What are the hurdles to using cell of origin in classification to treat DLBCL?

What are the hurdles to using cell of origin in classification to treat DLBCL? John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Associate Dean for Clinical Research Vice Chairman, Department of Medicine

Disclosures Consulting advice: Genentech, Medimmune, AstraZeneca, Spectrum, Boehringer Ingelheim, Vertex, ProNAI, Biotest, Seattle Genetics, Pfizer, Mirati, Gilead, Novartis, Teva

Diffuse large B cell lymphoma Practical objective of treatment cure Reasonably good clinical prognostic tools Most patients treated same (R-CHOP) R-EPOCH commonly used for primary mediastinal subtype Unmet need 1/3 not cured, reduce toxicity of treatments Should we use molecular subtyping (activated B cell/germinal center) or BCL2/BCL6/myc (double hit/double protein) to guide therapy? If refractory to second-line therapy, prognosis is poor

Treatment algorithms for aggressive NHL (DLBCL) CHOP-R (100%) Cure (60-70%) Relapsed/Refractory (30-40%) 2 nd line therapy R-ICE, R-DICE, R-DHAP, etc Transplant eligible (20-25%) Transplant ineligible (10-15%) ASCT + HDC Cure (5%) Relapse (15-20%) Relapse (10-15%) 3 rd line or later therapy (25-35%)

CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL Untreated patients with newly diagnosed DLBCL (N = 478) R-CHOP every 3 wks for 6 cycles R-EPOCH Doxorubicin, etoposide, vincristine Days 1-4; cyclophosphamide Day 5; prednisone Days 1-5 Primary endpoints: EFS, molecular predictors of outcome for each regimen Secondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis Clinical Trials.gov. NCT00118209. http://www.clinicaltrials.gov

Outcome by GCB vs non-gcb gene signatures in DLBCL N=233 patients treated with R-CHOP PFS OS Lenz G, et al, NEJM November 27, 2008

Oncogenic mechanisms and potential therapeutic targets in GCB and ABC DLBCLs Roschewski M. et al. Nat. Rev. Clin. 2013;11:12-23.

Upfront DLBCL Novel agent/regimen in specific clinical or molecular patient subsets Study design DLBCL Subset 1 CHOP-R CHOP-R Other regimen Subset 2 Other regimen CHOP-R Other regimen

PYRAMID study design DLBCL diagnosis & subtyping Non-GCB R Hans method GCB Not enrolled Vc-R-CHOP Bortezomib 1.3 mg/m 2, d 1, 4 Rituximab 375 mg/m 2, d 1 Cyclophosphamide 750 mg/m 2, d 1 Doxorubicin 50 mg/m 2, d 1 Vincristine 1.4 mg/m 2, d 1 Prednisone 100 mg/d, d 1 5 Six treatment cycles q21 days R-CHOP Rituximab 375 mg/m 2, d 1 Cyclophosphamide 750 mg/m 2, d 1 Doxorubicin 50 mg/m 2, d 1 Vincristine 1.4 mg/m 2, d 1 Prednisone 100 mg/d, d 1 5 Six treatment cycles q21 days Follow up every 3 months for 2 yrs

REMoDL-B study Randomized evaluation of molecular guided therapy in DLBCL with Bortezomib All patients undergo biopsy for profiling at diagnosis All patients receive cycle #1 R-CHOP Randomized from cycle #2-6 to receive bortezomib 1.3 mg/m2 d 1 and 8 All patients initially randomized, designed to close for GCB subjects if evidence of futility Up to 940 subjects, minimum 260 ABC subtype

ABC DLBCL-associated signaling Roschewski M. et al. Nat. Rev. Clin. 2013;11:12-23.

Ibrutinib in relapsed DLBCL patients with ABC versus GCB subtype ABC subtype (N=29) GCB subtype (N=20) Unclassifiable 1 (N=16) Unknown 2 (N=5) Total (N=70) Not Evaluable for Response 4 1 3 2 10 PP ORR 4 (CR + PR) 10 (40%) 1 (5.3%) 0 2 (66.7%) 13 (21.7%) Complete Response (CR) 2 (8%) 0 0 1 (33.3%) 3 (5%) Partial Response (PR) 8 (32%) 1 (5.3%) 0 1 (33.3%) 10 (16.7%) PFS (months) 2.5 1.28 0.95 NR 3 1.64 1 GEP performed, but not assignable to ABC or GCB subtypes. 2 GEP not yet performed or tissue not available. 3 Not reached. 4 PP = per protocol. N=70 Median age=63 Median prior treatments=3 (range 1-7) IPI high-intermediate/high risk 59% Wilson WH et al. Blood. 2012;120:686.

