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New Agents in Management of Indolent B-Cell NHLs

New Agents in Management of Indolent B-Cell NHLs. F B Hagemeister MD Department of Lymphoma/Myeloma M D Anderson Cancer Center Las Vegas, Nevada February 27, 2014. Monoclonal Antibodies Rituximab Ofatumumab Obinutuzumab Protein Inhibitors BTK Inhibitors PI3K Inhibitors Others

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New Agents in Management of Indolent B-Cell NHLs

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  1. New Agents in Management of Indolent B-Cell NHLs F B Hagemeister MD Department of Lymphoma/Myeloma M D Anderson Cancer Center Las Vegas, Nevada February 27, 2014

  2. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  3. Phase III MR, 2 Schedules, for Untreated FL Following SA Rituximab x 4: SAKK 35/03 • Med PFS: (MR = 4 doses, vs 5 years, both q 2 mo): • For all 165 enrolled: A-3.4 yr vs B-5.3 (p=0.14) • Thought due to higher relapse rate before MR begun for those in Gp A for “unexplained reasons” • For only those in remission at 8 mo: A-7.1 yr vs B-2.9 (p=0.004) • Gr 3-4 infections (Pt): A-1 vs B-5 • No differences in OS or ORR • Conclusion: If in remission after SA Rituximab, MR prevents relapse if given longer vs shorter interval Taverna et al, ASH 2013, # 508 But best duration of MR is still unclear.

  4. The PRIMA Trial: A 6 Year Update Salles et al. ASH 2013, # 509. • Med f/u 73 months (from randomization) • 6 year PFS results: • 60% with R vs 42% without R (p<0.0001) • Favorable features affecting PFS by MVA: • OS rates, transformation rates not different • Still No result on differences related to type of chemotherapy administered

  5. MR vs Obs after R-Chemo for FL: PFS in the PRIMA Trial Progression-Free Survival 24 72 Months Salles et al. ASH 2013 # 509

  6. Early Relapse Of R-CHOP for FL: Effect of Early Relapse on OS Result   Early Relapse in Lymphocare Study: <2 yrs from diagnosis (21% of 588 pts) By MVA: ER Associated with High LDH, PS > 1, Marrow DZ, and B Sx. Casulo et al. ASH 2013 # 510

  7. 90Y-Ibritumomab for Advanced Stage FL in First Remission: The FIT trial * All patients Note: Only 10-15% had received induction rituximab. A second randomized trial was planned with induction R-CHOP . High-risk pts receive RIT vs SCT, low risk receive RIT vs Obs. All would receive maintenance rituximab. But trial abandoned Hagenbeek et. al. ASH 2007, Abstract # 693

  8. 90YIbritumomab Consolidation vs MR for Untreated FL in CR/PR After R-CHOP Conclusion: MR is better than 90YIbritumomab after R-CHOP Lopez-Guillermo, et al. ASH 2013 # 369

  9. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  10. Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent Lymphomas Morschhauser. Ann Oncol. 2010; Morschhauser. JCO. 2009;27: 3346; Negrea. ASH. 2009 (abstr 3757); Hagenbeek. ASH. 2009 (abstr 935); Hagenbeek. Blood. 2008;111:5486; Salles. ASH. 2009 (abstr 1704).

  11. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  12. Obinutuzumab vs Rituximab for Rel iNHL: The GAUSS Study • 175 pt with rel CD20 pos iNHL, 149 had FL • Eligibility: CR or PR to rituximab-based therapy with response lasting > 6 months • Features: Median 2 prior Txs, others balanced • Therapy: G 1000 mg q wk X 4 or R X4. 4-6 wks later, pt with CR,PR,SD could receive drug q 2 mo X 2 yrs • Infusion-related RXNs more common with GA-101 (72% vs 49%, any Gr) • By IR panel, OR for all: G-42% vs R-24%; for FL: G-43% vs R-28% Sehn et al. ASH 2011, abst 269.

  13. Obinutuzumab plus FC or CHOP for Rel/Ref FL: Phase I GAUDI Study • Obinutuzumab (GA-101): glycosylated, Type II moab against CD20 • 56 pt, stratified by prior therapy • Two Ob regimens chosen based on phase I trial: 1600 mg d 1+8, cycle 1, then 800 mg d 1+8 vs 400/400 for max 8 (CHOP) or 6 (FC) cycles • Toxicity: Not increased with higher doses of Ob • Results: OR=96% (G-CHOP), 93% (G-FC) CR=39%(G-CHOP), 50% (G-FC) • Basis for new G-CHOP study vs R-CHOP for untreated FL Radford et al: ASH 2011, abst 270.

