New Developments in Lymphoma Therapy Sven De Vos, MD, Phd UCLA Lymphoma Program Los Angeles

Arrowhead 2018

New Developments in Lymphoma Therapy Sven de Vos, MD, PhD UCLA Lymphoma Program Los Angeles

SdV Sept 2018 Conflict of Interest

• Salary: none • Royalty: none • Receipt of Intellectual Property Rights/Patent Holder: none • Consulting Fees (e.g., advisory boards): Verastem • Fees for Non-CME Services Received Directly from a Commercial Interest or their Agents (e.g., speakers’ bureau): none • Contracted Research: none • Ownership Interest (stocks, stock options or other ownership interest excluding diversified mutual funds): none • Other: none

SdV Sept 2018 DLBCL Advancing Treatment in the Genomic Era

(Lenz et al. JCO, 2007, Lam et al. Clin Can Res. 2005, Hans et al. Blood. 2004, Rosenwald et al. NEJM. 2002, Ngo et.al Nature 2006, Davis J. Exp Med 2001) Double-Hit vs. Double-Expresser DLBCL

SdV Sept 2018 (Dunleavy et al., ICML Lugano, 2015) 2016 Revision of the WHO classification: New Category High-grade B-cell lymphoma (HGBL

HGBL

HGBL with MYC and BCL2 and/or BCL6 rearrangements

HGBL not otherwise specified

 Frequency of MYC/BCL2 DHL is approximately 10% of all DLBCL  Patients with HGBL should be enrolled into clinical trials

SdV Sept 2018 (Li et al., Expert Review of Hematology 2018; 11: 637–648) Genetically-Defined DLBCL Subsets Arise By Distinct Pathogenetic Mechanisms and Predict Outcome

. Comprehensive analysis of DLBCL with whole exome sequencing (WES) • mutations, copy number alterations (CNAs), structural variants (SVs)

. N=304 newly Dx DLBCL (R-CHOP) • Total of 158 SMGs (98), CNAs and SVs • Most exome mutations caused by spontaneous deamination at CpGs (c/w aging) • Most frequently rearranged genes: IGH (40%), BCL2 (21%), BCL6 (19%), MYC (8%) • SMGs more likely to reside within focal CNAs, c/w multiple mechanisms

• Individual DLBCLs had a median of 17 genetic drivers!!

. Integrated clustering approach: 5 genetically distinct DLBCL subtypes

. ABC, good risk genetic features of possibly marginal zone origin . ABC, poor risk frequent BCL2 gain and concordant MYD88L265P/CD79B mut . GCB, good risk pathway alterations in BCR/PI3K, JAK/STAT and BRAF and multiple histones . GCB, poor risk BCL2 SVs, alterations of PTEN and epigenetic enzymes . COO-independent biallelic inactivation of TP53, 9p21.3/CDKN2A and associated genomic instability

SdV Sept 2018 (Chapuy et al., ASH 2017, abstract # 38) Chromosomal rearrangements in primary DLBCLs - BCL2, BCL6, and MYC -

SdV Sept 2018 (Chapuy et al., Nature Med 2018, 24: 679- 690 ) Identification of groups of tumors with coordinate genetic signatures

Cluster 1 ABC - good risk

Cluster 2 COO-independent biallelic TP53 inactivation

Cluster 3 GCB - poor risk

Cluster 4 GCB - good risk

Cluster 5 ABC - poor risk

SdV Sept 2018 (Chapuy et al., Nature Med 2018, 24: 679- 690 ) Genetics and Pathogenesis of DLBCL

. Exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing . N=574 newly Dx DLBCL

. Four prominent genetic subtypes in DLBCL . MCD MYD88L265P and CD79B mutations “chronic active” . BN2 BCL6 fusions and NOTCH2 mutations B-cell receptor signaling . N1 NOTCH1 mutations . EZB EZH2 mutations and BCL2 translocations

SdV Sept 2018 (Schmitz et al., NEJM 2018, 378:1396-1407) Genetic Aberrations Targeting Oncogenic Signaling Pathways in DLBCL

SdV Sept 2018 (Schmitz et al., NEJM 2018, 378:1396-1407) Moving forward…

. More global approach to DLBCL classification, focusing much more on pathways than single gene abnormalities (Schmitz et al. and Chapuy et al.)

