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 OS 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 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)