[PPT] - How I treat high risk DLBCL in first line? Greg Nowakowski, MD PowerPoint Presentation

SLIDE 1 Rochester, Minnesota

Greg Nowakowski, MD Director, Aggressive Lymphoma Program Mayo Clinic

How I treat high risk DLBCL in first line?

SLIDE 2

DLBCL Outcomes in Mayo Clinic Lymphoma SPORE Database

SLIDE 3 Time (years) 10 8 6 4 2 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 Time to progression

Heterogeneity of outcomes in DLBCL

Two broad strategies:

Target both subgroups

– possibly overtreating RCHOP “sufficient group”

Target RCHOP “insufficient” group

provided

– it can be identified – It cab be targeted

RCHOP insufficient RCHOP sufficient

SLIDE 4 Time (years) 10 8 6 4 2 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 Time to progression

Heterogeneity of outcomes in DLBCL

Clinical factors

– IPI (R-IPI)

Interim PET scan
GEP

– ACB vs GCB

Protein expression

– MYC and BCL2

Chromosomal alterations

– MYC, BCL2, BCL6

Deep sequencing

mutation/combined expression analysis RCHOP insufficient RCHOP sufficient

SLIDE 5

Double hit lymphoma

“High grade B-cell lymphoma (HGBL)

with MYC and BCL2 and/or BCL6 rearrangements” - entity in the 2016 revision of the World Health Organization Classification of Lymphoid Neoplasms

Rearrangements as opposed to

expression

Outcomes have been reported to be

poor

Swerdlow SH, Campo E, Pileri SA, et al. Blood. 2016;127:2375-2390. J Clin Onc 2012 Oct 1; 30(28): 3452–3459.

SLIDE 6

MYC, BCL2, and BCL6

MYC is a transcription factor:

– Involved in cell cycle regulation, DNA damage repair, metabolism, protein synthesis, and response to stress – MYC rearranged in 7-12% of DLBCL; GCB or ABC subtype – In normal cells MYC activates the TP53 pathway

1/3 of MYC-rearranged DLBCL’s have concurrent TP53

inactivating mutations

BCL2 has an anti-apoptotic function

– BCL2 rearranged in 14-21% of DLBCL; GCB subtype

BCL6 is a transcription repressor

– Overexpression prevents apoptosis – BCL6 rearranged in 23-32% of DLBCL; ABC or GCB subtype – Does not inhibit TP53

SLIDE 7

Mayo Clinic Lymphoma Database DHL/THL, Event-Free Survival and Overall Survival (n=100)

Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

SLIDE 8

Not All DH/THL Are Created Equal

Event Free Survival (EFS) of Newly Diagnosed vs. Transformation Patients

Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

P=0.0008

SLIDE 9

EFS by Treatment

P=0.10

Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

SLIDE 10

EFS Age < 60 Years by Treatment

P=0.11

Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

SLIDE 11

Phase III study of R-CHOP vs DA-EPOCH-R in patients with untreated DLBCL (CALGB/Alliance 50303)

R-CHOP 6 cycles DA-EPOCH-R 6 cycles

Key eligibility criteria (N=524)

Age ≥18 years
Stage II or higher newly

diagnosed DLBCL (Stage I PMBCL)

ECOG PS 0–2
Fresh/frozen tumor biopsy

(4 cores)

R A N D O M I Z E 1:1 Bartlett, Wilson et al. ASH 2016. Abstract 469.

Study schema Event-free survival

Years from Study Entry Probability event free 1 2 3 4 5 0.0 0.2 0.4 0.6 0.8 R-CHOP DA-EPOCH-R Median follow-up 5.0 years HR=1.14 (0.82–1.61) p=0.4386 +

SLIDE 12

Transplant in DH/THL

Landsburg DJ et al. ASH 2016

SLIDE 13

How do I treat DHL frontline?

Patients <60 yo R-CODOX-M/IVAC
> 60 RCHOP, RCHOP with ASCT consolidation or DAEPOCH-R

Current US Intergroup Study

DLBCL Select by GEP – real time DHL Double “expresser” Ineligible DAEPOCH-R+ venetoclax DAEPOCH-R R 6 x R-CHOP21 R-CHOP21 + ventoclax R

SLIDE 14

DLBCL Molecular Subtypes

Two major molecular subtypes:

Activated B-cell like (ABC)

–B-cell receptor driven

Germinal center B-cell like (GCB)

Lenz et al. N Engl J Med 2008;359:2313–2323.

SLIDE 15

Pathways with therapeutic potential in ABC DLBCL

Figure from: Roschewski et al. Nat Rev Clin Oncol 2014;11:22–25.

