What is the best antibody therapy for CLL?

Transcription

1 What is the best antibody therapy for CLL? Lymphoma & Myeloma 2012 October 26, 2012 Myron S. Czuczman, MD Chief, Lymphoma/Myeloma Service Head, Lymphoma Translational Research Laboratory Professor of Medicine and Oncology Roswell Park Cancer Institute Buffalo, NY

2 Agenda Brief overview of CLL surface antigens Review anti-cd20 mabs in CLL Non-CD20-mAbs Standard-of-care: Combination immunochemotherapy Conclusions/Future directions

3 B-Cells: Express Many Surface Antigens That May Serve as Targets for mabs B-Cell Marker B-cell receptor (BCR) CD19 CD20 CD21 CD22 CD23 CD37 CD40 Antigen expression variable 1,2 Most involved in B-cell growth, differentiation, proliferation, and activation; other functions include 1,2 : Immune regulation Complement inhibition CD52 CD46, CD55, CD59 CD74 Many are targets of therapeutic mabs 1,2 CD80 1 Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007: Hotta T. Acta Histochem Cytochem. 2002;35(4):

4 CD20: An Excellent Target for Therapeutic MAbs CD20 Expressed 1-4 : Exclusively on B-cells On most B-cells in periphery On most malignant B-cells B-Cell 1 Bonilla FA. UpToDate Accessed Nov 2, Cragg et al. Curr Dir Autoimmun. 2005;8: Hotta T. Acta Histochem Cytochem. 2002;35(4): Teeling et al. J Immunol. 2006;177(1): Stable on B-cell surface, allowing sustained MAb binding 2-4 Some reports indicate that it is infrequently internalized or shed Function not well understood but may contribute to B-cell growth, proliferation, differentiation, and activation 1-4 No known ligand May form a membrane ion channel and play a role in calcium flux Involved in B-cell receptor activation and signaling 4

5 Anti-CD20 mabs: Proposed mechanisms-of-action Complement-dependent cytotoxicity (CDC) 1-3 Antibody-dependent cellular cytotoxicity (ADCC) 1-3 Programmed cell death (apoptosis) 1-3 Antibody-dependent cellular phagocytosis (ADCP) 1 Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007: Glennie et al. Mol Immunol. 2007;44(16): Jazirehi AR, Bonavida B. Oncogene. 2005;24(13):

6 Rituximab and CLL Many CLL cells express dim CD20 limiting killing by CDC CLL cells also prone to CD20-shaving after Rx Exhaustion of cytotoxic effector systems may occur* MOA of -CD20 mabs may depend on local tumor burden** low burden may be eliminated by CDC alone high burden requires multiple effector mechanisms ADCC and ADCP may be suboptimal in CLL Diminished activity of NK cell and monocytes T regs: ADCC Differences in Fc gamma receptor polymorphisms Not appear to influence response in CLL Apoptosis may be the most impt MOA in CLL *FJ Beurskens et al. J Immunol 2012; 188: **P Boross et al. Haematologica 2011; 96:

7 Rituximab Clinical Trials in CLL Initial Phase 3 pivotal trial approving R in B-NHL Included 33 CLL pts: 12% PR Limitations described on previous slide Trials evaluating 3 x week dosing or higher dosing schedules improved responses seen Improved efficacy also seen in previously untreated pts Rituximab-immunochemotherapy studies: Goldstandard Rx for CLL e.g. F+R, FCR, PCR, BR (to be discussed) Maintenance R in CLL? No randomized trial of MR in CLL yet published Only should be done as part of a clinical trial

8 Promising Novel Antibody-Based Therapeutics for CLL 2 nd -generation anti-cd20 mabs Other (non-cd20) unlabeled mabs Novel constructs and Bispecifics Combinations of mabs plus biologics / targeted agents

