New Targets and Treatments for Follicular Lymphoma Jonathon B. Cohen, - PDF document

Winship Cancer Institute of Emory University New Targets and Treatments for Follicular Lymphoma Jonathon B. Cohen, MD, MS Assistant Professor Div of BMT, Emory University Disclosures • Consulting fees from: Pharmacyclics, and Seattle Genetics • Contracted Research from: Bristol ‐ Myers Squibb, and Janssen Pharmaceuticals, Inc. 1

Intro/Outline • Follicular lymphoma, presentation and indications for treatment • Review of induction therapy options for advanced disease • Evidence for maintenance therapy • Novel therapies and investigational agents for relapsed follicular lymphoma Clinical Presentation • Often asymptomatic • Slowly progressive adenopathy • Incidental findings • Patients are often not sick 2

Criteria for Treatment (GELF) • Involvement of ≥ 3 sites, each measuring ≥ 3 cm • Any nodal or extranodal tumor mass with a diameter of ≥ 7 cm • B symptoms • Splenomegaly • Pleural effusions or peritoneal ascites • Cytopenias • Leukemic presentation FLIPI Characteristic RR (Death) Age > 60 years 2.38 Stage III-IV 2.00 Hgb < 12.0g.dL 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39 Solal ‐ Céligny, et al. Blood. 2004;104:1258 ‐ 1265. 3

FLIPI and OS Risk Group No. of Risk 5-year OS, % 10-Year OS, % Factors Low 0-1 91 71 Intermediate 2 78 51 High ≥ 3 53 36 • Roughly half of all patients with FLIPI 3 or higher die within 5 years • Original FLIPI score developed in the pre-rituximab era Solal ‐ Céligny, et al. Blood. 2004;104:1258 ‐ 1265. FLIPI: Survival Probability Solal ‐ Céligny, et al. Blood. 2004;104:1258 ‐ 1265. 4

Induction Therapy: B ‐ R vs R ‐ CHOP Pts with previously Bendamustine-rituximab untreated Stage III or IV NHL of the following types: R • Follicular • Waldenström • Marginal zone • Small lymphocytic • Mantle cell CHOP-rituximab Age ≥ 18 years WHO PS 0-2 Bendamustine 90 mg/m 2 Day 1, 2 + R Day 1, max 6 cycles, every 4 weeks. CHOP-R, max 6 cycles, every 3 weeks. Rummel MJ, et al. Blood. 2009;114: Abstract 405. B-R vs CHOP-R: PFS Rummel MJ, et al. Lancet Oncol 2013 . 5

B ‐ R vs R ‐ CHOP/R ‐ CVP • BRIGHT study (Flinn et al, Blood 2013) – Patients randomized to B ‐ R or R ‐ CHOP/R ‐ CVP (each site assigned one of the standard therapies) – Non ‐ inferiority study – B ‐ R non ‐ inferior to both R ‐ CHOP and R ‐ CVP with respect to CR rate. – Non ‐ hematologic toxicity improved with B ‐ R. Novel Approaches • B ‐ R + Bortezomib – Current ECOG study in comparison to B ‐ R. – Overall Response Rate is 88% in relapsed FL • R ‐ Lenalidomide – CALGB Phase II Study • Rituximab x 4, then cycles 4, 6, 8 and 10 • Lenalidomide 20mg daily days 1 ‐ 21 of a 28 day cycle x 12 – Overall Response Rate: 93% – 2 ‐ year PFS 89% Fowler et al, J Clin Oncol 2011; Martin et al, ASCO Abstracts 2014 6