. Complexity of DLBCLs, median of 17 different genetic alterations per tumor

. Key genetic features included mutations, SCNAs, and SVs

. All three types of alterations needed to capture disease heterogeneity and outcome differences

. The new genetic subtypes will guide the development of rational single-agent and combination therapies in patients with the greatest need

SdV Sept 2018 Rand., double-blind, placebo-controlled ph3 study of Ibrutinib in comb. BTK with R-CHOP in newly diagnosed non-GCB DLBCL (PHOENIX)

ACCURAL COMPLETE

Sub-typing Regimen GCB DLBCL Ø

Newly Central R-CHOP diagnosed Lab 48 hrs DLBCL Non-GCB Randomized DLBCL R-CHOP + Ibrutinib . N=800 non-GCB DLBCL . Primary endpoint: EFS 6 cycles Q 3weeks . Study aims at improving Ibrutinib: 560 mg QD the cure rate by 10%

Press release (July 11, 2108) . Missing the primary endpoint. No improved EFS. . “Clinically meaningful improvements were observed in a patient subpopulation that warrant further analysis.”  Update at ASH 2018

SdV Sept 2018 (Clinicaltrials.gov: NCT01855750) Synthetic Lethal Therapy of ABC DLBCL

Rationale for Ibrutinib + Lenalidomide combination

SdV Sept 2018 (Yang et al., Cancer Cell 2012, 21:723) A Multicenter Open-Label, Randomized Phase 1b/2, Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Lenalidomide, with and without Rituximab in Subjects with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PCYC-1123-CA)

UCLA trial open

Chemotherapy free novel combination

Phase 1b:

• Determine MTD • N ~ 48 patients • All types of rel/refr DLBCL

Phase 2:

• Evaluate efficacy, identify signaling pathways or Ibrutinib + Lenalidomide biomarkers that predict response to Ibrutinib • N = 150 patients Randomization • Rel/refr de novo non-CGB DLBCL 1:1 Ibrutinib + Lenalidomide • s/p ASCT or not candidate for ASCT + • No transformed DLBCL Rituximab • No CNS involvement Ibrutinib daily Lenalidomide days 1-21 on 28 day cylce Rituximab day 1 per cycle (cycle 1-6)

 Update at ASH 2018

SdV Sept 2018 LEN R2CHOP in untreated DLBCL compared to R-CHOP

R-CHOP R2-CHOP

(Grzegorz S. Nowakowski et al. JCO 2015;33:251-257) ROBUST (NCT02285062) . Lenalidomide + R-CHOP vs Placebo Plus R-CHOP in 1st line ABC-DLBCL, Phase 3, double-blind, placebo-controlled (completed enrollment)

REMARC . Lenalidomide vs Placebo in elderly patients with DLBCL. No survival benefit.

SdV Sept 2018 A Phase II, Single-Arm, Open-Label, Multicenter Study to Evaluate the CD19 Safety and Efficacy of Lenalidomide Combined with MOR00208 in Patients with Relapsed or Refractory DLBCL TRIO-US trial completed enrolment

Inclusion: Fc-engineered, humanized, CD19 antibody • DLBCL, Transformed DLBCL • ineligible for HDC and ASCT MOR00208 (anti CD19) + MOR00208: Lenalidomide • Dose: 12 mg/kg, 28-day cycles. • Study Duration • Cycles 1-3: Day 1, Day 8, Day 15 and Day 22 • Thereafter bi-weekly • MOR00208 for up to 24 months • LEN up to 12 months Lenalidomide: • 25 mg oral LEN daily on Days 1–21 of each cycle • LEN may be modified in a de-escalating fashion Oct. 23 2017: Results: FDA Breakthrough Therapy • 31 of 80 planned pts Designation for MOR208 in • ORR 58% with CR 27% R/R DLBCL in combination • median follow-up 3.3 months with Lenalidomide • AE > gr3 neutropenia (26%), thrombocytopenia (6%),  Update at ASH 2018 infections (10%), rashes (6%) SdV Sept 2018 (Maddocks, et al., ASCO 2017; # 7514) CC-122 CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Model of CC-122 co-stimulation of T cells and tumoricidal activity

. CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity . Binds CRBN and degrades Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL . Cell-of-origin independent anti-lymphoma activity

SdV Sept 2018 (Hagner et al., Blood 2015; 126: 779-789) Study of Safety and Efficacy of CC-122 Combined With RCHOP for CC-122 Newly-diagnosed DLBCL With Poor Risk Factors

TRIO-US trial planned

Newly Both diagnosed subtypes R-CHOP DLBCL eligible + CC-122 Poor-risk GCB Non-GCB avadomide IPI ≥ 3 DLBCL DLBCL 6 cycles Q 3

Phase 1 • Safety and phase 2 dose

Phase 2 • ORR when adding avadomide (CC-122) to R-CHOP-21

Principal Investigator: Sven de Vos, MD

SdV Sept 2018 (Clinicaltrials.gov: NCT03283202) Bcl-2 Phase Ib/II – CAVALLI: R/G-CHOP + venetoclax

