prezentacja programu powerpoint - pokonaj chłoniaka · 2020-03-14 · prof. wojciech jurczak...
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![Page 1: Prezentacja programu PowerPoint - Pokonaj Chłoniaka · 2020-03-14 · Prof. Wojciech Jurczak MD,PhD ESMO recommendations for R/R DLBCL 1. Tilly H et al. Annals of Oncology 2015;26(Suppl](https://reader034.vdocuments.mx/reader034/viewer/2022042415/5f30104885e20478d1690bdb/html5/thumbnails/1.jpg)
Prof. Wojciech Jurczak MD,PhD
Disclosures
PROF. WOJCIECH JURCZAK, M.D., PH.D.
ADVISORY BOARDS :
SANDOZ NOVARTIS, ROCHE, CELTRION, JANSSEN, ACERTA, ASTRA ZENECA, ABBVIE, TG THERAPEUTICS, TAKEDA, NOVONORDISK, GILEAD, SERVIER
RESEARCH FUNDING:
CELGENE, ABBVIE, GILEAD, TGTHERAPEUTICS, JANSSEN, ACERTA,, MERCK, BEGENE, PHARMACYCLICS, PFIZER, ROCHE, SANDOZ – NOVARTIS, TAKEDA, TEVA,
SERVUIER, DOVA PHARMECEUTICALS, .
A warm welcome to you. And your 39 trillion bacteria.
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Prof. Wojciech Jurczak MD,PhD
Leczenie chorych z R/R NHL o wysokim stopniu złośliwości
Prof. dr hab. n. med. Wojciech JurczakCentrum Onkologii – InstytutIm. Marii Skłodowskiej - Curie
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Prof. Wojciech Jurczak MD,PhD
Chłoniaki o dużej dynamice –duża szansa na całkowite wyleczenie choroby
Chłoniaki indolentne• Przewlekła białaczka limfatyczna• Chłoniak grudkowy• Chłoniak strefy brzeżnej, MALT
Chłoniaki agresywneChłoniak Hodgkina(Ziarnica złośliwa)
Chłoniaki agresywne• Chłoniak rozlany z dużych
komórek B• High grade BCL• PTCL
Chłoniaki o niepewnym rokowaniu• Chłoniak z komórek płaszcza• Szpiczak mnogi
PembrolizumabR/R PMBCL
Pixantrone
CAR-T cells
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Prof. Wojciech Jurczak MD,PhD
DLBCL – wyniki z Mayo Clinic(6-8 x R-CHOP i podobne, 2002 – 2012, N = 1030)
• Wysoko postawiona poprzeczka – trudnobędzie poprawić te wyniki.
• Chorzy uczestniczący w badaniachklinicznych mają lepsze wyniki od obserwowanych w “real life” (również w grupach kontrolnych)
• Wczesna wznowa / oporność na R-CHOP, oznacza niekorzystne rokowanie
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Prof. Wojciech Jurczak MD,PhD
Time (years)
1086420
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Tim
e t
o P
rog
ressio
n
DLBCL – heterogenna grupa chorych
RCHOP insufficient
RCHOP sufficient
➢ Clinical factors• IPI (R-IPI)
➢ GEP• ACB vs GCB
➢ Protein expression• MYC and BCL2
➢ Chromosomal alterations • MYC, BCL2, BCL6
➢ Somatic mutations • MYD88, EZH2…
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Prof. Wojciech Jurczak MD,PhD
BCL-2-R
MYC-R
HighBCL-2expression
HighMYCexpression
GCB ABC
Double-hitlymphomas
Double ExpressorLymphomas
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Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
![Page 8: Prezentacja programu PowerPoint - Pokonaj Chłoniaka · 2020-03-14 · Prof. Wojciech Jurczak MD,PhD ESMO recommendations for R/R DLBCL 1. Tilly H et al. Annals of Oncology 2015;26(Suppl](https://reader034.vdocuments.mx/reader034/viewer/2022042415/5f30104885e20478d1690bdb/html5/thumbnails/8.jpg)
Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
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Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
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Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
Bad prognosis:MCD (MY D88L265P and CD79B mutations), N1 (NOTCH1 mutations),
Good Prognosis:EZB (EZH2 mutations and BCL2 translocations)BN2 (BCL6 fusions and NOTCH2 mutations),
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Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
Bad prognosis:MCD (MY D88L265P and CD79B mutations), N1 (NOTCH1 mutations),
Good Prognosis:EZB (EZH2 mutations and BCL2 translocations)BN2 (BCL6 fusions and NOTCH2 mutations),
![Page 12: Prezentacja programu PowerPoint - Pokonaj Chłoniaka · 2020-03-14 · Prof. Wojciech Jurczak MD,PhD ESMO recommendations for R/R DLBCL 1. Tilly H et al. Annals of Oncology 2015;26(Suppl](https://reader034.vdocuments.mx/reader034/viewer/2022042415/5f30104885e20478d1690bdb/html5/thumbnails/12.jpg)
Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
Bad prognosis: MCD (MY D88L265P and CD79B mutations), Good Prognosis: BN2(BCL6 fusions and NOTCH2 mutations),
rely on “chronic active” B-cell receptor signaling that is amenable to therapeutic inhibition
BTK inhibition in MCD
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Prof. Wojciech Jurczak MD,PhD
Precision Medicine – DLBCL (Margaret Shipp)
Chapuy et al., Nature Med. @018
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Prof. Wojciech Jurczak MD,PhD
Precision Medicine – DLBCL (Margaret Shipp)
Chapuy et al., Nature Med. @018
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Prof. Wojciech Jurczak MD,PhD
Próba unifikacji
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Prof. Wojciech Jurczak MD,PhD
2016: Revision of the WHO classification of lymphoid neoplasms (HGBCL)
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Prof. Wojciech Jurczak MD,PhD
DLBCL – rokowanie w zależności od odpowiedzi na leczenie
Coiffier et al. Ann Oncol 2008 [oral communication; ICML Lugano 2008]
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Prof. Wojciech Jurczak MD,PhD
R/R DLBCL – SCHOLAR-1 study
Crump et al. Blood 2017
Need to identify at dgnthese unfavorable group of patients and improve or change their first line treatment (R-CHOP)
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Prof. Wojciech Jurczak MD,PhD
The standard of care in R/R DLBCL
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Prof. Wojciech Jurczak MD,PhD
ESMO recommendations for R/R DLBCL
1. Tilly H et al. Annals of Oncology 2015;26(Suppl 5): v116–v125.
Eligible for transplant Not eligible for transplant
• Platinum-based chemotherapy regimens(i.e. R-DHAP, R-ICE, R-GDP) as salvage treatment
• For chemosensitive patients: R-HDCT with ASCT as remission consolidation
• Consider allogeneic transplantation in patients relapsed after R-HDCT with ASCT or in patients with poor-risk factors at relapse
• Platinum and/or gemcitabine-based regimens
• Clinical trials with novel drugs
Eligible for transplant Not eligible for transplant
• Allogeneic transplantation• CART
• Clinical trials with novel drugs
• Clinical trials with novel drugs
• Palliative care
• >2 relapse/progression1
• First relapse/progression1
Potentialycurrativeattempt
Potentialycurrativeattempt
Palliative attempt
Palliative attempt`
Palliative attempt
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Prof. Wojciech Jurczak MD,PhD
Transplant eligible ptients
Friedberg JW. et al. 2011
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Prof. Wojciech Jurczak MD,PhD
ESMO recommendations for R/R DLBCL
1. Tilly H et al. Annals of Oncology 2015;26(Suppl 5): v116–v125.
Eligible for transplant Not eligible for transplant
• Platinum-based chemotherapy regimens(i.e. R-DHAP, R-ICE, R-GDP) as salvage treatment
• For chemosensitive patients: R-HDCT with ASCT as remission consolidation
• Consider allogeneic transplantation in patients relapsed after R-HDCT with ASCT or in patients with poor-risk factors at relapse
• Platinum and/or gemcitabine-based regimens
• Clinical trials with novel drugs
Eligible for transplant Not eligible for transplant
• Allogeneic transplantation• CART
• Clinical trials with novel drugs
• Clinical trials with novel drugs
• Palliative care
• >2 relapse/progression1
• First relapse/progression1
![Page 23: Prezentacja programu PowerPoint - Pokonaj Chłoniaka · 2020-03-14 · Prof. Wojciech Jurczak MD,PhD ESMO recommendations for R/R DLBCL 1. Tilly H et al. Annals of Oncology 2015;26(Suppl](https://reader034.vdocuments.mx/reader034/viewer/2022042415/5f30104885e20478d1690bdb/html5/thumbnails/23.jpg)
Prof. Wojciech Jurczak MD,PhD
RR-DLBCL: eligible for HDCT-ASCT (CORAL study)
Gisselbrecht C, et al. 2011
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Prof. Wojciech Jurczak MD,PhD
RR-DLBCL: eligible for HDCT-ASCT (CORAL study)
Gisselbrecht C, et al. 2011
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Prof. Wojciech Jurczak MD,PhD
Jaki jest najlepszy schemat chemioterapii ratującej ?