Conclusions ‐ Induction Therapy • Bendamustine ‐ Rituximab appropriate in most cases • Studies underway to both intensify and lessen therapy • Expect therapy to become more tailored based on individual risk factors Rituximab Maintenance PRIMA: Study Design MAINTENANCE Rituximab maintenance INDUCTION Registration 375 mg/m 2 every 8 weeks Immunochemotherapy High for 2 years † 8 x Rituximab tumor burden CR/Cru + Random 1:1* untreated PR 8 x CVP or follicular 6 x CHOP or lymphoma 6 x FCM Observation † PD/SD off study Primary endpoint: • Progression ‐ free survival (PFS) from randomization (to rituximab maintenance or observation) Secondary endpoints • Event ‐ free survival (EFS), overall survival (OS) • Time to next anti ‐ lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT) • Response rates at end of maintenance • Safety and toxicity • Quality of life (QoL) (FACT ‐ G and EORTC scales) *Stratified by response after induction, regimen of chemo, and geographic region † Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up Salles GA, et al. J Clin Oncol. 2010;28(7s): Abstract 8004. 7

Patient disposition Patients registered: N = 1217 Induction * 15 pts in 3 sites closed Patients evaluable (N = 1202)* prematurely R-CHOP R-CVP R-FCM  9 pts did not receive chemo N = 885 N = 272 N = 45  147 pts withdrew during or at the end of induction (failure to Randomized Randomized Randomized respond; toxicity) N = 769 N = 222 N = 28  28 pts failed to be randomized Maintenance Patients randomized: ‡ 1 pt died during the N = 1018 ‡ randomization process Observation Rituximab N = 513 N = 505 PRIMA ‐ PFS OUTCOME 3 ‐ year PFS: 79% (R Maint) 57.6% (Obs) Salles G, Lancet 2011. 8

PRIMA ‐ OS No significant OS benefit E4402 (RESORT) • Pts with low tumor burden treated with R x 4 followed by maintenance vs retreatment at progression. Time to Treatment Failure Time to Chemotherapy Kahl et al, ASH 2011 9

Maintenance Rituximab ‐ Summary • Likely a PFS benefit and opportunity to delay next therapy • Unclear role after B ‐ R (E2408 may help answer this) • No evidence of OS benefit • Should be discussed individually with each patient Relapsed/Refractory FL B ‐ cell receptor signaling pathway Woyach et al, Blood 2012 10

Ibrutinib – BTK inhibitor • Phase I Study of Ibrutinib – MTD not reached; standard dose is 560mg – ORR 54.5%, median duration of response 12.3 months • Ongoing multisite study just completed enrollment Fowler et al, ASH 2012 Idelalisib – PI3K δ inhibitor • Phase 2 Study of Idelalisib – Dose 150mg twice daily – Response rate 57%, median duration 12.5 months • Toxicities: – Neutropenia – LFT abnormalities – Diarrhea – Pneumonia Gopal et al, NEJM 2014 11

CD20 Antibodies • Ofatumumab: – ORR 10 ‐ 13% – Median PFS: 5.8 months Czuczman et al, Blood 2012 CD20 Antibodies • GA101 – Obinutuzumab – Phase II study in rel/ref follicular lymphoma – ORR 55% at recommended dose – Median PFS 11.9 months Salles G, et al. J Clin Oncol 2013 12

BCL2 Inhibitor – ABT199 • Oral agent active in several subtypes of NHL • Responses seen in 2/7 patients with follicular lymphoma in Phase I Study. • Toxicities: – Tumor lysis syndrome – Cytopenias – Febrile Neutropenia Davids et al, ASCO Abstracts 2013 Agents Under Investigation at Emory • ABT ‐ 199 • Nivolumab (PD1 inhibitor) • Buparlisib (Pan ‐ selective PI3K inhibitor) • Alisertib (Aurora Kinase inhibitor) 13

Other Treatments for Rel/Ref FL • Chemo ‐ immunotherapy – B ‐ R – R ‐ CVP/R ‐ CHOP – Fludarabine – Salvage NHL regimens • Radioimmunotherapy • Lenalidomide • Autologous/Allogeneic Transplants Conclusions • Several options that are better than R ‐ CHOP for induction therapy • Consider maintenance rituximab in all cases, but with no clear OS benefit • Numerous options for relapsed/refractory FL • Strongly consider enrollment on clinical trial • For fit/motivated patients, transplant can be considered 14