TRIO-US trial completed enrolment Dose escalation cohorts Phase II cohort

Arm A R-CHOP + VEN N~160–200 R-CHOP + VEN N=12–24

Two major goals: Arm B G-CHOP + VEN N=12–24 1. DLBCL Phase III planning 2. Focus on Bcl-2/MYC DE • Patients: – Escalation: mixed histology NHL – Phase II: previously untreated DLBCL, IPI 2–5 • Cohorts: R-CHOP or G-CHOP + venetoclax designed at 4 dose escalation levels: 200mg, 400mg, 600mg, 800mg – 800mg in Phase II • Phase II: R-CHOP arm aims to enroll: – 50+ DE patients – ~40 patients in each additional subset (subgroup-specific efficacy data for Phase III planning) – Primary efficacy endpoint: PET-CR  Update at ASH 2018 • Historical control: R-CHOP GOYA data SdV Sept 2018 (Clinicaltrials.gov: NCT02055820) Bcl-2 Phase Ib/II – CAVALLI: R/G-CHOP + venetoclax - report on phase 1 -

SdV Sept 2018 (Zelenetz, et al., ASH 2016) Bcl-2 Phase Ib/II – CAVALLI: R/G-CHOP + venetoclax - report on phase 1 -

DLBCL patients: biomarker expression and PET response (R-CHOP and G-CHOP arms combined) Biomarker expression (IHC) and PET/CT (Lugano 2014 criteria by investigator) response Double Double Data Bcl-2 – /MYC+ Total=15 expressor negative unavailable n=4 n (%) n=8 n=1 n=2

CR 7 3 1 2 13 (87%)

PR 0 0 0 0 0

PD 1† 1‡ 0 0 2 (13%)

Summary of efficacy in front line 1L DLBCL • Two PDs: 1PD‡ on day 5, 1PD† at EOT (R-CHOP arm)

SdV Sept 2018 (Zelenetz, et al., ASH 2016) CD79B Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL

SdV Sept 2018 (Sehn, et al., ASCO 2016) CD79B Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL

SdV Sept 2018 (Sehn, et al., ASCO 2016) CD79B

SdV Sept 2018 (Sehn, et al., ASCO 2016) CD79B Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL

SdV Sept 2018 (Sehn, et al., ASCO 2016) Phase III, randomized, double-blind, placebo-controlled trial comparing CD79B the efficacy and safety of Polatuzumab Vedotin in combination with R-CHP vs. R-CHOP in untreated DLBCL

. Polatuzumab vedotin, an ADC that delivers the microtubule inhibitor monomethyl auristatin E (MMAE) to cells expressing CD79b

Principal Investigator: Herbert Eradat, MD

SdV Sept 2018 CAR- Genetically Engineered T Cells Directed T cells Against CD19

SdV Sept 2018 (Maude et al., Blood 2015 125:4017-4023) CAR- Multicenter clinical trials with CAR T cell T cells therapies in rel/refr aggressive NHL

SdV Sept 2018 (Quintás-Cardama, Oncotarget, 2018, Vol. 9, (No. 52), pp: 29843-29844) CAR- T cells

SdV Sept 2018 (Abramson et al., ASCO 2018) CAR- T cells

SdV Sept 2018 (Abramson et al., ASCO 2018) CAR- T cells Key differences between the 3 CAR T studies

Higher disease burden may be associated with lower response rates and increased CRS/neurotoxicity

SdV Sept 2018 (Abramson et al., ASCO 2018) CAR- The risk of toxicity due to CD19 CAR-T cells is T cells determined by interacting factors

SdV Sept 2018 (Turtle; SCLG, Los Angeles Aug 2016) CAR- Engineered Tumor-Targeted T Cells Mediate Enhanced Anti- T cells Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System

SdV Sept 2018 (Avanzi et al., 2018, Cell Reports 23, 2130–2141 ) FL OS of patients with Follicular Lymphoma who relapsed within 2 years of R-CHOP

80% of patients

Outstanding OS

20% of patients Median OS 5 yrs

SdV Sept 2018 (Casulo et al., JCO 23: 2516-22) FL M7FLIPI A Follicular Lymphoma Prognostic Model

. 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11) . FLIPI . ECOG-PS

. High-risk group with 25% 5 yr PFS

. Low-risk group with 68% 5 yr PFS

. First prognostic score in lymphoma to incorporate both genetic and clinical factors . Step in right direction….

SdV Sept 2018 (Pastore et al.,Lancel Oncology 16: 1111-22, 2015) RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) FL versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma.