  14. Novel Therapeutics for Cancer Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.

  15. Novel Therapeutics for NHLs Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.

  16. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  17. The B-Cell Receptor Pathway: A Useful Target in Therapy of B-Cell NHL • A transmembrane receptor protein on B cells • An antibody which binds antigen, inducing proliferation of plasma and memory B cells • Composed of two parts: • Ligand-binding moiety (IgM or IgD) • Signal transduction moiety (CD79) with an ITAM

  18. Results of Activation of the B-Cell Receptor and Targets for Manipulation Idelalisib fostamatinib Ibrutinib ? enzastaurin ? temsirolimus everolimusdeferolimus bortezomibcarfilzomib

  19. Phase I Ibrutinib for Relapsed NHL/CLL: Response Rates • * 1 CLL pt had nodal response, but increased lymphocytosis • **On the basis of decreased IgM Advani R, Fowler N et al. ICML 2011.

  20. Phase I/II Trial of Ibrutinib for Ref/Ref MCL: Best Response by Patient Features Breakthrough approval for MCL and CLL granted by FDA 2013. Wang et al. NEJM 2013.

  21. Ongoing studies: Placebo Controlled I + BR for Untreated MCL; I + R for Rituximab-Refractory FL

  22. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  23. PI3Kδ Inhibition Impacts Multiple Critical Pathways in iNHL

  24. Idelalisib: Inhibitor of PI3K DeltaSelect Phase I Results in NHL (ASCO 2013) Fowler, N. ASH 2013 Education Session

  25. Phase I Idelalisib for iNHL and MCL: Response Rates PFS Longer with Doses of 150 mg BID Kahl, B et al. ICML 2011.

  26. Idelalisib Doses of 150 mg BID Were Associated With Longer PFS Results Kahl, B et al. ICML 2011.

  27. Phase 2 Idelalisib for 125 Alkylator-Rituximab Ref iNHL: Nodal Response and PFS Results Maximum Nodal Response Median PFS = 11.4 months Historical Control: Bendamustine: DOR 10mo 53% ORR • 90% had improvement in lymphadenopathy • 57% had ≥50% decrease from baseline Gopal et al. ASH 2013 #85

  28. Phase 1 Idelalisib for 40 Rel/Ref MCL: Dose 50-350 mg po BID Continuously ORR: 16 (40%), CR 3 (7.5%) ORR at < 150 = 29% (8/28), ORR with > 150 = 67% (8/12) Spurgeon et al. Lugano 2013.

  29. Tumor Shrinkage in MCL Following Therapy with Idelalisib Kahl, B et al. ICML 2011.

  30. Idelalisib + Bendamustine: Response Rates De Vose S, et al. ASH 2011 Abstract 2699.

  31. Other PI3k Inhibitors for Rel/Ref FL: The ARD12130 Study and BAY 80-6046 • Phase II SAR245409: Inhibits Isos α, β, γ and δ, mTORC1, TORC2. • Study enrolls FL, CLL/SLL, MCL, and DLBCL. • Phase 2, Stage 1 results for FL (Gr 1, 2, 3A) reported. • Doses: 50 mg PO BID; Resp: ORR= 12/24 (50%), CR=2/24 (8%) • AEs: Diarrhea, Pneumonias, cataracts • BAY 80–6946, Inhibits Isoforms δ and α. May overcome resistance to PI3K-δ. • Phase II Study: 27 iNHL and 34 aggNHLs • Med Prior TXs: 3. Prior ASCT: 20% Brown et al. ASH 2013 # 86, Dreyling et al. ASH 2013 # 87.

  32. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  33. Aurora Kinase A and B: Effects on the Cell Cycle Meraldi et al. Curr Op Genet Dev 2004.

  34. Alisertib for Rel/Ref Aggressive NHLs: Response and Survival Rates • Response: ORR – 13/48 (27%), CR – 10% • Path: DLBCL-3/21, MCL-3/13, BL-1/1, Tr FL-2/5, TCL-4/8 Waterfall Plot Progression-Free Survival • Gr 3-4 Toxicities: Heme - ANC-63%, HGB-35%, PLT-33% Non-Heme – Stomatitis-15% Friedberg et al. JCO 32: 2014.

  35. Alisertib in Aggressive B-Cell and T-Cell NHL: Response Rates • ORR: 32% (95% CI: 18-48) in overall population and responses observed in all histologic disease subtypes Friedberg J, et al. ASH 2011. Abstract 95.

  36. Potential Effects of Anti-PD-1 Antibody in Therapy of Cancer Anti-PD-1 Antibodies: Pidilizumab, Nivolumab, Lambrolizumab McDermott and Atkins. Cancer Medicine 2: 662-673, 2013.

  37. Phase 2 Anti-PD-1 (Pidilizumab) and Rituximab for Relapsed FL: Results • Response in 29 Evaluable Pts: OR-19 (66), CR-15 (52%) NO factor identified a poor response • Med Time to Response-88 days, with 6 more than 4 mo from initial infusion • Med PFS for all pts-18.9 mo • PFS Affected by FLIPI and FLIPI2 Scores PFS by FLIPI PFS by FLIPI2 Months Months Westin et al. Lancet Oncol 15: 69-77, 2014.