SLIDE 16

XR-CHOP(s)

What X?

Bortezomib: Bor-RCHOP (Phase 2/3)
Ibrutinib: IR-CHOP (Phase 3)
Everolimus: EveR-CHOP (Phase 1b)
Lenalidomide: R2-CHOP (Phase 3)

SLIDE 17

PYRAMID: Non-GCB DLBCL

Prospective randomized, open-label, Phase II study Treatment-naïve, non-GCB DLBCL by Hans IHC with measurable disease, ECOG PS 0–2 (N=183) Bortezomib 1.3 mg/m2 i.v. Days 1, 4 + R-CHOP* 21 days x 6 cycles (n = 92) R-CHOP* 21 days x 6 cycles (n = 91) Leonard JP, et al. Blood 2015;126:811a. (Updated data presented in oral presentation at ASH annual meeting) VR-CHOP, bortezomib, rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone.

Limits:

Patient selection in the PYRAMID trial may

have played a role  R-CHOP alone produced better outcomes than expected

IHC based on Hans algorithm
2-year PFS: 78% R-CHOP vs 82% VR-CHOP

– HR (95% CI): 0.73 (0.43–1.24); p=0.611

PFS Study design

Patients at risk: R-CHOP VR-CHOP PFS probability Time to event (months) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 5 10 15 20 25 30 35 50 55 60 65 70 75 40 45 91 92 72 75 65 72 61 66 57 61 50 51 37 38 28 27 5 7 2 2 2 1 22 24 15 13 Treatment group: Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP R-CHOP (N=91) 25% Events VR-CHOP (N=92) 18%

SLIDE 18 DASL, cDNA-mediated annealing, selection, extension and ligation; HMDS, Haematological Malignancy Diagnostic Service.

REMoDL trial

Con- sent

Biopsy sent to HMDS for molecular profiling

R- CHOP #1 Rando- misation Stratified for molecular phenotype and IPI

5 x R-CHOP + bortezomib 1.3 mg/m2 days 1+8 5 x R-CHOP Patients with DLBCL in need

f full

course

f R-

CHOP (stage IIAx-IV)

Davies AJ, et al. ICML 2017. Abstract 121. Updated data presented at ICML. HR=0.841, p=0.225

74.3% 70.1% ABC: N=244 GCB: N=475

SLIDE 19

DLBCL Molecular Subtypes and Outcomes

Lenz et al. N Engl J Med 2008;359:2313–2323.

SLIDE 20

Investigator-assessed PFS by Cell of Origin*

*Exploratory analysis; COO classification determined for 933 pts by gene expression profiling assay (Nanostring); missing COO classifications due to: restricted Chinese export license, n=252; CD20+ DLBCL not confirmed, n=102; missing/inadequate tissue, n=131; PFS HR=0.82 (0.64, 1.04) in pts with COO classification; PFS HR=1.18 (0.85, 1.64) in pts without COO classification

Kaplan-Meier plot of investigator- assessed PFS by COO

ABC, n=243 GCB, n=540 Unclassified, n=150 Pts with event, n (%) 92 (37.9) 129 (23.9) 54 (36.0) 2-year PFS, % 66.4 78.0 65.9 3-year PFS, % 59.3 75.0 63.2 HR (95% CI) ABC vs GCB Unclassified vs GCB 1.70 (1.30, 2.23) 1.57 (1.14, 2.16) 243 540 150 209 480 128 174 417 111 161 398 103 144 344 86 78 207 64 52 139 42 32 96 25 13 41 9 2 3 1 Probability

No. of patients at risk

ABC GCB Unclassified 6 12 18 24 30 36 42 48 54 Time (months) 1.0 0.8 0.6 0.4 0.2 ABC (n=243) GCB (n=540) Unclassified (n=150) Censored 60 Vitolo et al. ASH 2016. Abstract 470.

SLIDE 21

Phoenix: Study schema

DLBCL Select by IHC – real time Non-GCB GCB Ineligible 6 to 8 x R-CHOP21* + ibrutinib 560 mg daily N=400 6 to 8 x R-CHOP21 + placebo daily N=400 *Option for 2 additional cycles if considered standard of care per local practice R ClinicalTrials.gov Identifier: NCT02285062.