• R-ESHAP/ R-DHAP
• R-IGEV
• PREBEN
• R-ICE
• .....
CHEMIOTERAPIA
„MINE”
„MINE”
„MINE”
„MINE”
„MINE”
„MINE”
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Prof. Wojciech Jurczak MD,PhD
PREBEN - Pixantrone, Etoposide, Bendamustine (& Rituximab)
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Prof. Wojciech Jurczak MD,PhD
PREBEN – real life experience (PLRG)
Danecka et al., Pharmacol. Reports 2019
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Prof. Wojciech Jurczak MD,PhD
ESMO recommendations for R/R DLBCL
1. Tilly H et al. Annals of Oncology 2015;26(Suppl 5): v116–v125.
Eligible for transplant Not eligible for transplant
• Platinum-based chemotherapy regimens(i.e. R-DHAP, R-ICE, R-GDP) as salvage treatment
• For chemosensitive patients: R-HDCT with ASCT as remission consolidation
• Consider allogeneic transplantation in patients relapsed after R-HDCT with ASCT or in patients with poor-risk factors at relapse
• Platinum and/or gemcitabine-based regimens
• Clinical trials with novel drugs
Eligible for transplant Not eligible for transplant
• Allogeneic transplantation,• CART
• Clinical trials with novel drugs
• Clinical trials with novel drugs
• Palliative care
• >2 relapse/progression1
• First relapse/progression1
Potentialycurrativeattempt
Potentialycurrativeattempt
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Prof. Wojciech Jurczak MD,PhD
Who should be considered for allo SCT
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Prof. Wojciech Jurczak MD,PhD
>2nd relapse DLBCL patients eligible for allo SCT
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Prof. Wojciech Jurczak MD,PhD
Ewolucja immunoterapii
MoAb(PrzeciwciałaMonoklonalne)
MoAbsprzężoneZ toksyną lub izotopem Biwalentne
MoAb
CAR T cells ZmodyfikowaneCAR T cells
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Prof. Wojciech Jurczak MD,PhD
CAR-T cells – nowe możliwości, nowe wyzwania
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Prof. Wojciech Jurczak MD,PhD
CD19 Chimeric Antigen Receptor (CAR)-T-cell therapies in R/R DLBCL
CD19 Ab
CD28/4-1BBCD3ζ
Gene transfer
Lentivirus RetrovirusRetrovirus
UPennCD19-BB-z
NCIFMC63-28z
MSKCC19-28z
CD3ζ CD3ζ CD3ζ
CD28 4-1BB CD28
Axi-cel CTL19 JCAR017
scFv
TM
SignallingDomain
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Prof. Wojciech Jurczak MD,PhD
CD19 CAR-T-cell therapies in R/R DLBCL
CONFIDENTIAL 34
Axi-cel1ZUMA-1
CTL19²JULIET
JCAR017³TRANSCEND NHL001
Pts (pheresed/ treated) 111/101 147/111 134/114
Age median (range) 58 (23–76) 56 (24-75) 61(29-82)
ECOG 0-1 64% 100% 87%
Stage III-IV 85% NA NA
Prior therapies
Median (range) 64% with ≥3 lines Median 3 (2-7) Median 3 (1-11)
Refractoriness77% refractory* to
≥2nd line76% chemorefractory+
Prior ASCT 21% 51% 44%
1. Neelapu et al. ICML 2017; 2. Schuster et al. ICML 2017; 3. Abramson et al. ASCO 2017
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Prof. Wojciech Jurczak MD,PhD
CD19 CAR-T-cell therapies in R/R DLBCL patients –Summary of preliminary efficacy and safety
35
Axi-cel1
ZUMA-1n=101
Tisagenlecleucel²JULIETn=51
JCAR017³TRANSCEND
n=54
Best ORR 82% 59% 76%
Best CR 54% 43% 52%
Median DoR 8.2 mo na 9 mo
Median Follow-up 8.7 mo na na
Ongoing Responses 39% (31% CR) 37% (CRs) na
1. Neelapu et al. ICML 2017; 2. Schuster et al. ICML 2017; 3. Abramson et al. ASCO 2017
