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

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.


Leczenie chorych z R/R NHL o wysokim stopniu złośliwości

Prof. dr hab. n. med. Wojciech JurczakCentrum Onkologii – InstytutIm. Marii Skłodowskiej - Curie


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


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


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…


BCL-2-R

MYC-R

HighBCL-2expression

HighMYCexpression

GCB ABC

Double-hitlymphomas

Double ExpressorLymphomas


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),




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),




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


Precision Medicine – DLBCL (Margaret Shipp)

Chapuy et al., Nature Med. @018


Precision Medicine – DLBCL (Margaret Shipp)

Chapuy et al., Nature Med. @018


Próba unifikacji


2016: Revision of the WHO classification of lymphoid neoplasms (HGBCL)


DLBCL – rokowanie w zależności od odpowiedzi na leczenie

Coiffier et al. Ann Oncol 2008 [oral communication; ICML Lugano 2008]


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)


The standard of care in R/R DLBCL


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


• Allogeneic transplantation• CART



• Palliative care

• >2 relapse/progression1

• First relapse/progression1

Potentialycurrativeattempt


Palliative attempt

Palliative attempt`

Palliative attempt


Transplant eligible ptients

Friedberg JW. et al. 2011











• Allogeneic transplantation• CART



• Palliative care




RR-DLBCL: eligible for HDCT-ASCT (CORAL study)

Gisselbrecht C, et al. 2011


RR-DLBCL: eligible for HDCT-ASCT (CORAL study)

Gisselbrecht C, et al. 2011


Jaki jest najlepszy schemat chemioterapii ratującej ?

• R-ESHAP/ R-DHAP

• R-IGEV

• PREBEN

• R-ICE

• .....

CHEMIOTERAPIA

„MINE”

„MINE”

„MINE”

„MINE”

„MINE”

„MINE”


PREBEN - Pixantrone, Etoposide, Bendamustine (& Rituximab)


PREBEN – real life experience (PLRG)

Danecka et al., Pharmacol. Reports 2019











• Allogeneic transplantation,• CART



• Palliative care






Who should be considered for allo SCT


>2nd relapse DLBCL patients eligible for allo SCT


Ewolucja immunoterapii

MoAb(PrzeciwciałaMonoklonalne)

MoAbsprzężoneZ toksyną lub izotopem Biwalentne

MoAb

CAR T cells ZmodyfikowaneCAR T cells


CAR-T cells – nowe możliwości, nowe wyzwania


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


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


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


ZUMA-1: AxicabtageneCiloleucel (Axi-Cel) in Patients R/R DLBCL


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


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


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











• Allogeneic transplantation, • CART



• Palliative care



Palliative attempt`

Palliative attempt

Palliative attempt


Transplant ineligible ptients

Friedberg JW. et al. 2011N=90


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


No standard regimen for R/R DLBCLin transplant ineligible patients


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


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


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.


BTK inhibition in DLBCL – ONO/GS-4509

Walter HS, et al., Blood 2016;127:411–9


R-CHOP +/- ibrutinib in 1 st line NGCB DLBCL

Younes et al. JCO 2019


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


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


Tazemetostat ongoing Phase 2 NHL study design

Salles G, ICML 2017.


Jeszcze raz o immunoterapii ….

MoAb(PrzeciwciałaMonoklonalne)

MoAbsprzężoneZ toksyną lub izotopem Biwalentne

MoAb

CAR T cells ZmodyfikowaneCAR T cells


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.


CD19 antibody MOR208 shows single-agent activity in R/R DLBCL patients

Best overall response Best tumor size reduction


MOR 208 - Synergy with all tested B cell therapies


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


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


Rituximab+ Bendamustine

Rituximab


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


Salles et al., ASH 2018

L-MIND, phase II trial: MOR 208 + LEN


L-MIND, phase II trial: MOR 208 + LENPrognostic role of NKCC

Salles et al., ASH 2018


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.


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


• 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)


Polatuzumab vedotin: CD79b target


BR +/- Polatuzumab Vedotin in R/R DLBCL

Sehn et al; ASH 2017








BR +/- Polatuzumab Vedotin in R/R DLBCL - safety



Polarix III phase protocol – completed recruitment


KEYNOTE-170/KEYNOTE-013: Pembrolizumab in R/R PMBCL


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.


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


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


www.chloniak.org


www.chloniak.org

Documents

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