  38. Phase 2 Anti-PD-1 (Pidilizumab) and Rituximab for Relapsed FL: Results Westin et al. Lancet Oncol 15: 69-77, 2014.

  39. Monoclonal Antibodies • Rituximab • Ofatumumab • Obinutuzumab • Protein Inhibitors • BTK Inhibitors • PI3K Inhibitors • Others • Immunomodulatory Agents New Agents in Management of Indolent B-Cell NHLs

  40. Cereblon A Target for Lenalidomide? Cereblon: Component of the E3 ubiquitin ligase complex Target protein for thalidomide, lenalidomide and pomalidomide These Inhibit the ubiquitin ligase activity May explain many of the known effects of immunomodulatory agents: Teratogenic activity Anti-myeloma activity T-cell activation

  41. Tumor Cells IL-6 TNF IL-1 Tumor Stroma ICAM-1 Blood Vessels NFAT IL-2 IFN  PKC IL-2 NK Cells VEGF bFGF CD28 PI3K CD8+ T Cells Dendritic Cells Lenalidomide: Targeting the Tumor Cell and Its Microenvironment Chng. Cancer Control.2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.

  42. Phase II Lenalidomide/Rituximab for Relapsed MCL: Response Duration Results for CR/PR patients (N = 24) Results for Patients with SD (N = 36) Goy et al. ASH 2012, abst 905.

  43. Rituximab and Lenalidomide for Untreated iNHL: Study Design 7 8 9 10 11 12 1 2 3 4 5 6 Lenalidomide 20mg Days 1-21 Cycles 1-6* Lenalidomide 20mg Days 1-21 Cycles 7-12* Rituximab 375mg/M2 Day 1 of Cycles 1-6 Rituximab 375mg/M2 Day 1 of Cycles 7-12 R R R = RESTAGE If clinical benefit, can proceed to 12 cycles R R • Phase II, single institution • Planned Enrollment • 50 Follicular Lymphoma (grade I/II) • 30 Small Lymphocytic Lymphoma • 30 Marginal Zone Lymphoma • Groups analyzed independently for response and toxicity *For SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg) Fowler N, et al ASH 2012.

  44. Follicular Lymphoma Response by Tumor Burden and Molecular Features Fowler et al. ASH 2012, abst 901.

  45. Lenalidomide Plus Rituximab as Initial Therapy for iNHL: Response Rates • Responses for FL independent of GELF criteria or disease bulk • Molecular responses for FL increased with treatment duration *Major or minor breakpoints from bone marrow, peripheral blood samples. Fowler et al. ASH 2012. Abst 901.

  46. Lenalidomide/Rituximab for iNHLs: PFS by Histology Follicular Lymphoma Marginal Zone N=46 36 mo PFS: 81% N=27 36 mo PFS: 89% SLL N=30 36 mo PFS: 66% Fowler et al. ASH 2012, abst 901.

  47. Lenalidomide-R for FcγRIIIa-F iNHLs or MCLs Refractory To Rituximab   • FCGR3A polymorphisms cause significant impact on ORR, CR rate, and TTP after SA rituximab (ORR 26% and 2-Yr PFS of only 14% if F allele present). • Study: R-Refractory (SA or chemo combo) and F • Schema: 2 mo Len/Dex (10 mg QD/8 mg QWk, Part 1), then Rituximab q Wk X 4 with Len/Dex (Part 2), then continue Len/Dex alone. • Pts: 17/18 tested had F/F alleles, one V/V. Cartron 2002, Weng 2003, Chong et al. ASH 2013, #250.

  48. Lenalidomide-R for FcγRIIIa-F iNHLs or MCLs Refractory To Rituximab   Med f/u of 52 months, Med PFS is 24.5 months, 2 Yr PFS = 50% compared to 14% for historical controls. Chong, ASH 2013 # 250

  49. Phase II Lenalidomide-R-CHOP for Untreated High- Risk (GELF) FL  • Patients: 80 with FL Gr 1, 2, 3a; Med age 57, High LDH-40%, FLIPI 3-5 in 63%, Mass > 10 cm-25% • Therapy: Induction of Standard R-CHOP, plus Len 25 mg QD days 1-14, X 6 cycles + 2 R doses • Maintenance: MR q 8 wks X 2 yrs • Supportive: Pegfilgrastim day 4, QASA 10 mg QD • Med F/U 12 mo: ORR – 94%, CR/CRu – 74% • Gr 4 Toxicity: ANC-64%, PLT-12.5% • Gr 3 neuropathy: 36%, Gr 1-3 rash (2 Gr 3) • Thrombosis in 5 (3 catheter related) Tilly et al. ASH 2013 # 248

  50. Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days X 6, and if CR, reduce to 10 mg

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