SCREENING
COHORT ALLOCATION
ELIGIBILTY,
ENROLLMENT
EOT FOLLOW-UP
DLBCL, GCBEZH2 Mt (N=60)
FL, EZH2 WT (N=45)
FL, EZH2 Mt (N=45)
DLBCL, NON-GCB (N=60)
DLBCL, GCBEZH2 WT (N=60)Archival Tissue
Central Lab COO, EZH2
Tazemetostat, 800 mg BID until PD or withdrawal
ORR, PFS, DOR, safety, PK
OS
PROTOCOL SPECIFIED MOLECULAR CHARACTERIZATION OF B-CELL NHL PATIENTS
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• Prospective testing: required for cohort allocation‒ FL & DLBCL – cobas® EZH2 Mutation Test (Roche Molecular Systems, in development) • Allele specific PCR test for EZH2 hot spot mutations
‒ DLBCL only – Hans IHC for determination of cell of origin (COO)
• Retrospective testing:‒ NGS on archival and circulating tumor DNA collected at screening for common NHL mutations in a panel of 62 genes
‒ Lymph2Cx nanoString assay for more accurate COO determination• Published discordance rate of ~20% between nanoString vs. Hans
PHASE 2 NHL STUDY PROGRESS
• Data cut-off: June 1, 2017
• 218 patients enrolled into monotherapy cohorts‒ 81% of total of 270‒ Closed to accrual:• FL wild-type EZH2 – 54 pts, 54 evaluable for efficacy• DLBCL wild-type EZH2 (GCB EZH2 WT + non-GCB) – 120 pts, 119 evaluable for efficacy
‒ Open to accrual: • FL mutated EZH2 – 19 pts, 13 evaluable for efficacy• DLBCL mutated EZH2 – 22 pts, 17 evaluable for efficacy
• Evaluable population‒ Safety: 210 pts‒ Efficacy: 203 pts
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Characteristic Follicular Lymphoma DLBCL
EZH2 Status Mutant Wild-type Mutant Wild-typen 13 54 17 120
Age, median years 62 61 61 69
Males 46% 63% 53% 58%
ECOG PS, median (range) 0 (0 - 2) 0 (0 - 2) 1 (0 - 2) 1 (0 - 2)
Prior lines of therapy, n (%) 1 1 ( 8%) 0 0 3 ( 3%)
2 2 (15%) 11 (20%) 4 (24%) 40 (33%)
3 3 (23%) 9 (17%) 7 (41%) 28 (23%)
4 1 ( 8%) 14 (26%) 3 (18%) 18 (15%)
≥ 5 6 (46%) 20 (37%) 3 (18%) 31 (26%)
median 4 4 3 3
Refractory to last regimen, n (%) 7 (54%) 26 (48%) 14 (82%) 75 (63%)
Prior HSCT 23% 41% 41% 24%
Median time from initial diagnosis years 7.4 4.9 1.0 2.0
Median time from last prior therapy weeks 13.0 41.3 8.6 11.6
Data as of 6/1/2017Refractory to last regimen defined as SD or PD as best response to most recent prior therapy
PHASE 2 NHL DEMOGRAPHICS & DISEASE CHARACTERISTICS
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Characteristic Follicular Lymphoma DLBCL
EZH2 Status Mutant Wild-type Mutant Wild-typen 13 54 17 120
Age, median years 62 61 61 69
Males 46% 63% 53% 58%
ECOG PS, median (range) 0 (0 - 2) 0 (0 - 2) 1 (0 - 2) 1 (0 - 2)
Prior lines of therapy, n (%) 1 1 ( 8%) 0 0 3 ( 3%)
2 2 (15%) 11 (20%) 4 (24%) 40 (33%)
3 3 (23%) 9 (17%) 7 (41%) 28 (23%)
4 1 ( 8%) 14 (26%) 3 (18%) 18 (15%)
≥ 5 6 (46%) 20 (37%) 3 (18%) 31 (26%)
median 4 4 3 3
Refractory to last regimen, n (%) 7 (54%) 26 (48%) 14 (82%) 75 (63%)
Prior HSCT 23% 41% 41% 24%
Median time from initial diagnosis years 7.4 4.9 1.0 2.0
Median time from last prior therapy weeks 13.0 41.3 8.6 11.6
PHASE 2 NHL DEMOGRAPHICS & DISEASE CHARACTERISTICS
Data as of 6/1/2017Refractory to last regimen defined as SD or PD as best response to most recent prior therapy
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Characteristic Follicular Lymphoma DLBCL
EZH2 Status Mutant Wild-type Mutant Wild-typen 13 54 17 120