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Prof. Wojciech Jurczak MD,PhD
ZUMA-1: AxicabtageneCiloleucel (Axi-Cel) in Patients R/R DLBCL
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Prof. Wojciech Jurczak MD,PhD
ZUMA-1 Study Schema
Axi-Cel Infusion2 × 106 CAR+ cells/kg
Manufacturing Day 0 Day 28
Cyclophosphamide 500 mg/m2 + fludarabine 30
mg/m2 for 3 days
Leukapheresis
First Tumor AssessmentScreening
Day 7
Follow-Up Period (posttreatment assessment and
long-term follow-up)
HospitalizationPeriod
Conditioning Chemotherapy
No bridging therapy allowed
Day -5 to Day -3
Neelapu SS, et al. New Engl J Med. 2017;377(26):2531-2544
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Prof. Wojciech Jurczak MD,PhD
2-Year Follow-Up and High-Risk Subset Analysis of ZUMA-1, Axicabtagene Ciloleucel (Axi-Cel) in Patients R/R DLBCL
Sattva S. Neelapu et al. - Poset 2967 ASH 2018
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Prof. Wojciech Jurczak MD,PhD
2-Year Follow-Up and High-Risk Subset Analysis of ZUMA-1, Axicabtagene Ciloleucel (Axi-Cel) in Patients R/R DLBCL
Sattva S. Neelapu et al. - Poset 2967 ASH 2018
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Prof. Wojciech Jurczak MD,PhD
ESMO recommendations for R/R DLBCL
1. Tilly H et al. Annals of Oncology 2015;26(Suppl 5): v116–v125.
Eligible for transplant Not eligible for transplant
• Platinum-based chemotherapy regimens(i.e. R-DHAP, R-ICE, R-GDP) as salvage treatment
• For chemosensitive patients: R-HDCT with ASCT as remission consolidation
• Consider allogeneic transplantation in patients relapsed after R-HDCT with ASCT or in patients with poor-risk factors at relapse
• Platinum and/or gemcitabine-based regimens
• Clinical trials with novel drugs
Eligible for transplant Not eligible for transplant
• Allogeneic transplantation, • CART
• Clinical trials with novel drugs
• Clinical trials with novel drugs
• Palliative care
• >2 relapse/progression1
• First relapse/progression1
Palliative attempt`
Palliative attempt
Palliative attempt
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Prof. Wojciech Jurczak MD,PhD
Transplant ineligible ptients
Friedberg JW. et al. 2011N=90
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Prof. Wojciech Jurczak MD,PhD
No standard regimen for R/R DLBCLin transplant ineligible patients
◆ PECC - prednisone, etoposide, chlorambucil, lomustin+/-R
◆ CEPP - cyclophosphamide, etoposide, prednisone, procarbazine+/-R
◆ CEOP - cyclophosphamide, etoposide, vincristine, prednisone +/-R
◆ GDP - gemcitabine, dexamethasone, carboplatin +/-R
◆ GemOX - gemcitabine, oxaliplatin+/-R
◆ Bendamustine+/-R
◆ Lenalidomide+/-R
◆ Lenalidomide + MOR 208
◆ Palliative RT
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Prof. Wojciech Jurczak MD,PhD
No standard regimen for R/R DLBCLin transplant ineligible patients
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Prof. Wojciech Jurczak MD,PhD
Pathway Target Drug
Response rate
DLBCL FL MCL SLL/CLL
T-Cell HL
PI3K/AKT/mTOR
mTOREverolimus 30% 50% 32% 18% 63% 42%
Temsirolimus 36% 56% 38% 10% - -
AKT MK2206 0% 25% 9% (50%) 0% 20%
PI3KδIdelalisib - 57% 40% 72% - 12%
TGR-1202 11% 42% 33% 63% - 13%
PI3K-γδ IPI-145 0% 67% 67% 54% 33% 33%
PI3K-αδBAY80-6946 13% 40% 71% 67% 50% -
BKM120 12% 25% 23% - - -
B-Cell receptor (BCR)Syk Fostamatinib 22% 10% 11% 55% 0% -