SdV Sept 2018 (Fowler et al., ASCO 2018) RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) FL versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma.

. Similar CR/Cru and PFS between arms

. No difference in treatment discontinuations

. No difference in 2nd malignancies (short observation time)

. No difference in OS

SdV Sept 2018 (Fowler et al., ASCO 2018) FL DYNAMO: A phase 2 study of duvelisib in patients with refractory indolent follicular lymphoma.

SdV Sept 2018 (Flinn et al., ASH 2016) FL DYNAMO: A phase 2 study of duvelisib in patients with refractory indolent follicular lymphoma.

SdV Sept 2018 (Flinn et al., ASH 2016) MZL INCB050465, a PI3Kδ Inhibitor for Rel/Refr MZL

TRIO-US trial

20 mg weekly Rel/Refr 20 mg QD x INCB050465 MZL 8 wks

Ibrutinib n = 60 2.5 mg QD Ibrutinib n = 60

A Phase 2, Open-Label, 2-Cohort Study • Rel/Refr MZL (extranodal, nodal, and splenic) • 1 or more lines of systemic therapy, including anti-CD20 antibodies • Excluded: Transformation, + CNS, prior other PI3K inhibitor

Principal Investigator: Sven de Vos, MD

SdV Sept 2018 HL Role of LAG-3 in T-cell exhaustion and anti-PD1 resistance: rationale for anti-LAG-3 and anti-PD-1 commination therapy

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth

SdV Sept 2018 (BMS, ASCO 2017) An Open-Label, Phase 2 Study of Relatlimab Combined with LAG-3 Nivolumab and Nivolumab in Participants with Select LAG-3+ Solid Tumors and Classical Hodgkin Lymphoma (BMS CA224-022) TRIO-US trial

Incl/Excl

• Solid tumors or classical HL, relapsed, refractory, no alternative SOC treatment option

Treatment • BMS-986213 fixed-dose comb relatlimab/nivolumab at a 1:3 ratio.

• Relatlimab 160 mg/nivolumab 480 mg.

• Nivolumab monotherapy dosing for adults is 480 mg.

Prim Endpoint • ORR

LAG3 nearly universally expressed in the tumor microenvironment of cHL. (el Halabi et al., Blood 2016 128:2952)

The immune checkpoint inhibitor BMS-986016 has shown promising results in patients with multiple hematological and solid malignancies either alone or in combination with Nivolumab, according to interim results from 2 Phase 1/2a clinical trials

Principal Investigator: John Timmerman, MD SdV Sept 2018 Study to Evaluate the Safety and Efficacy of a Combination of MK- LAG-3 4280 and Pembrolizumab in Participants With Hematologic Malignancies (MK-4280-003) Possible TRIO-US trial

Incl/Excl • Rel/refr: DLBCL, classical Hodgkin, indolent NHL Design • The study will have 2 phases: a safety lead-in and an efficacy expansion phase. • Non-randomized, n = 134 • Participants receive pembrolizumab by intravenous (IV) infusion followed by MK-4280 by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. Part A: - MK-4280 Dose A+ pembrolizumab 200 mg - MK-4280 Dose B+ pembrolizumab 200 mg - MK-4280 Dose C+ pembrolizumab 200 mg Part B: - MK-4280 RPTD + pembrolizumab 200 mg • Primary Endpoints: Safety, RPTD • Second Endpoints: Efficacy

LAG3 nearly universally expressed in the tumor microenvironment of cHL. (el Halabi et al., Blood 2016 128:2952)

Principal Investigator: John Timmerman, MD

SdV Sept 2018 (Clinicaltrials.gov: NCT03598608) CLL Zanubrutinib (BGB-3111) Response Rate of 96 % in rel/refr CLL/SLL (Phase 1 )

. Zanubrutinib potent, highly selective, and irreversible BTK inhibitor . Greater selectivity for BTK vs. other TEC- and EGFR-family kinases . Superior oral bioavailability compared to ibrutinib

Phase 1 in rel/refr CLL

• Responses • ORR of 96% • PRs 67%, PRs with lymphocytosis 28% • (del17p and/or del11q; n = 17) ORR of 100%

• Tolerability: • Common AEs: • Contusion/petechiae/purpura (48%), upper respiratory tract infection (33%), fatigue (28%), cough (20%), diarrhea (20%), headache (20%), muscle spasms (17%), nausea (15%), arthralgia (13%), dizziness (11%), constipation (11%), neutropenia (11%), and rash (11%)

• Grade ≥3 Aes in 35% of patients, with 22% serious AEs • Toxicity led to treatment discontinuation in 1 patient (grade 2 pleural effusion)