9 Newer mabs in clinical development Agent Target Humanized/Chimeric Direct Cell Death ADCC CDC Blinatumumab CD19 Unique construct BITE No No Ofatumumab CD20 Human Yes Yes Yes GA-101 CD20 Humanized Yes Yes No PRO CD20 Humanized Yes Yes Yes Veltuzumab CD20 Humanized Yes Yes Yes LFB-R603 CD20 Chimeric Yes Yes Yes Lumiliximab CD23 Primatized Yes Yes Yes TRU-016 CD37 Humanized Yes Yes No HCD122 CD40 Human No Yes No Milztuzumab CD74 Humanized Yes No No Ipilimumab CTLA-4 Humanized Yes No No ADCC = antibody-dependent cell-mediated cytotoxicity; CDC = complement-dependent cytotoxicity

10 CD20 Type I and Type II mabs Type I mabs Localize CD20 to lipid rafts High CDC ADCC activity Full number of binding sites / B-cell Weak homotypic aggregation Limited direct apoptosis Rituximab Ofatumumab Veltuzumab Ocrelizumab AME-133 PRO Type II mabs Do not localize CD20 to lipid rafts Minimal CDC ADCC activity Half number of binding sites / B-cell Strong homotypic aggregation Strong direct apoptosis Tositumumab (B1) GA101

11 1. Teeling et al. J Immunol 2006;177:362; 2. Teeling et al. Blood 2004;104:1793; 3. Beum et al. J Immunol 2008;181: ; 4. Pawluczkowycz et al. J Immunol 2009;183: Coiffier et al. Blood 2008;111:1094 Ofatumumab: characteristics 1 4 Ofatumumab binding site Rituximab binding site Human CD20 mab that binds to membrane-proximal epitope encompassing small and large loops of CD20 1,2 Potent lysis of B cells 1 4 Effective ADCC More rapid and potent in vitro complement dependent cytotoxicity (CDC) versus rituximab Effective CDC in cells with low CD20 expression, including in CLL cells

12 Ofatumumab in refractory CLL Multicenter, open-label, single-arm study: Europe and US Overall study objectives: efficacy and safety Patient populations: Fludarabine- & Alemtuzumab- Refractory (FA-ref) Refractory to 2 cycles fludarabine-based regimen Refractory to 12 doses alemtuzumab regimen Fludarabine-Refractory with Bulky Lymph Nodes (BF-ref) Refractory to 2 cycles fludarabine-based regimen Ineligible for alemtuzumab due to bulky (>5 cm) lymph node No age limit ECOG PS: 0 2 No exclusion for cytopenia Wierda et al. (2010) JCO 28: 1749; Wierda et al. (2011) Blood 118: 5126

13 Ofatumumab in CLL: Clinical Results ORR in both patient groups significantly higher than 15% null hypothesis; P<.001 for both subgroups Prolonged survival in week 12 for responders vs. non-responders Ofatumumab activity independent of previous rituximab treatment, age, Rai stage, or prior treatment Ofatumumab generally well tolerated; no unexpected toxicities Most common event: infusion-related reactions (63%) a P<.05, Fisher s exact test Based on: Wierda WG et al. ASH 2010 Abst 921

14 Ublituximab (LFB-R603) epitope recognition differs from rituximab and ofatumumab Ublituximab (LFB-R603): novel chimeric IgG1 anti-cd20 mab Discontinued epitope with two regions is specific to R603 ( rituximab and ofatumumab) Red : Amino acids contributing to ofatumumab binding Yellow : Amino acids essential for rituximab, but not ofatumumab binding Purple : Core amino acids of ublituximab epitope 14 Exhibits enhanced ADCC; comparable CMC to rituximab Higher NK cell activation c/w R in presence of CLL cells Clinically active in r/r CLL; n=33 (CD dose-escalation study*); ORR=45% Future studies in development *Cazin et al, Abstr #2862, ASH 2011)

15 Obinutuzumab (GA101): new Type II, glycoengineered anti-cd20 monoclonal antibody First type II, glycoengineered, humanized anti-cd20 monoclonal antibody In preclinical studies compared to rituximab, GA101 provides: Increased direct cell death induction Enhanced ADCC GA101 is being evaluated in several B cell malignancies Umana P, et al. Blood 2006: 108; Abst # 229 Umana P, et al, Ann Oncol. 2008; 19(Suppl.4): Abst #098