Btk Ibrutinib 26% 28% 75% 67% - -
Apoptosis Bcl-2 Venetoclax 15% 28% 75% 77%
Immune checkpoint PD1Nivolumab 36% 40% - - - 87%
Pembrolizumab - - - - - 66%
Molecular targets and drugs in R/R lymphoma
Presented By Anas Younes at 2016 ASCO Annual Meeting
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Prof. Wojciech Jurczak MD,PhD
Molecular driven therapy: R-CHOP + Novel drugs
New Agent Mechanism
Lenalidomide Immunomodulator
Bortezomib Proteasome inhibitor
Everolimus mTOR inhibitor
Panobinostat HDACs inihibitor
Ibrutinib BTK inhibitor
Tamatinib Inhibitors of Syk in B-cell signaling pathway
EnzastaurinPKCβ-selective
inhibitors
ABT 199Pro-apoptotic ABT-263
Bcl-2 family
SELINEXORSelective inhibitor ofnuclear export (SINE)
ABC
Proteasomeinhibitors
BTK inhibitors
Immunomodulators
GCB
Histone modifiers
BCL2 inhibitors
PTEN/PI3K
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Prof. Wojciech Jurczak MD,PhD
ORR, 37% in ABCvs. 5% in GCB DLBCL
BTK inhibition in DLBCL –Ibrutinib
46
BCR=B-cell receptor.Wilson WH et al. Nat Med. 2015;21(8):922-926.
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Prof. Wojciech Jurczak MD,PhD
BTK inhibition in DLBCL – ONO/GS-4509
Walter HS, et al., Blood 2016;127:411–9
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Prof. Wojciech Jurczak MD,PhD
R-CHOP +/- ibrutinib in 1 st line NGCB DLBCL
Younes et al. JCO 2019
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Prof. Wojciech Jurczak MD,PhD
Genetics and pathogenesis of DLBCL
R Schmitz et al.: N Eng J Med. 2018: 378: 1396-1407
MCD MYD88, CD79B
BN2 BCL6, NOTCH2
N1 NOTCH1
EZB EZH2, BCL2
Genetic aberrations thatdistinguish genetic subtypesof DLBCL
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Prof. Wojciech Jurczak MD,PhD
EZH2 Activating Mutations and Other Genetic Lesions in Follicular Lymphoma and DLBCL
Adapted from Basso et al, NRI, 2015
Activated B cell-like (ABC) DLBCL
GC B cell-like (GCB) DLBCLFollicular lymphoma
• EZH2 activation• Ga13 pathway inactivation• Ectopic expression of BCL2
and/or MYC
• EZH2 activation• MLL2 inactivation
• Constitutive NF-kB activation
• PRDM1 inactivation
• CREBBP or EP300 inactivation• MLL2 inactivation• Constitutive BCL6 expression• Immune escape
EzH2
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Prof. Wojciech Jurczak MD,PhD
Tazemetostat ongoing Phase 2 NHL study design
Salles G, ICML 2017.
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Prof. Wojciech Jurczak MD,PhD
Jeszcze raz o immunoterapii ….
MoAb(PrzeciwciałaMonoklonalne)
MoAbsprzężoneZ toksyną lub izotopem Biwalentne
MoAb
CAR T cells ZmodyfikowaneCAR T cells
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Prof. Wojciech Jurczak MD,PhD
CD19: Role and therapeutic target
• CD19 plays a key role in B-cell:– Development1
– Proliferation1
– Signalling1
• CD19 enhances B-cell antigen receptor (BCR) signalling2-4
– CD19 amplifies PI3K and BTK activity2-4
• CD19 expression is maintained despite loss of CD20 expression following treatment with CD20 antibodies2
Therefore, CD19 appears an attractive target for new therapeutic approaches to B-cell malignancies
1. Katz B-Z and Herishanu Y. Leukemia & Lymphoma 2014; 55:999–1006; 2. Fujimoto M, et al. Semin Immunol 1998;10:267-77;3.Fujimoto M, et al. Immunity 2000;13:47-57; 4. Poe JC, et al. J Immunol;2012:2318-25.