Newly diagnosed DLBCL of non-GCB type
IPI ≥ 2; ECOG PS ≤ 2; Age >18
Primary Endpoint = EFS
N = 800

SLIDE 22

Phoenix: Study schema

DLBCL Select by IHC – real time Non-GCB GCB Ineligible 6 to 8 x R-CHOP21* + ibrutinib 560 mg daily N=400 6 to 8 x R-CHOP21 + placebo daily N=400 *Option for 2 additional cycles if considered standard of care per local practice R

Newly diagnosed DLBCL of non-GCB type
IPI ≥ 2; ECOG PS ≤ 2; Age >18
Primary Endpoint = EFS
N = 800

ClinicalTrials.gov Identifier: NCT02285062. Press release available from: https://www.jnj.com/janssen-provides-update-on-imbruvica-ibrutinib-phase-3-phoenix-trial-in-newly-diagnosed-non-germinal-center-b-cell-non-gcb-subtype-of- diffuse-large-b-cell-lymphoma-dlbcl

SLIDE 23

Phase II studies of lenalidomide R-CHOP (R2-CHOP) in front-line DLBCL

N=64 ORR 98% CR 80% N=44 ORR 92% CR 86% Nowakowski et al. J Clin Oncol 2015;33:251–257; Vitolo et al. Lancet Oncol 2014;15:730–737.

SLIDE 24

Long Term Results of R2CHOP: Combined Analysis of Two Phase 2 Studies (n=108)

1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Event-Free 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Event-Free Censor 77.4 (69.4-86.4%) 5 Years 25/107 OS 69.9 (61.2-79.9%) 5 Years 31/106 TTP 65.4 (56.6-75.5%) 5 Years 38/106 PFS KM Est (95% CI) Time-Point Events/Total Outcome

Castellino et al. ASCO, 2018, In Press

Overall Survival by COO (IHC) 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive Censor Logrank P-value: 0.3327 71.7 (59.2-86.9%) 5 Years 15/45 GCB 75.3 (62.3-91.1%) 5 Years 9/40 Non-GCB KM Est (95% CI) Time-Point Events/Total COO Overall Survival by COO (Nanostring) 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive Censor Logrank P-value: 0.6580 79.0 (60.4-100.0%) 5 Years 3/15 Unclassified 76.0 (62.0-93.2%) 5 Years 10/30 GCB 74.8 (57.5-97.3%) 5 Years 5/22 ABC KM Est (95% CI) Time-Point Events/Total Nanostring

SLIDE 25

DLBCL RCHOP R2CHOP

1:1 Stratification

Age
IPI

GCB vs non-GCB tissue analysis:

GEP - NanoStrings
IHC - Hans and other algorithms

Tissue Efficacy analysis based on DLBCL subtype

ClinicalTrials.gov Identifier: NCT01856192.

E1412: R2CHOP vs RCHOP

N=346 Accrual met January 2017 50 ABC patients per arm

R

SLIDE 26

DLC-002 (ROBUST) study schema

Phase III, randomised, double-blind, placebo controlled, multicenter study to compare the efficacy and safety of lenalidomide plus R-CHOP chemotherapy (R2-CHOP) versus placebo plus R-CHOP chemotherapy in subjects with previously untreated ABC type DLBCL

DLBCL

Select by GEP – real time

ABC GCB, unclassified Ineligible Stratification:

Age (≥65 years)
Bulky disease (≥7 cm)
IPI (2 vs 3)

6 x R-CHOP21 + lenalidomide 15 mg x 14* n=280 6 x R-CHOP21 + placebo x 14* n=280

*Option for two additional rituximab doses after completing treatment regimen (if considered standard of care per local practice)

R

ClinicalTrials.gov Identifier: NCT02285062.

Newly diagnosed DLBCL of

ABC type

IPI ≥2; ECOG PS ≤2;

age 18–80 years

Primary endpoint = PFS
N=560

SLIDE 27

ROBUST Subtype Analysis Results

No. of Patients Screened (N = 2093)
No. of Patient Samples (n = 2113)

Successfully tested samples (n = 1798) 44% ABC (n = 788) 27% Enrolled (n = 570) 56% Non-ABC (n = 1010) Non-processable samples (n = 315)

Improper sample submission

99 (31%) Duplicate test cancellation
72 (23%) Insufficient amount of tissue for testing†
39 (12%) Insufficient tumor surface area or tumor cellularity
19 (6%) Incorrect sample, slides, or specimen type

Technical difficulties

80 (25%) RNA testing criteria not met*
6 (2%) System failure or testing cancelled in error

*RNA concentration and/or purity did not meet criteria or low RNA signal at hybridization step. †Tissue/block from site was small core or tissue biopsy, block from site nearly exhausted, insufficient slide numbers, or no tissue or tumor on slides.

