Treatment of DLBCL

Andy Davies

Chair UK National Caner Research Institute High-Grade Lymphoma Sub-Group

ESMO Preceptorship Programme: Lymphoma

Lugano Nov 2018

1 DISCLOSURE OF INTEREST

Celgene: Research funding; Advisory Board; Honorarium Roche : Advisory Boards; Honorarium; Research support Gilead : Advisory Boards; Honorarium; Research support Takeda : Advisory Boards; Honorarium; Research support, Travel to scientific conferences CTI : Advisory Boards; Honorarium; Travel to scientific conferences GSK : Research support Bayer : Research support Janssen : Honorarium; Research support Karyopharma : Advisory Board; Research support Pfizer : Research support; Honorarium Acerta Pharma : Research funding and Advisory Board Kite Pharma: Advisory Board DLBCL

Haematological Malignancies Research Network 2017 DLBCL is a curable disease

Overall survival: UK R-CHOP 14 vs 21

1.0 2-year OS: 81% (95% CI: 78%-84%) 0.8

0.6

0.4

0.2 Events Totals 150 1080 0.0 0 6 12 18 24 30 36 42 48 PATIENTS at Risk Months from randomisation 1080 834 621 434 278 134 61 8 0

Cunningham, J Clin Oncol (2009) 27:15s, Real World Data

Haematological Malignancies research Network 2017 CHOP PLUS RITUXIMAB VS. CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE LARGE-B- CELL LYMPHOMA

CHOP CHEMOTHERAPY PLUS RITUXIMAB COMPARED WITH CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE LARGE-B-CELL LYMPHOMA

BERTRAND COIFFIER , M.D., E RIC LEPAGE , M.D., P H.D., J OSETTE BRIÈRE , M.D., R AOUL HERBRECHT , M.D., H ERVÉ TILLY , M.D., R EDA BOUABDALLAH , M.D., P IERRE MOREL , M.D., E RIC VAN DEN NESTE , M.D., G ILLES SALLES , M.D., P H.D., PHILIPPE GAULARD , M.D., F ELIX REYES , M.D., AND CHRISTIAN GISSELBRECHT , M.D. The benefit of rituximab is maintained over time

GELA LNH-98.5 10-year follow-up 1.00

0.75

0.50

0.25 Overall survival Overall

0.00 0 2 4 6 8 10 12 Time (years) Arm A: CHOP Arm B: CHOP + Rituximab Coiffier B et al. Blood 2010;116:2040-2045 We are going to talk about:

• Risk adapted approach to DLBCL management.

• Tailoring therapy according to genotypes/phenotypes of DLBCL that have been explored to date.

• Is the Cell-of-Origin classification ready for therapeutic stratification? We are NOT going to talk about:

• Approaches to particular anatomical sites (eg CNS, testis, bone..).

• Management of limited stage disease.

• The difficult problem of elderly patients with DLBCL, where physiology may reduce tolerability of immunochemotherapy.

• Those patients where co-morbidities may require modification of our standard approaches. Revision to WHO classification 2016

Diffuse large B-cell (NOS) Germinal Centre B-cell type Activated B-cell type T-cell/histiocyte rich large B-cell Primary DLBCL of central nervous system Primary cutaneous DLBCL leg type EBV+ DLBCL, NOS EBV+ mucocutaneous ulcer Primary mediastinal lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Plasmablastic lymphoma High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement

Swerdlow et al. Blood 2016 There is clear heterogeneity in clinical outcomes

IPI

Age greater than 60 years Stage III or IV disease Elevated serum LDH ECOG > 2 More than 1 extranodal site

Age adjusted IPI

Stage LDH Performance status

Ziepert at al. J Clin Oncol 28:2373-2380. ESMO Guidelines

Young (age <61)

aaIPI=0 no bulk aaIPI=1/aaIPI=0 +bulk aaIPI>2

R-CHOP 21 x6 R-ACVBP + consolid. R-CHOP 21 x8 R-CHOP 21 x6 + IFRT R-CHOP 14 x6 +Rx2 (to bulk) R-CHEOP14 x6 R-ACVBP + HDT R-CHOP14 +HDT Clinical trial

Tilly et al. 2015 Annals of Oncol, 26,116–125 No clear standard in this group Is there much yet to be achieved with conventional chemotherapy ? Probably not….. Intensified regimens…might they hold the answer?

