New Agents in Management of Indolent B-Cell NHLs

New Agents in Management of Indolent B-Cell NHLsF B Hagemeister MDDepartment of Lymphoma/MyelomaM D Anderson Cancer CenterLas Vegas, NevadaFebruary 27, 2014

New Agents in Management of Indolent B-Cell NHLsMonoclonal AntibodiesRituximabOfatumumabObinutuzumab Protein InhibitorsBTK InhibitorsPI3K InhibitorsOthers Immunomodulatory Agents

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 reasonsFor 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-5No differences in OS or ORRConclusion: 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.

Med f/u 73 months (from randomization)6 year PFS results:60% with R vs 42% without R (p

MR vs Obs after R-Chemo for FL: PFS in the PRIMA TrialSalles et al. ASH 2013 # 509Progression-Free Survival2472Months

Early Relapse Of R-CHOP for FL: Effect of Early Relapse on OS Result Casulo et al. ASH 2013 # 510Early Relapse in Lymphocare Study: 1, Marrow DZ, and B Sx.

90Y-Ibritumomab for Advanced Stage FL in First Remission: The FIT trialHagenbeek et. al. ASH 2007, Abstract # 693* All patientsNote: 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

Med PFS Results (Mo)Control90Y IPHRPatients in CR (%)53.387.4NRNRAll Pts13.537

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

Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent LymphomasMorschhauser. 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).

MoAbPhaseEfficacyOfatumumabI/IIDose (ORR): 300 mg (63%); 500 mg (33%); 700 mg (20%); 1000 mg (50%)IIORR: 11%, 6-mo PFS in 116 pts withrituximab-refractory FLVeltuzumabI/IIIV administration: ORR: 44%, CR: 27%DOR in pts with FL: 19.7 mosSubcutaneous administration: ORR: 53% CR: 20% in pts with indolent NHLOcrelizumabI/IIORR: 38%; PFS: 11.4 mos in pts with FLGA101I/II/IIIORR: 69%, CR: 38% in 13 pts with FL

Obinutuzumab vs Rituximab for Rel iNHL: The GAUSS Study175 pt with rel CD20 pos iNHL, 149 had FLEligibility: CR or PR to rituximab-based therapy with response lasting > 6 monthsFeatures: Median 2 prior Txs, others balancedTherapy: 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 yrsInfusion-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.

Obinutuzumab plus FC or CHOP for Rel/Ref FL: Phase I GAUDI StudyObinutuzumab (GA-101): glycosylated, Type II moab against CD2056 pt, stratified by prior therapyTwo 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) cyclesToxicity: Not increased with higher doses of ObResults: 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 FLRadford et al: ASH 2011, abst 270.

Novel Therapeutics for CancerMahadavan and Fisher. JCO 29: 1876, 1884, 2011.

Cancer HallmarkTherapeutic TargetTreatmentProliferationSyk, Btk, PKCB, MToR, PI3KFosD, PCI-32765, Enzastaurin, Temsirolimus, IdelalisibInsensitive to Growth InhibitionHDAC, DNMTVorinostat, Romidepsin, Belinostat, Panabinostat, VidazaEvading apoptosisBCL2/BCLX, MCL-1, SurvivinABT-263, Obatoclax, YM155Limitless ReplicationCDK, PARPAT7519, AZD7762, AT9283NeoangiogenesisVEGFR, FGFRSorafenib, Imatinib, SunitinibInvasion/MetastasisSrc, Fak, TGFDasatinib, LY2109761, XL228Immune EvasionNK/T cellsLenalidomide, PomalidomideStress ResponseProteasomeBortezomib, CarfilzomibStromal SubversionSHh, Wnt, NotchGDC-0449, XL139, XAV939, MK-0752Cytokine ResponseCXCR4, IL-21RAMD3100, BKT140, IL-21

Novel Therapeutics for NHLsMahadavan and Fisher. JCO 29: 1876, 1884, 2011.