16 CLL and GA101 Phase 1 study in r/r CLL (n=13)* 62% ORR = 8 (CR=1;PR=7) Most common gr 3-4 tox: transient neutropenia (n=9) No clear dose-effect relationship established Being evaluated in: Phase 2 single-agent in r/r CLL In combo with Chlorambucil (Chl) in previously untreated elderly CLL Phase 3 in elderly pts with comorbidities (CLL II Trial) Chlorambucil alone vs. Chl + R vs. GA101 Also, being evaluated in previously untreated CLL Alone GA101 plus FC versus Benda *Morschhauser et al; Abstr# 884, ASH 2009

17 Alemtuzumab Humanized IgG 1 kappa mab recognizing CD52 Target is widely expressed on normal cells CD52 expressed on tumor cells: T-PLL, CLL, MCL, B-NHL, ALL Single-agent activity demonstrated Approx ORR of 33% to 54% in r/r CLL Activity in Blood/BM > LN compartments Subq dosing: Good anti-tumor activity with less infusional tox Major issue: Rx-associated cytopenia and INFECTION (esp. COMBO Rx s) Studied as consolidation Rx for CLL In general: highly toxic Future: allow an extended recovery time before starting ALEM

18 Lucatumumab (HCD122) in Lucatumumab Fully human anti-cd40 mab relapsed CLL* Blocks interaction of CD40L and CD40; mediates ADCC Phase I trial in r/r CLL n=26 pts (5 dose cohorts given weekly x 4 doses) MTD = 3 mg/kg Toxicity: included grade 3 or 4 asymptomatic amylase / lipase levels Activity: Nodular PR (n=1); Stable disease for mean of 76 d (n=17) Conclusion: minimal single-agent activity demonstrated *JC Byrd et al. Leuk & Lymph 2012; Early Online 1-7; DOI: /

19 Combination mab-based Immunochemotherapy Trials

20 FC +/- Rituximab in untreated CLL: German CLL Study Group (CLL8, phase III) Eligibility criteria: Untreated CLL Cumulative illness rating scale 6 CrCl 70 ml/min R A N D O M I Z E Fludarabine 25 mg/m 2, D 1-3 Cyclophosphamide 250 mg/m 2, D1-3 q 28D x 6 cycles n=817 (7/03 3/06) Fludarabine 25 mg/m 2, D 1-3 Cyclophosphamide 250 mg/m 2, D1-3 Rituximab 500 mg/m 2, D1 (375 mg/m 2,C1) q. 28D x 6 cycles Endpoints: PFS, OS, response, safety

21 Efficacy of FCR versus FC in CLL Overall Response Rate Complete Response FCR (n = 408) FC (n = 409) Hazard Ratio p-value 90% 80% < % 22% < Median PFS 51.8 months 32.8 months 0.56 < Year OS 87% 83% Hallek M et al. Lancet 2010;376(9747):

22 O-FC in First-Line CLL: 407 Study R A N D O M I Z E Treatment 500 mg O-FC q4wk 6 courses 1000 mg O-FC q4wk 6 courses Follow up At Month 1 after last course, Month 3 and q3mo thereafter Course Ofatumumab Fludarabine Cyclophosphamide mg d1 25 mg/m 2 IV d mg/m 2 IV d or 1000 mg d1 25 mg/m 2 IV d mg/m 2 IV d1 3 Population: untreated CLL with active disease Primary endpoint: Overall Response Rate Wierda et al. (2011) Blood 117: 6450

23 O-FC in 1 st -line CLL: Conclusions O-FC is an active first-line regimen in CLL CR rate: 50% (1000 mg arm); 32% (500 mg arm) Trend for higher CR rate with ofatumumab 1000mg High b 2 -microglobulin level may have affected results O-FC appeared to be safe and tolerable Myelosuppression was most frequent adverse event with O-FC regimen No unexpected toxicity Current studies looking at Ofatumumab in combination with bendamustine in untreated and relapsed CLL

24 Current ofatumumab trials in CLL Study 911 (COMPLEMENT 1): Ph3 Study of Ofatumumab + Chlorambucil vs. Chlorambucil in previously untreated CLL Study 991: Phase 2 Bendamustine + Ofa in CLL Study 913 (COMPLEMENT 2): Ph3 Study of Ofatumumab + Flu/Cy vs. Flu/Cy in Relapsed CLL Study 517 (PROLONG): Ph3 Trial of Ofatumumab Maintenance Therapy in Relapsed CLL Study 242: Ofatumumab vs. Physician s Choice for Patients with Bulky Fludara-Refractory CLL