Fisher RI, et al . N Engl J Med1993; 328:1002– 006. Dose Density: UK R-CHOP14 vs. 21

n=540 R-CHOP21 CHOP21 × 8 cycles × Newly Rituximab 8 cycles diagnosed R CD20+ve DLBCL n=540 R-CHOP14 CHOP14 × 6 cycles Stratified by Rituximab × 8 cycles • IPI (0-1, 2, 3, 4-5) Lenograstim Day 4-12 • Age ≤60 vs. >60 • Treatment centre 1080 patients; 119 sites Recruitment March 2005 - Nov 2008

Cunningham, D, et al. Lance t 2013; 381:1817–1826. R-CHOP14 vs 21: no difference in outcome

Progression -free survival

Overall survival

Cunningham, D, et al. Lance t 2013; 381:1817–1826. R-CHOP14 vs 21: no subgroup could be identified

Cunningham, D, et al. Lance t 2013; 381:1817–1826. Other ways of improving dose intensity: GELA LNH03-2B

Young (age 18-59) aa IPI 1 n=380 Median age 47 55% stage III/IV, 44% bulk

Recher C, et al Lancet 2011: 378:1858-18676. Improved outcome in R-ACVBP arm

Recher C, et al Lancet 2011: 378:1858-18676. ► Improvement in EFS, PFS and OS ► Outcome of R-CHOP x 8 arm inferior to those observed in MInT with R-CHOP x 6 ► Excess utilisation of healthcare resource ► Excess of toxicity

R-ACVBP R-CHOP Toxicity (grade >3) Neutropenia 78% 64% Anemia 35% 5% Thrombocytopenia 30% 3% Febrile neutropenia 38% 9% Toxic deaths (n) 3 2

Recher C, et al Lancet 2011: 378:1858-1867. Phase III Randomized Study of R-CHOP vs. DA-EPOCH-R and Molecular Analysis of Untreated Large B-Cell Lymphoma: CALGB/Alliance 50303

Wyndham H. Wilson, Sin-Ho Jung, Brandelyn N. Pitcher, Eric D.Hsi, Jonathan Friedberg, Bruce Cheson, Nancy L. Bartlett , Scott Smith, Nina Wagner-Johnston, Brad S. Kahl, Louis M. Staudt, Kristie A. Blum, Jeremy Abramson, Oliver W. Press, Richard I. Fisher, Kristy L. Richards, Heiko Schoder, Julie E. Chang, Andrew D. Zelenetz, John P. Leonard

Abstract 469, American Society of Hematology, Dec 4, 2016 50303 Event Free Survival 0.6 0.8

Probability event free event Probability Median follow-up 5.0 y HR=1.14 (0.82-1.61) R-CHOP p = 0.4386 DA-EPOCH-R 0.0 0.2 0.4 0 1 2 3 4 5 Years from Study Entry Arm N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP 233 64 0.81 (0.75-0.85) 0.69 (0.62-0.75) DA-EPOCH-R 232 70 0.79 (0.73-0.84) 0.66 (0.59-0.72) Increasing dose intensity…High dose therapy

Greb A, et al. Cancer Treat Rev 2007; 33: 338–346 Survival Rates among All Eligible Patients Who Underwent Randomization. …may improve PFS for poorer prognosis patients (not OS)

All patients high or high-intermediate IPI

PFS OS

Similar findings in Italian DLCL04 Study Chiappella Lancet Oncol 2017

Stiff PJ et al. N Engl J Med 2013;369:1681-1690 Intensification of therapy based in interim PET…

PETAL Trial

Aggressive lymphoma (DLBCL n=606)

R-CHOP-14 x2

Interim PET negative positive

A2 A1 R-CHOP14 x4 B1 B2 R-CHOP14 x4 + Rx2 R-CHOP14 x6 B-ALL

Duehrsen et al. Blood 128:1857 We should be capitalising on biological insights

Integrative Genetic and Clinical Analysis through Whole Exome Sequencing in 1001 Diffuse Large B Cell Lymphoma (DLBCL) Patients Reveals Novel Disease Drivers and Risk Groups

Zhang et al ASH 2016 and Reddy Cell 2017 Overall survival of R-CHOP-treated patients in Lunenburg analysis

Salles G et al. Blood 2011;117:7070-7078 Application of complex models of biological heterogeneity

Wright, George et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9991-9996 But how to distinguish phenotype?