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Prof. Wojciech Jurczak MD,PhD
CD19 antibody MOR208 shows single-agent activity in R/R DLBCL patients
Best overall response Best tumor size reduction
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Prof. Wojciech Jurczak MD,PhD
MOR 208 - Synergy with all tested B cell therapies
Prof. Wojciech Jurczak MD,PhD
ADCC
ADCP
MOR 208 - Synergy with all tested B cell therapies
Synergy in vitro + in vivoSynergy in vitro
Fludarabine
Effector cell activation
Inhibition of DNA Replication
OfatumumabRituximab
Lenalidomide
Bendamustine
ADCC, CDC
Direct cytotoxicity
DNA Alkylation
Novel Agents (IdelalisibVenetoclax)
Inhibition of Pi3K/BCL signaling, apoptosis, LN ‚clearance‘
L-MIND II phase trial in R/R DLBCL
B-MIND III pase trial in R/R DLBCL
COSMOS phase II study in R/R CLL
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Prof. Wojciech Jurczak MD,PhD
MOR208 as combination partner: Ongoing trialsin Non-transplant eligible R/R DLBCL patients
MOR208 + Lenalidomide
MOR208
Cycle 1 – 12 Until PD, max. 24 cycles
L-MIND1
NCT02399085; recruitment ongoing
B-MIND2
NCT02763319; recruitment ongoing
Best overall response (preliminary*)1
MOR208 + Bendamustine
MOR208
Cycle 1 – 6 Until PD, max. 24 cycles
Rituximab+ Bendamustine
Rituximab
Cycle 1 – 6 Until PD, max. 24 cycles
ORR:56%
*Updated results to be presented at EHA 2017.1. Maddocks et al. ASCO 2017; 2. Nowakowski et al. ASCO 2017.
[Phase III part of B-MIND opened for recruitment in June 2017]
1:1
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Prof. Wojciech Jurczak MD,PhD
Salles et al., ASH 2018
L-MIND, phase II trial: MOR 208 + LEN
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Prof. Wojciech Jurczak MD,PhD
L-MIND, phase II trial: MOR 208 + LENPrognostic role of NKCC
Salles et al., ASH 2018
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Prof. Wojciech Jurczak MD,PhD
Second generation immunomodulatorLenalidomide -/+ CD20 in R/R DLBCL
Single-agentlenalidomide(Phase II/III)1
No. ofpatients N=51
ORR 28%
CR 10%
Median PFS,weeks
13.6
Lenalidomide+ rituximab(Phase II)2
Lenalidomide+ obinutuzumab
(Phase II)3
Lenalidomide+ MOR208 (Phase II;
preliminary data)4
No. ofpatients
N=32
ORR 28%
CR 22%
Median PFS,months
3.7
No. ofpatients
N=71
ORR 45%
CR 16%
Median PFS,months
4.1
No. ofpatients
N=34
ORR 56%
CR 32%
Median PFS,months
N/A
1. Czuczman MS, et al. Clin Cancer Res 2017; doi: 10.1158/1078-0432.CCR-16-2818; 2. Wang M, et al. Leukemia 2013;27:1902–1909; 3. Morschhauser F, et al. ASH 2016; 4. Maddocks KJ, et al. ASCO 2017.
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Prof. Wojciech Jurczak MD,PhD
ROBUST study (I Line DLBCL)
• At a median follow-up of 27.1 mo (range, 0-47), the primary endpoint of PFS was not met (medians not reached)
• ORR and CR rates were high in both arms
• Median time from diagnosis to treatment was 31 days for each arm
PFS RatesR2-CHOP(n = 285)
Placebo/R-CHOP(n = 285)
1-y 77% 75%
2-y 67% 64%
91%
69%
91%
65%
0%
20%
40%
60%
80%
100%
ORR CR
Be
st R
esp
on
se R
ate
, %
R2-CHOP
Placebo/R-CHOP
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Prof. Wojciech Jurczak MD,PhD
• Positive trends for PFS favoring R2-CHOP over placebo/R-CHOP were observed in patients with IPI score ≥ 3
65
IPI = 2 IPI ≥ 3
POBUST study (I Line DLBCL)
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Prof. Wojciech Jurczak MD,PhD
Polatuzumab vedotin: CD79b target
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Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
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Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
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Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
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Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL - safety
Sehn et al; ASH 2017
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Prof. Wojciech Jurczak MD,PhD
Polarix III phase protocol – completed recruitment
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Prof. Wojciech Jurczak MD,PhD
KEYNOTE-170/KEYNOTE-013: Pembrolizumab in R/R PMBCL
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Prof. Wojciech Jurczak MD,PhD
Phase II KEYNOTE-170/KEYNOTE-013: Pembrolizumab in R/R PMBCL - Baseline Characteristics
CharacteristicKEYNOTE-013
(N = 21)KEYNOTE-170
(N = 53)
Median age, yrs (range) 31 (22-62) 33 (20-61)
Female, n % 14 (67) 30 (57)
Prior transplant, n (%) 8 (38) 14 (26)
Median prior therapies, n (range) 3 (2-9) 3 (2-8)
Prior radiation, n (%) 15 (71) 17 (32)
Prior rituximab, n (%) 21 (100) 53 (100)
Armand. ASH 2018. Abstr 228.