25 Bendamustine Chemical Structure ClH 2 C Bendamustine ClH 2 C N N COOH Carboxylic acid Nitrogen mustard N Benzimidazole ring Cl N Cl Cyclophosphamide O O P N H CH 3 NH 2 Cladribine MOA: Leads to mitotic catastrophe in cells N Cl N HOCH 2 O OH N N

26 Phase II trial of bendamustine/rituximab in relapsed CLL: Efficacy (n =78) Bendamustine: 70 mg/m 2 D1-2 q 4 wks x 6 cycles Rituximab: 375 mg/m 2, cycle 1; 500 mg/m 2 D1, cycle 2-6 # of pts % CR 7 9 PR + npr ORR (n=71 evaluable) Response by genetics IgV H unmutated (n = 46) del(11q) (n = 13) del(17p) (n = 14) 1 7 Fischer et al, J Clin Oncol 29: , 2011

27 Phase II study of bendamustine and rituximab in untreated CLL: GCCLSG (N = 110) Bendamustine: 90 mg/m 2 D1-2 q 28D x 6 cycles Rituximab: 375 mg/m 2, C1; 500 mg/m 2 D1, C2-6 No. of responders Response, CR PR + npr ORR Unmutated IgV H (n = 63) q del (n = 21) p del (n = 7) 3 43 % Fischer et al, Abstr #205, ASH 2009

28 CLL10 1 : FCR vs. BR in Untreated CLL FCR being tested against BR in newly diagnosed patients with CLL 1 trials.gov/ct2/show/nct Accessed February 3, 2011

29 CD80 CD20 CD40 CD22 NHL/CLL: emerging agents Microenvironment Surface markers Bevacizumab 1 Lenalidomide 2* Anti-CD20 mab/ radioimmunotherapy (RIT) 2* Anti-CD19 mab 4 Chemotherapy Bendamustine 3* Anti-CD22 mab/ immunoconjugates/ RIT 1,2* Pathways Bcl-2 family Proteasome inhibitors: inhibitors: mtor ABT-263, 5 GX Bortezomib; 2,5,6 inhibitors: 2 nd generation 6 Everolimus 6,7 Temsirolimus 6,7 PKC inhibitors: HDAC inhibitors: Enzastaurin 6,7 Vorinostat (SAHA) 6 Panobinostat (LBH589) 6 BCR-signaling 7 *Denotes agent is licensed for a B-cell NHL indication 1. Kahl B. SeminHematol 2008;45: Gregory SA, et al. Oncology 2010;24:5. 3. Cheson BD, et al. Clin Lymphoma Myeloma Leuk 2010;10: Gerber H-P, et al. Blood 2009;113: Tageja N, et al. J Hematol Oncol 2009;2: Delmonte A, et al. Oncologist 2009;14: Witzig TE & Gupta M. Hematology Am Soc Hematol Educ Program 2010;2010:

30 Small Modular ImmunoPharmaceutical (SMIP) VH VL Single chain polypeptide is a dimer in solution Antibody-like target specificity and binding CH2* CH3 Smaller than an antibody, size albumin designed for better biodistribution *CH2 domain contains a consensus N-linked glycosylation site Molecular weight ~105 kda Courtesy of B. Cheson

31 Schema of the mechanism of action of blinatumomab (MT103/MEDI-538), a bispecific T-cell engager (BiTE) (CD19) Quintás-Cardama A et al. JCO 2010;28: by American Society of Clinical Oncology

32 Best antibody for CLL? Conclusions Rituximab must be beaten in a head-to-head evaluation Likely differs depending on specific conditions Antigen density/expression; tumor and host variations Better understanding of mab-associated MOA and MOR needed Combination of two mabs beats monotherapy! mab + chemotherapy / targeted agents = Optimal anti-cll activity Improved understanding of synergy between mab + other agents will further improve outcomes in CLL

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