• Most common grade 3/4 AEs were neutropenia (9%), contusion/petechiae/purpura (2%), serious hemorrhage (2%), and atrial fibrillation (2%)

SdV Sept 2018 (Tam et al., ASH 2016) CLL A phase 3, rand study of Zanubrutinib (BGB-3111) compared with Ibrutinib in patients with rel/rel CLL or SLL (BGB-3111-305)

Possible TRIO-US trial

Incl/Excl • Rel/refr CLL/SLL in need of treatment • At least 1 prior thx • No Richter’s transformation Design

• N= 400 Zanubrutinib • • Arm A: Zanubrutinib 160 mg po BID potent, highly selective, and irreversible BTK inhibitor • Arm B: Ibrutinib 420 mg po QD Prim Endpoint • ORR Sec Endpoints • Other response parameters, Safety

Aiming at a more effective BTK inhibitor in CLL

Principal Investigator: Herbert Eradat, MD

SdV Sept 2018 Version: 27-Aug-2018 In start up TRIO - US trial

DLBCL DLBCL MZL Hodgkin 1st line Relapsed (cont.) Relapsed Relapsed BMS CA224-022 ZUMA-7 INCYTE CITAδEL-204 Celgene - High risk DLBCL Anti-LAG3 +/- Nivolumab R-CHOP + CC-122 KTE-C19 CAR T-cells INCB050465 (PI3K-δ inhib) 2nd line High Risk rel DLBCL (pleiotropic pathway modifier) BMS CA209-812 (GCB/ABC) Multiple NHL Nivolumab + BVed vs. BVed ZUMA-11 KTE-C19 CAR T-cells POLARIX Valor IGN001-101 CLL/SLL + 4-1BB agonistic Ab Polatuzumab Vedotin Anti-CD20/IFN-α fusion prot Relapsed R-CHPola vs R-CHOP (CD20+ B-cell NHL: DLBCL, FL, Miragen MRG 106-11-101 (anti-CD79b ADC) Incyte INCB-53914-201 MCL, t-DLBCL, PMBCL) MRG1106 (target: miR-155) (GCB/ABC) PI3K inhib + PIM-inhib (CTCL, CLL, DLBCL) KITE ZUMA-5 Atara EBV-CTL KTE-C19 CAR T-cells Oncternal Therapeutics Relapsed Allogeneic EBV-CTLs iNHL (FL, MZL) Cirmtuzumab + Ibrutinib (EBV-associated LPD) ROR1 moAb + BTK inhib PCYC 1123 (CLL/SLL, MCL) Ibrutinib + Lenalidomide Miragen MRG 106-11-101 FL (target: miR-155) +/- Rituximab (ABC) st MRG1106 1 line (CTCL, CLL, DLBCL) KITE ZUMA-8 PCYC-1141 FL KTE-C19 CAR T-cells CLL KCP-330-009 Rituximab +/- Ibrutinib Regeneron R1979-ONC-1504 Selinexor 1. R2810 (anti PD-1) (iNHL) (SINE™ XPO1 antagonist) Relapsed 2. R2810 + R1979 (anti-CD20 x Relapsed PTCL (DLBCL - GCB/ABC, anti-CD3) (iNHL, aNHL) no t-DLBCL) KITE ZUMA-5 Portola KTE-C19 CAR T-cells Cerdulatinib (PRT062070) TG Thx (UNITY-NHL) (SYK/JAK inhibitor) Incyte INCB-53914-101 MCL Pending: PIM-kinase inhibitor 1st line Umbralisib/Ublituximab CerRx 130002 (DLBCL) (FL, MZL) Fenretinide Acerta ACY-LY-308 Pending: BR +/- ACP-319 Umbralisib Verastem 225 PTCL Novel BTK inhibitor Novartis (BELINDA) (MCL) Duvelisib (PI3K-γ/δ inhib) CTL019 CAR T-cells 2nd line High Risk rel DLBCL Relapsed Merck Relapsed CTCL (Pembro + STING agonist) KITE ZUMA-2 Miragen MRG 106-11-101 CAR T-cells (B-cell or T-cell NHL, Solid CA) Acerta-Ly-111 (PRISM) KTE-C19 MRG1106 Acalabrutinib + AZD9150 (targets miR-155) (STAT3 inhib) PCYC 1143 Curis CA-4948 Acalabrutinib + AZD6738 Ibrutinib + Venetoclax IRAK4 inhibitor Portola Cerdulatinib (ATR inhib) BTK + Bcl-2 inhibition (NHL) (SYK/JAK inhibitor) Version: 27-Aug-2018 CAR T-cell trials In start up TRIO - US trial