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Prof. Wojciech Jurczak MD,PhD
Phase II KEYNOTE-170/KEYNOTE-013: Pembrolizumab in R/R PMBCL - efficacy
Characteristic, n (%)
KEYNOTE-013
(N = 21)
KEYNOTE-170†
(N = 53)
OR▪ CR▪ PR
10 (48)7 (33)3 (14)
24 (45)7 (13)
17 (32)
SD 5 (24) 5 (9)
PD 4 (19) 12 (23)
Nonevaluable/ no assessment*
2 (10) 12 (23)
Armand. ASH 2018. Abstr 228.
CharacteristicKEYNOTE-
013(N = 21)
KEYNOTE-170
(N = 53)
Median duration of follow-up, mos
29.1 12.5
Median time to response, mos
2.7§ 2.8ǁ
PFS▪ 12-mo, %▪ Median, (range)
4710.4 months
(3.4-NR)
385.5 months (2.8-12.1)
OS▪ 12-mo, %▪ Median, (range)
6531.4 months
(4.9-NR)
58NR months
(7.3-NR)
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Prof. Wojciech Jurczak MD,PhDLesokhin AM, et al. J Clin Oncol 2016;34:2698–2704.
DLBCL
N 11
OR 4/11 (36%)
CR 2/11 (18%)
PFS (weeks) 7 (6-29)
• Phase I, open-label, dose-escalation, cohort-expansion study
• Patients received anti–PD-1 monoclonal antibody nivolumab at 1 or 3 mg/kg every 2 weeks
• Study evaluated nivolumab safety and efficacy andPD-L1/PD-L2 locus integrity and protein expression
Anti-PD1 in aggressive NHL
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Prof. Wojciech Jurczak MD,PhD59th ASH Annual Meeting 2017, LYM1002 Study, Younes A, et al. Abstract #833. Funded by Janssen Research & Development, LLC.
Ibrutinib + NivolumabEfficacy: Diffuse Large B-Cell Lymphoma
n (%)DLBCL
(n = 45)
ORR,a,b 16 (36)
CR 7 (16)
PR 9 (20)
SD 6 (13)
PDc 19 (42)
Missing 4 (9)
aORR includes CR and PR.bLugano classification.cData not available for 3 patients (PD based on clinical progression).
Evaluable: DLBCL (n = 38)
Maximum Decrease in Target Lesions
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Prof. Wojciech Jurczak MD,PhD
R/R DLBCL - podsumowanie
• Im lepsze są wyniki leczenia I rzutu, tym gorzej rokują chorzy ze wznową/ opornością procesu
• Małe prawdopodobieństwo wieloletnich remisji chorych leczonych „chemioterapią ratującą”, spadek znaczenia ASCT
• Male prawdopodobieństwo wieloletnich remisji chorych leczonych lekami o alternatywnym do cytosatatyków mechanizmach działania, w monoterapii można się w większości przypadków spodziewać jedynie PR czy SD, optymalne schematy w których kojarzy się 2-3 leki nie są jeszcze znane (za to na pewną są niezwykle kosztowne)
• Kwestie jakości życia i efektów działań niepożądanych
• Nadzieje jakie wiąże się z nowoczesną immunoterapią, CAR-T cells, Allo (MUD) SCT
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Prof. Wojciech Jurczak MD,PhD
www.chloniak.org
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Prof. Wojciech Jurczak MD,PhD
www.chloniak.org