Age, median years 62 61 61 69
Males 46% 63% 53% 58%
ECOG PS, median (range) 0 (0 - 2) 0 (0 - 2) 1 (0 - 2) 1 (0 - 2)
Prior lines of therapy, n (%) 1 1 ( 8%) 0 0 3 ( 3%)
2 2 (15%) 11 (20%) 4 (24%) 40 (33%)
3 3 (23%) 9 (17%) 7 (41%) 28 (23%)
4 1 ( 8%) 14 (26%) 3 (18%) 18 (15%)
≥ 5 6 (46%) 20 (37%) 3 (18%) 31 (26%)
median 4 4 3 3
Refractory to last regimen, n (%) 7 (54%) 26 (48%) 14 (82%) 75 (63%)
Prior HSCT 23% 41% 41% 24%
Median time from initial diagnosis years 7.4 4.9 1.0 2.0
Median time from last prior therapy weeks 13.0 41.3 8.6 11.6
PHASE 2 NHL DEMOGRAPHICS & DISEASE CHARACTERISTICS
Data as of 6/1/2017Refractory to last regimen defined as SD or PD as best response to most recent prior therapy
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TAZEMETOSTAT DEMONSTRATED FAVORABLE SAFETY PROFILETreatment-EmergentAdverse Event
Patients (n=210) with:
All TEAEs Treatment-Related TEAEs
All Grades Grade ≥3 All Grades Grade ≥3Nausea 42 (20%) 1 (<1%) 29 (14%) 0
Thrombocytopenia 39 (19%) 19 ( 9%) 28 (13%) 12 ( 6%)
Anaemia 33 (16%) 16 ( 8%) 21 (10%) 9 ( 4%)
Cough 30 (14%) 1 (<1%) 4 ( 2%) 1 (<1%)
Fatigue 26 (12%) 5 ( 2%) 15 ( 7%) 2 ( 1%)
Diarrhoea 24 (11%) 1 (<1%) 17 ( 8%) 1 (<1%)
Asthenia 22 (10%) 3 ( 1%) 16 ( 8%) 1 (<1%)
Neutropenia 21 (10%) 15 ( 7%) 19 ( 9%) 13 ( 6%)
Pyrexia 21 (10%) 1 (<1%) 2 ( 1%) 0
Vomiting 21 (10%) 2 ( 1%) 7 ( 3%) 1 (<1%)
Bronchitis 14 ( 7%) 0 2 ( 1%) 0
Constipation 13 ( 6%) 1 (<1%) 4 ( 2%) 1 (<1%)
Decreased appetite 13 ( 6%) 0 6 ( 3%) 0
Upper respiratory tract infection 13 ( 6%) 0 1 (<1%) 0
Abdominal pain 12 ( 6%) 3 ( 1%) 4 ( 2%) 0
Headache 12 ( 6%) 0 4 ( 2%) 0
Urinary tract infection 12 ( 6%) 0 4 ( 2%) 0
Back pain 11 ( 5%) 2 ( 1%) 1 (<1%) 0
Oedema peripheral 11 ( 5%) 2 ( 1%) 1 (<1%) 0
Dysgeusia 10 ( 5%) 0 7 ( 3%) 0
Rhinitis 10 ( 5%) 0 1 (<1%) 0Data as of 6/1/20171 One (1) TEAEs of Febrile Neutropenia Adverse events reported in ≥5% of patients
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ADVERSE EVENTS LED TO LOW RATE OFDOSE REDUCTIONS AND DISCONTINUATIONS
Patients(n=210)
Treatment-Emergent Adverse Events (TEAEs) *
Treatment-Related TEAEs
Adverse Event (any) 190 (90%) 123 (59%)
Grade ≥ 3 91 (43%) 38 (18%)
Serious AE 81 (39%) 20 (10%)
AE Leading to Dose Interruption 50 (24%) 31 (15%)
AE Leading to Dose Reduction 8 ( 4%) 7 ( 3%)
AE Leading to Drug Discontinuationor Study Withdrawal 26 (12%) 5 ( 2%)
Data as of 6/1/2017* TEAEs are adverse events that first appear during treatment, which were absent before or which worsen relative to the pre-treatment
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TAZEMETOSTAT DEMONSTRATED HIGHER RESPONSE RATES IN EZH2 MUTATED NHL
Best ResponseFL
EZH2 MT(n=13)
FLEZH2 WT(n=54)
DLBCLEZH2 MT(n=17)
DLBCLEZH2 WT(n=119)
Objective Response Rate (CR + PR) 12 (92%) 14 (26%) 5 (29%) 18 (15%)
Complete Response (CR) 1 (8%) 3 (6%) 0 10 (8%)
Partial Response (PR) 11 (85%) 11 (20%) 5 (29%) 8 (7%)
Stable Disease 1 (8%) 23 (43%) 6 (35%) 22 (18%)
SD study drug ongoing 1 (8%) 12 (22%) 1 (6%) 4 (3%)
Progressive Disease 0 13 (24%) 6 (35%) 60 (50%)
No Data, Unknown (UNK) 0 4 (7%) 0 19 (16%)
Time to first Response (wks)median (range)
11.9(6.9 – 35.9)
15.2(8.1 - 32.1)
8.3(4.6 – 48.1)
8.5(5.3 – 24.7)
Data as of 06/1/2017Ongoing patients with Best Response of 'No Data, Unknown' are not included in this table