Cancer HallmarkTherapeutic TargetTreatmentProliferationSyk, Btk, PKCB, MToR, PI3KFosD, Ibrutinib, Enzastaurin, Temsirolimus, IdelalisibInsensitive to Growth InhibitionHDAC, DNMTVorinostat, Romidepsin, Belinostat, Panabinostat, VidazaEvading apoptosisBCL2/BCLX, MCL-1, SurvivinABT-263, Obatoclax, YM155Limitless ReplicationCDK, PARPAT7519, AZD7762, AT9283NeoangiogenesisVEGFR, FGFRSorafenib, Imatinib, SunitinibInvasion/MetastasisSrc, Fak, TGFDasatinib, LY2109761, XL228Immune EvasionNK/T cellsLenalidomide, PomalidomideStress ResponseProteasomeBortezomib, CarfilzomibStromal SubversionSHh, Wnt, NotchGDC-0449, XL139, XAV939, MK-0752Cytokine ResponseCXCR4, IL-21RAMD3100, BKT140, IL-21

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

Results of Activation of the B-Cell Receptor and Targets for Manipulationbortezomib carfilzomib??fostamatinibtemsirolimus everolimus deferolimusIdelalisibenzastaurinIbrutinib

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

HistologyNCRPRSDORR% (ITT, n=56)ORR% (Eval, n=50)CLL/SLL161103*6979MCL93417878WM43**17575FL163333846MZL/MALT4112533DLBCL7212929TOTAL5672495562

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

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

PI3K Inhibition Impacts Multiple Critical Pathways in iNHL

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

AgentsPathNORRPFS (mo)investIdelalisibiNHL6448%7.8Benson Idelalisib + RituximabiNHL3272%2 yr 60%LeonardIdelalisib + BendaiNHL3385%2 yr 62%LeonardIdelalisibMCL4040%3.7SpurgeonIdelalisib + R + BendaMCL4100%NRWagner Idelalisib + EverolimusMCL1839%4.3Wagner Idelalisib + BortezomibMCL1146%5.2Wagner

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

Idelalisib Doses of 150 mg BID Were Associated With Longer PFS ResultsKahl, B et al. ICML 2011.

Phase 2 Idelalisib for 125 Alkylator-Rituximab Ref iNHL: Nodal Response and PFS Results90% had improvement in lymphadenopathy57% had 50% decrease from baselineGopal et al. ASH 2013 #85 Median PFS = 11.4 monthsMaximum Nodal ResponseHistorical Control:Bendamustine: DOR 10mo53% ORR

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

Features(N = 40)Median age (range), years69 (52-83)Age >6035 (88) PS 2 4 (10)LDH > ULN19 (48)Bulky Disease (>5cm)24 (60) MIPI-High (>6.2)14 (35)Med No Prior TX (Range)4 (1-14)Refractory to Last TX (< 6 mo)17 (43)

Tumor Shrinkage in MCL Following Therapy with IdelalisibKahl, B et al. ICML 2011.

Idelalisib + Bendamustine: Response RatesDe Vose S, et al. ASH 2011 Abstract 2699.

Other PI3k Inhibitors for Rel/Ref FL: The ARD12130 Study and BAY 80-6046Phase II SAR245409: Inhibits Isos , , and , 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, cataractsBrown et al. ASH 2013 # 86, Dreyling et al. ASH 2013 # 87.BAY 806946, Inhibits Isoforms and . May overcome resistance to PI3K-. Phase II Study: 27 iNHL and 34 aggNHLsMed Prior TXs: 3. Prior ASCT: 20%

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

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 Gr 3-4 Toxicities: Heme - ANC-63%, HGB-35%, PLT-33% Non-Heme Stomatitis-15%Waterfall Plot Progression-Free SurvivalFriedberg et al. JCO 32: 2014.