► Getting it right is important when looking prospectively at therapy, not prognosis ► The immunophenotype is not that good: ► CD10+ (about 1/3), Mum-1-: Almost all GCB ► CD10- (2/3) hard to distinguish ABC from GCB on immuno’s ► Bcl-6 is a difficult stain ► Discordance with mRNA (~20%) ► Conflicting IHC datasets ► Lunenberg project demonstrates poor correlation between centres (technical and interpretative)

Hans, C. P. et al. Blood 2004;103:275-282 Lots of different IHC Algorithms…

Rita Coutinho et al. Clin Cancer Res 2013;19:6686-6695 Other emerging platforms Deeper biological insights

A Reddy et al., 2017; R Schmitz et al., 2018 B Chapuy et al., 2018 Cell, 171:481-494 N Engl J Med;378:1396-1407. Nat Med; 24:679–690 A new taxonomy

MCD/Cluster 5

ABC N1

BN2/Cluster 1 DLBL UNC Cluster 2

GCB Cluster 4

Cluster 3/EZB Microenvironment Surface markers

EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab

CD20

CD80 GA-101 • HeaderT-cell exhaustion First level bold bullet: text… Anti CD40 moAb • Dacetuzumab ActionableFirst level mutations bold old bullet • Anti CD22 - SecondCD79a/b level bullet Epratuzumab EZH2 Inotuzumab Ozogamicin AEB071 E7438- Third level bullet Pathways polatuzumab - Third level bullet mTOR inhibitors HDAC inhibitors Proteosome inhibitors Everolimus Second level bullet Vorinostat - Bortezomib Temsirolimus Panobinostat - PI3K inhibitors Bcl-2 family Idelalisib PKC inhibitors • Header Copanlisib Enzastaurin inhibitors Duvelisib • First levelABT-263 bullet: text… TGR-1202 Aurora kinase Survivin inhibitors Btk inhibitors inhibitors YM155 Ibrutinib ONO/GS-4059 Nedd8-activating ACP-196 References… Syk inhibitors enzyme inhibitors …Footnote Fostamatinib Hsp 90 inhibitors MLN4924 entosplentib KW 2478 Microenvironment Surface markers

EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab

CD20

International, open-label, randomized Phase III study in 1L DLBCL pts • Scientific support from the Fondazione Italiana Linfomi ` Previously untreated DLBCL G-CHOP arm • Age ≥18 years G 1000mg C1 D1/8/15 and C2–8 D1 • IPI ≥2 or IPI 1 not due to age alone or IPI CHOP 6 or 8 cycles every 21 days 0 with bulky disease (one lesion ≥7.5cm) Randomized • Adequate hematologic function 1:1 • ≥1 bi-dimensionally measurable lesion R-CHOP arm • ECOG PS ≤2 R 375mg/m 2 C1–8 D1 • Target enrolment: 1400 CHOP 6 or 8 cycles every 21 days

• Number of CHOP cycles pre-planned in advance for all pts at each site • Randomization stratification factors: planned number of CHOP cycles, IPI, geographic region

Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537 36 Investigator-assessed PFS (primary endpoint)

Kaplan-Meier plot of investigator-assessed PFS by treatment arm R-CHOP, G-CHOP, n=712 n=706 1.0 Pts with event, 215 201 0.8 n (%) (30.2) (28.5) 1-yr PFS, % 79.8 81.6 0.6

0.4 2-yr PFS, % 71.3 73.4 Probability

0.2 R-CHOP (n=712) 3-yr PFS, % 66.9 69.6 G-CHOP (n=706) 0 HR (95% CI), 0.92 (0.76, 1.11), 0 6 12 18 24 30 36 42 48 54 60 p-value* p=0.3868 Time (months) No. of patients at risk Median follow-up: 29 months R-CHOP 712 616 527 488 413 227 142 96 41 6 G-CHOP 706 622 540 502 425 240 158 102 39 2

*Stratified analysis; stratification factors: IPI score, number of planned chemotherapy cycles

Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537 37 Microenvironment Surface markers

EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab

CD20

• Immunomodulatory properties • Modulation of both cellular and cytokine tumour cell microenvironment • Activates T cell and NK response to tumour cell • Down regulates pro-survival cytokines • Enhanced ADCC activity with rituximab

Chanan-Khan, A. A. et al. J Clin Oncol; 26:1544-1552 2008 Differential response according to cell of origin in DLBCL (n=40). Retrospective review.