Phase I trial of R-CHOP+ibrutinib Total of 24 DLBCL patients, 11 with available cell of origin data GCB: 5/7 CR, 2/7 PR Non GCB: 4/4 CR MTD (with R-CHOP) not reached, recommended dose of ibrutinib 560 mg/d 82% of patients had a grade 3+ event though were mainly cytopenias Growth factors were used Adverse events comparable to historical studies with R- CHOP alone One patient died during the study Younes A et al. Lancet Oncology. 2014;15:1019-1026.

Upfront DLBCL Novel agent/regimen in specific clinical or molecular patient subsets Study design DLBCL GCB CHOP-R CHOP-R Other regimen Non-GCB CHOP-R Ibrutinib + CHOP-R

ABC DLBCL-associated signaling Roschewski M. et al. Nat. Rev. Clin. 2013;11:12-23.

Response to Lenalidomide in Relapsed and Refractory DLBCL Based on Subtype RCHOP - inferior results in non-gcb Retrospective analysis of patients with relapsed DLBCL treated with lenalidomide as a single agent or in combination with rituximab/steroids at several institutions (N=56) suggests activity in the non-gcb subset Hernandez-Illizaliturri et al. Cancer 2011

Mayo Phase 2 R2CHOP vs RCHOP Case-matched Controls Nowakowski et al. JCO 2015

PFS by GCB vs. non-gcb Subtype* in Case-matched RCHOP cohort vs R2CHOP RCHOP R2CHOP p=0.004 DLBCL subtype (Hans) * GCB non-gcb unknown p=ns 12 (42%) 11 (40%) 5 (18%) Nowakowski et al. JCO 2015 * As defined by Hans et al. Blood 2004

E1412: R2CHOP vs. RCHOP RCHOP N=100 evaluable pts DLBCL R 1:1 Stratification Age IPI 10% path ineligibility rate total ~220 pts# R2CHOP N=100 evaluable pts up to 300 patients can be enrolled to meet a goal of 50 ABC DLBCL patients per arm as defined by GEP

Lumping vs Splitting in DLBCL Can you identify subsets reliably and quickly? A 50% subset ends up being 30-40% of those screened Is the drug activity specific to a subset? Maybe Is the drug specificity relevant in combination with standard therapy? If not, is single agent activity robust? Not usually in DLBCL Are there enough patients to enroll just a subset? Appear to be 2015: Either Lumping or Splitting feasible

LYM2034 study schema DLBCL diagnosis & subtyping GCB Non-GCB Not enrolled Eligibility: Confirmed non-gcb subtype of DLBCL by Hans method IHC at central lab Male or female 18 years or older No prior chemotherapy No CNS disease No transformed lymphoma R Vc-R-CAP Six cycles of treatment (3 weeks per cycle) R-CHOP Six cycles of treatment (3 weeks per cycle) Response assessment after cycle 3 and cycle 6 with CT and PET scan

Offner et al, Blood 2015

Comparison of R-CHOP in ABC/non-GCB Retrospective vs Prospective studies Lenz 2 year PFS 40% ABC by GEP with R-CHOP Retrospective Offner 2 year PFS 80% Non-GCB by IHC with R-CHOP Prospective

Why splitting in DLBCL and applying a targeted drug in a subset might not work Targeted drug might not be effective Assay used to split subsets may not be sufficiently robust Patient selection Time involved in identifying subset may exclude less favorable patients (those that would benefit) Control patients treated with R-CHOP in these randomized trials seem to be doing better than expected

A051301 Study Schema Relapsed/Refractory DLBCL-ABC Salvage PR, stem cells collected Randomization Stratify by time to relapse, conditioning regimen Arm A Arm B ASCT: CBV or BEAM + Ibrutinib 560 mg ASCT: CBV or BEAM Ibrutinib x 12 months Placebo x 12 months Follow Up Follow Up

Cautions in using cell of origin for patient selection in DLBCL Effectiveness of targeted drug Ability to identify appropriate subset in a robust fashion Patient selection issues in prospective studies may mitigate effect size