prezentacja programu powerpoint - pokonaj chłoniaka · 2020-03-14 · prof. wojciech jurczak...
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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.
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
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
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
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…
Prof. Wojciech Jurczak MD,PhD
BCL-2-R
MYC-R
HighBCL-2expression
HighMYCexpression
GCB ABC
Double-hitlymphomas
Double ExpressorLymphomas
Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
Prof. Wojciech Jurczak MD,PhD
Precision medicine – DLBCL
Schmitz et al. NEJM 2018
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),
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),
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
Prof. Wojciech Jurczak MD,PhD
Precision Medicine – DLBCL (Margaret Shipp)
Chapuy et al., Nature Med. @018
Prof. Wojciech Jurczak MD,PhD
Precision Medicine – DLBCL (Margaret Shipp)
Chapuy et al., Nature Med. @018
Prof. Wojciech Jurczak MD,PhD
Próba unifikacji
Prof. Wojciech Jurczak MD,PhD
2016: Revision of the WHO classification of lymphoid neoplasms (HGBCL)
Prof. Wojciech Jurczak MD,PhD
DLBCL – rokowanie w zależności od odpowiedzi na leczenie
Coiffier et al. Ann Oncol 2008 [oral communication; ICML Lugano 2008]
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)
Prof. Wojciech Jurczak MD,PhD
The standard of care in R/R DLBCL
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
Prof. Wojciech Jurczak MD,PhD
Transplant eligible ptients
Friedberg JW. et al. 2011
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
Prof. Wojciech Jurczak MD,PhD
RR-DLBCL: eligible for HDCT-ASCT (CORAL study)
Gisselbrecht C, et al. 2011
Prof. Wojciech Jurczak MD,PhD
RR-DLBCL: eligible for HDCT-ASCT (CORAL study)
Gisselbrecht C, et al. 2011
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”
Prof. Wojciech Jurczak MD,PhD
PREBEN - Pixantrone, Etoposide, Bendamustine (& Rituximab)
Prof. Wojciech Jurczak MD,PhD
PREBEN – real life experience (PLRG)
Danecka et al., Pharmacol. Reports 2019
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
Prof. Wojciech Jurczak MD,PhD
Who should be considered for allo SCT
Prof. Wojciech Jurczak MD,PhD
>2nd relapse DLBCL patients eligible for allo SCT
Prof. Wojciech Jurczak MD,PhD
Ewolucja immunoterapii
MoAb(PrzeciwciałaMonoklonalne)
MoAbsprzężoneZ toksyną lub izotopem Biwalentne
MoAb
CAR T cells ZmodyfikowaneCAR T cells
Prof. Wojciech Jurczak MD,PhD
CAR-T cells – nowe możliwości, nowe wyzwania
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
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
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
Prof. Wojciech Jurczak MD,PhD
ZUMA-1: AxicabtageneCiloleucel (Axi-Cel) in Patients R/R DLBCL
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
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
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
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
Prof. Wojciech Jurczak MD,PhD
Transplant ineligible ptients
Friedberg JW. et al. 2011N=90
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
Prof. Wojciech Jurczak MD,PhD
No standard regimen for R/R DLBCLin transplant ineligible patients
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
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
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.
Prof. Wojciech Jurczak MD,PhD
BTK inhibition in DLBCL – ONO/GS-4509
Walter HS, et al., Blood 2016;127:411–9
Prof. Wojciech Jurczak MD,PhD
R-CHOP +/- ibrutinib in 1 st line NGCB DLBCL
Younes et al. JCO 2019
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
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
Prof. Wojciech Jurczak MD,PhD
Tazemetostat ongoing Phase 2 NHL study design
Salles G, ICML 2017.
Prof. Wojciech Jurczak MD,PhD
Jeszcze raz o immunoterapii ….
MoAb(PrzeciwciałaMonoklonalne)
MoAbsprzężoneZ toksyną lub izotopem Biwalentne
MoAb
CAR T cells ZmodyfikowaneCAR T cells
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.
Prof. Wojciech Jurczak MD,PhD
CD19 antibody MOR208 shows single-agent activity in R/R DLBCL patients
Best overall response Best tumor size reduction
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
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
Prof. Wojciech Jurczak MD,PhD
Salles et al., ASH 2018
L-MIND, phase II trial: MOR 208 + LEN
Prof. Wojciech Jurczak MD,PhD
L-MIND, phase II trial: MOR 208 + LENPrognostic role of NKCC
Salles et al., ASH 2018
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.
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
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)
Prof. Wojciech Jurczak MD,PhD
Polatuzumab vedotin: CD79b target
Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL
Sehn et al; ASH 2017
Prof. Wojciech Jurczak MD,PhD
BR +/- Polatuzumab Vedotin in R/R DLBCL - safety
Sehn et al; ASH 2017
Prof. Wojciech Jurczak MD,PhD
Polarix III phase protocol – completed recruitment
Prof. Wojciech Jurczak MD,PhD
KEYNOTE-170/KEYNOTE-013: Pembrolizumab in R/R PMBCL
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.
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)
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
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
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
Prof. Wojciech Jurczak MD,PhD
www.chloniak.org
Prof. Wojciech Jurczak MD,PhD
www.chloniak.org