Response rates Progression-free survival

Hernandez-Ilizaliturri et al. Cancer 2011 Can over come the adverse outcome of ABC phenotype….

R-CHOP R2-CHOP

Grzegorz S. Nowakowski et al. JCO 2015;33:251-257 ROBUST Clinical Study Design: Phase III double blind

6 x R-CHOP21 + Lenalidomide 15 mg x 14* n=280 ABC R 6 x R-CHOP21 + Placebo x 14* n=280 DLBCL Select by GEP *Option for 2 additional rituximab doses after completing treatment regimen (if considered standard of care per local practice )

GCB, unclassified Ineligible

° Newly diagnosed DLBCL of ABC type ° IPI ≥ 2; ECOG PS ≤ 2; Age 18–80 ° Primary Endpoint = PFS ° N = 560 ClinicalTrials.gov.NCT02285062 REMARC: Lenalidomide maintenance (aaIPI>1; 60-80 yrs)

Thieblemont et al. JCO 2017 36% patients discontinued PFS OS therapy as a result of toxicity (vs 16% placebo)

72% required a dose reduction

55% aged <70..? Fit for an alternative approach

PET positive at end

Thieblemont et al. JCO 2017 of induction had greatest benefit (HR=0.59 vs 0.78) Microenvironment Surface markers

EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab

CD20

• The nuclear factor-kB (NF-kB) pathway is constitutively activated in ABC DLBCL 1

• The proteasome inhibitor bortezomib is a potent inhibitor of NF-ĸB2; may therefore have specific utility in non-GCB Ruan J et al. J Clin Oncol. 2011;29(6):690-697 DLBCL and overcoming the negative prognosis associated with non-GCB phenotype 3,4 1Davis RE et al. J Exp Med. 2001;194(12):1861-1874. 2Bu R et al. Leuk Lymphoma. 2014; 55(2):415-424. 3Ruan J et al. J Clin Oncol. 2011;29(6):690-697. 4Dunleavy et al. Blood. 2009; 113(24):6069-6076. 46 Progression-free survival: Treatment arm and phenotype

ABC: N=244 GCB: N=475 Unc. N=199

71.6% 75.8% 68.2%

64.7% 72.9% 67.8%

HR=0.792, p=0.309 HR=0.873, p=0.458 HR=1.096, p=0.729

Davies et al ICML 2017 How about targeting BTK?...no

• Schaffer A L, et al. 2012. Ann. Rev. Immunol 30:565-610 Ibrutinib: Activity in ABC

Wilson et al 2015 PHEONIX Clinical Study Design: Double blind randomised phase III

6 x R-CHOP21 + ibrutinib

Non-GC R 6 x R-CHOP21 + Placebo

Select by DLBCL IHC *Option for 2 additional rituximab doses after completing treatment regimen (if considered standard of care per local practice )

GC Ineligible

° Newly diagnosed DLBCL of non-GC ° ECOG PS ≤ 2; Age 18–80 ° Primary Endpoint = EFS ° N = 800 ClinicalTrials.gov.NCT02285062 <65 EFS OS

>65 EFS OS

Younes et al. ASH 2018 Top line… • 67.7% had ABC subtype. In receipt of >6 Age Ibr + R-CHOP R-CHOP cycles <65 90.4% 91.1% >65 69.0% 90.0%

• Ibr + RCHOP did not improve EFS in pts with non-GCB (by IHC) or ABC (by GEP) DLBCL: (HR) for EFS was 0.934 (95%CI: 0.726-1.200) for non-GC and 0.949 (95% CI, 0.704-1.279) for ABC • SAEs were greater in the ibr + RCHOP vs pbo + RCHOP arm (53.1% vs 34.0%), particularly febrile neutropenia and pneumonia, • In pts ≥ 65 yrs, there were more SAEs (67.4% vs 40.6%). In pts < 65 yrs, grade ≥ 3 AEs were similar. The paradigm for study design….don’t change practice yet

R-CHOP Biological and DLBCL R clinical stratification R-CHOP+X

Ongoing X= Lenalidomide Ibrutinib Can we practically Bortezomib deliver this design in Brentuximab phase III with so many Everolimus agents? Tazemetostat More to come… Events occur early…