Chiappella et al. EHA 2018 Median turnaround time for identification of DLBCL subtype was 2.4 days

SLIDE 28 28

Figure 7. COO by Geographic Region

ABC 60% Non- ABC 40% Russia/ Europe/ Middle East

Belgium
Czech Republic
France
Ireland
Israel
Italy
Netherlands
Poland
Portugal
Russia
Spain
Switzerland
Turkey

North America/ Australia/ New Zealand

United States
Canada
Puerto Rico
Australia
New Zealand

Asia/PAC

China
Japan
South Korea
Taiwan

ABC 37% Non- ABC 63% ABC 40% Non- ABC 60% (241/404) (441/1105) (106/289)

Nowakowski et al. ASCO 2018, Chiappella et al. EHA 2018

Geography and COO in ROBUST Trial

SLIDE 29

How do I treat ABC DLBCL?

R-CHOP remains standard of care

SLIDE 30

PFS/EFS in Recent Trials

CALGB GOYA HOVON

10 8 6 4 2 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

TTF BCCA Population >1200 pts

Bartlett, Wilson et al. ASH 2016. Abstract 469; Vitolo U, et al. J Clin Oncol. 2017 Nov 1;35(31):3529-3537; Lugtenburg PJ, et al. ASCO Annual Meeting 2016, abstract 7504 – updated data presented at ASCO; Sehn LH, and Gascoyne RD, Blood. 2015 Jan 1;125(1):22-32.

SLIDE 31

PFS in non-GCB and ABC DLBCL in Recent Trials

Remodel B GOYA PYRAMID

Davies AJ, et al. ICML 2017. Abstract 121. Updated data presented at ICML; Vitolo U, et al. J Clin Oncol. 2017 Nov 1;35(31):3529-3537; Leonard JP, et al. Blood 2015;126:811a. (Updated data presented in oral presentation at ASH); Lenz et al. N Engl J Med 2008;359:2313–2323.

SLIDE 32

Signor Presto and Signor Lento

67 yo male
Newly diagnosed non-GCB DLBCL

stage 4

LDH 800
Extranodal bone and liver

involvement

ECOG PS2
IPI 4
Large abdominal mass with
bstructive symptoms, biliary
bstruction requiring stenting
Initiated urgently on RCHOP in the

hospital

67 yo male
Newly diagnosed non-GCB DLBCL

stage 4

LDH 400
Extranodal bone and lung

involvement

ECOG PS2
IPI 4
Screened; path centrally reviewed and

GEP – ABC - successfully enrolled in

ngoing clinical trial
Initiated on XRCHOP trial

SLIDE 33

Time from Diagnosis to Treatment Mayo and LYSA

Maurer, Nowakowski JCO, 2018

SLIDE 34

Time from Diagnosis to Treatment and Outcome

Maurer, Nowakowski JCO, 2018

SLIDE 35

Time From Diagnosis to Initiation of Treatment, IPI and Outcomes in DLBCL

Maurer MJ, et al. ASH 2016. Abstract 3034.

Unpublished data

SLIDE 36

Time From Diagnosis to Initiation of Treatment, ABC by GEP and Outcomes in DLBCL

Maurer MJ, et al. ASH 2016. Abstract 3034.

Unpublished data

SLIDE 37

New Prognostic Factor – Urgency of Therapy

Patients with urgent need of therapy (signore preste) have

poor outcomes

–< 14 days –Regardless of IPI and COO

These patients are frequently excluded from clinical trials

–Need for inclusive clinical trials including allowing for pretreatment, cycle 1 of therapy, poor PS and labs

SLIDE 38

Near Future of DLBCL Therapy – XRCHOP Precision Medicine Approach

Several X candidates
X likely DLBCL

subtype specific (ABC) – X in non-GCB (ABC) DLBCL) – Y-RCHOP in GCB DLBCL

Newly dx DLBCL ABC X-RCHOP GCB Y-RCHOP “Double hit” ? Intensive chemotherapy with novel agents Unclassified and composite ?

SLIDE 39

Near Future of DLBCL Therapy – XRCHOP Precision Medicine Approach

Several X candidates
X likely DLBCL

subtype specific (ABC) – X in non-GCB (ABC) DLBCL) – Y-RCHOP in GCB DLBCL

Newly dx DLBCL ABC X-RCHOP GCB Y-RCHOP “Double hit” ? Intensive chemotherapy with novel agents Unclassified and composite ? Classify according to GEP

SLIDE 40

How Do I Treat High Genomic Risk DLBCL

Nat Med 18:2018: 679–690 N Engl J Med 2018;378:1396-407. Nat Med 9:2016: 218–221

SLIDE 41

How Do I Treat High Genomic Risk DLBCL

Nat Med 18:2018: 679–690 N Engl J Med 2018;378:1396-407. Nat Med 9:2016: 218–221

R-CHOP

SLIDE 42

Thank you nowakowski.grzegorz@mayo.edu