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TUMOR REDUCTION IN FOLLICULAR LYMPHOMA
75% of patients experienced reduction of tumor burden
Data as of 6/1/201712
DURATION OF TUMOR RESPONSE IN FOLLICULAR LYMPHOMA
Data as of 6/1/2017
48% of patients remain on study
0 5 1510Months Since Treatment Initiation
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TUMOR RESPONSE IN FL WITH MUTATED EZH2cobas® Test Y646F;; NGS Y646F;; ctDNA Y646F
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Baseline
Week 24
68 y.o female
1999
Tazemetostat: week 36+
2017
ChlorambucilPrednisone R-CHOP
2007 2012 20141998
PI3K/mTOR inhibitor
CR CR SD2016
PR at week16
DURATION OF TUMOR RESPONSE IN DLBCL
Data as of 6/1/2017
12% of patients remain on study
0 5 2010 15Months Since Treatment Initiation 15
TUMOR RESPONSE IN DLBCL WITH MUTATED EZH2cobas® Test Y646X;; NGS Y646H;; ctDNA Y646H
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0 2 0 4 0 6 00
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
T im e p o s t t r e a t m e n t , w k
Lesio
n size, SPD
2003
Tazemetostat: week 60+
2016
R-CHOPCarmustineEtoposideCytarabineMelphalan
RituximabEpratuzumab
1999 2005
hA20 Rituximab
2007 2012
LenalidomideObinutuzumab Bendamustine
2014
Baseline Week 24
CR PR PR PR PD SD2017
PR at week 48
61 y.o. male
RESPONSE AFTER INITIAL DISEASE PROGRESSION IN DLBCL NON-GCB (PMBCL)
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Screening Week 8 Week 16
0 8 1 6 2 40
5 0 0 0
1 0 0 0 0
1 5 0 0 0
T im e p o s t t re a tm e n t , w k
Les
ion size, SPD
36 y.o. male
• NGS analysis performed on archive tumor and circulating tumor DNA (ctDNA) for a subset (n = 92) of patients‒ Custom 62 gene panel includes common NHL somatic mutations‒ Responder (CR+PR) vs. Non-Responder analyses‒ Details presented in Poster #154 (Blakemore et al.)
• Results: ‒ Positive and negative predictors for tazemetostat response (PR/CR) identified• Positive predictors = EZH2 & MYD88 activating mutations• Negative predictors = MYC, TP53 and HIST1H1E• EZH2 and MYD88 mutually exclusive in this cohort i.e. potential for independent mechanism of sensitivity to tazemetostat in these patients
‒ Detection of EZH2 mutations in ctDNA indicates potential for future potential use of plasma for patient identification
MOLECULAR PROFILING IDENTIFIES POTENTIAL TAZEMETOSTAT RESPONSE PREDICTORS
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364
421
020406080100
MYD88 MT MYD88 WT
Patients, %
Non-Responder Responder
3
637
18
020406080100
EZH2 MT EZH2 WT
Patients, %
Non-Responder Responder
Data as of 6/1/2017
SUMMARY
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• Tazemetostat shows efficacy in heavily pretreated relapsed/refractory FL and DLBCL‒ Follicular Lymphoma
• 92% ORR in patients with mutated EZH2• 26% ORR in patients with wild-type EZH2 with 22% of patients on-study in SD• 48% overall with treatment ongoing
‒ DLBCL• 29% ORR in patients with mutated EZH2• 15% ORR with 8% CRs in WT patients• Durable responses in both WT and mutants
• Late responses and conversion to CR in both subtypes
• Molecular profiling may help predict response
• Tazemetostat is safe‒ Low incidence of treatment-related grade ≥3, mainly thrombocytopenia (6%) and neutropenia (6%)
• Enrollment of EZH2 mutated DLBCL and FL continues