Overall survival from Overall survival from diagnosis 2 years event free

Maurer M J et al. JCO 2014;32:1066-1073 Primary Refractory Early relapse Late relapse

Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest

Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT Primary Refractory Early relapse Late relapse

Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest

Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT PARMA Trail (Phillip NEJM 1995)

• PARMA study (n=215 aggressive relapsed disease)

• 109 demonstrated chemosenstivity after DHAP x2: randomised DHAP x4 more or BEAC + ABMT

• OS 53 vs 32% at 5 years (P=0.038)

• Time to relapse (< or > 12 months most important prognostic factor, along with second line aaIPI and response to salvage PR vs CR Evolving Standards of Care in Non-Hodgkin’s Lymphoma clinicaloptions.com/oncology Guideline Recommendations for Treatment of Relapsed DLBCL ° Second-line therapy in candidates ° Second-line therapy for patients who for high-dose therapy + ASCT are not candidates for high-dose therapy – DHAP ± rituximab – Clinical trial – ESHAP ± rituximab – Rituximab – GDP ± rituximab – CEPP ± rituximab – GemOx ± rituximab – Lenalidomide – ICE ± rituximab – EPOCH ± rituximab – MINE ± rituximab

NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. High Dose Chemotherapy plus ASCT: CORAL trial experience

Gisselbrecht C et al, JCO 2010 Gisselbrecht C et al. JCO 2010;28:4184-4190

Friedberg 2011 ORCHARRD Van Imhoff et al JCO 2016 Value of pre-auto PET

Van Imhoff et al JCO 2016 Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.. Fenske et al. BJH 2016

n=503 Median age 51 Primary Refractory Early relapse Late relapse

Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest

Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT R-GemOX in R/R DLBCL

Mournier er al. Pixantrone..real world experience (Eyre et al 2016)

92 R/R DLBCL 85% refractory disease 72% had an international prognostic index (IPI) 3–5 Median PFS 2·0 months (95% confidence interval (CI) 1·5–2·4 Median OS was 3·4 months (95% CI 2·7–4·5). ORR 24% (complete response 10%; partial response 14%). Microenvironment Surface markers

EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab

CD20

Polatuzumab Vedotin

Target CD79b

Goy A, et al. Blood . 2010;116(21): Abstract 430. DLBCL: PFS and OS significantly longer with Pola-BR

Progression Free Survival Overall Survival % Patients % Patients %

Months Months

Sehn et al. EHA 2018 71 Adverse Events at Rate ≥20% by Treatment Group 1

BR Pola-BR Neutropenia Nausea Grade Diarrhea 1 Peripheral neuropathy 2 Grade Fatigue 2 Grade Thrombocytopenia 3 Anemia Grade Pyrexia 4 Decreased appetite 40 30 20 10 00 10 20 30 40 50 60

° SAEs occurred more frequently in pola-BR (33% BR vs 55% pola-BR) – Most common were infections (18% vs 23%) and febrile neutropenia (3% vs 12%)

1Combined DLBCL and FL cohorts 2Peripheral neuropathy reported by MedRA SMQ (Standardized MedRa Query)

Sehn et al. EHA 2018 72 CAR-T CAR-T cell manufacturing process

Apheresis to product release <21 days ASH 2017 update: Strange and difficult names… Name Company Abstract Trial Specifiction

Axibcabtagene Gilead/KITE No. 577 ZUMA-1 CD28 signal Ciloleucel Schuster et al Tisagenlecleuc Novartis No. 578 JULIET Lentiviral el Neelapu et al transduction 41BB signal Lisocabtagene Juno / Celgene No. 581 TRANSCEND 41BB signal Maraleucel Abramson et NHL-001 al Zuma-1 DOR

3/7 (43% ) phase 1 patients have ongoing CR at 24 months Neelapu et al (2017) NEJM ZUMA-1: Safety

30% patient remain in response without detectable T-cells A molecular precision approach to DLBCL?...almost

• Don’t think of DLBCL as one disease

• There are challenges in defining molecular sub-groups in a timely fashion and the appropriate diagnostic platform.

• Targeted therapies may potentially change the landscape of therapy for DLBCL...not yet. Next year it may be different.

• Much still needs to be proved and phase III studies are needed (no matter how difficult)…

• We need to better refine the molecular heterogeneity and to continue to better exploit our new knowledge of the biology.