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

Response, %Pts (N = 41)ORR32CR12PR20SD39PD29

ORR by Histology,*%B-cellDLBCL20MCL23Transformed FL40Burkitts lymphoma100T-cell57

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

Phase 2 Anti-PD-1 (Pidilizumab) and Rituximab for Relapsed FL: ResultsResponse in 29 Evaluable Pts: OR-19 (66), CR-15 (52%) NO factor identified a poor responseMed Time to Response-88 days, with 6 more than 4 mo from initial infusionMed PFS for all pts-18.9 moPFS Affected by FLIPI and FLIPI2 ScoresWestin et al. Lancet Oncol 15: 69-77, 2014.PFS by FLIPIPFS by FLIPI2MonthsMonths

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

Cereblon A Target for Lenalidomide? Cereblon: Component of the E3 ubiquitin ligase complexTarget protein for thalidomide, lenalidomide and pomalidomideThese Inhibit the ubiquitin ligase activityMay explain many of the known effects of immunomodulatory agents:Teratogenic activity Anti-myeloma activityT-cell activation

*

Lenalidomide: Targeting the Tumor Cell and Its Microenvironment

Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.

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

Rituximab and Lenalidomide for Untreated iNHL: Study Design

Lenalidomide 20mg Days 1-21 Cycles 1-6*1 2 3 4 5 6 If clinical benefit, can proceed to 12 cyclesPhase II, single institutionPlanned Enrollment50 Follicular Lymphoma (grade I/II)30 Small Lymphocytic Lymphoma30 Marginal Zone LymphomaGroups analyzed independently for response and toxicityR = RESTAGE7 8 9 10 11 12 *For SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg)Fowler N, et al ASH 2012.

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

By GELF Criteria (N=46)High Tumor Burden (N=22, 48%)Low Tumor Burden (N=24, 52%)SDPRCR/CRuORRSDPRCR/CRuORR01 (5%)21(95%)100%1(4%)4(17%)19 (79%)96%

By Bulk of Disease (N=46) Bulky (N=13, 28%)Non-Bulky (N=33, 72%)SDPRCR/CRuORRSDPRCR/CRuORR01(8%)12(92%)100%1(3%)4 (12%)28 (85%)97%

Molecular Response (N=44 Evaluable, Marrow and Blood) PCR PositivePCR NegativePRETREATMENT17(41%)26(59%)POST CYCLE 35(11%)39(89%)POST CYCLE 62(5%)42(95%)

Lenalidomide Plus Rituximab as Initial Therapy for iNHL: Response Rates

Responses for FL independent of GELF criteria or disease bulkMolecular responses for FL increased with treatment duration

Fowler et al. ASH 2012. Abst 901. *Major or minor breakpoints from bone marrow, peripheral blood samples.

Resp, %SLL, N=30MZL, N=27FL, N=46All PatientsEval, N=103ITT, N=110ORR8089989085CR/CRu2767876460PR5322112625SD1311287PD70022

Molecular Response, %PCR POSPCR NEGPretreatment4159After cycle 31189After cycle 6595

Lenalidomide/Rituximab for iNHLs: PFS by HistologyN=4636 mo PFS: 81%Follicular LymphomaMarginal ZoneSLLN=2736 mo PFS: 89%N=3036 mo PFS: 66%Fowler et al. ASH 2012, abst 901.

Lenalidomide-R for FcRIIIa-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 FSchema: 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.

RespAllFMCL , SLL , MZL Pts17125ORR (Part 1/2)24/53%25/50%24/51%CR (Part 1/2)3/5 pt2/4 pt1/1 pt

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

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 yrsSupportive: Pegfilgrastim day 4, QASA 10 mg QDMed 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

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

New Agents in Management of Indolent B-Cell NHLsF B Hagemeister MDDepartment of Lymphoma/MyelomaM D Anderson Cancer CenterLas Vegas, NevadaFebruary 27, 2014

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New Agents in Management of Indolent B-Cell NHLs