New targeted therapies in lymphoma

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1 MONASH CLINICAL SCIENCES New targeted therapies in lymphoma Dr Gareth Gregory Clinical & Laboratory Haematologist Monash Health Clinical Lead for Aggressive Lymphoma

2 Conflicts of interest Advisory role Stock ownership Gilead No Royalties/licensing fees No Honoraria Research funding Clinical Trial Support Subsidised Drug Travel fees Off-label use Roche Merck, AbbVie, Astra-Zeneca, Pharmacyclics, Amgen No No Roche, Novartis, Gilead Bortezomib, Lenalidomide, Azacitidine, Enasidenib, Eculizumab 2

3 Cheah et al. Ann Oncol. 2016; 27:

4 Checkpoint inhibitors Cheah et al. Ann Oncol. 2016; 27:

5 Hodgkin lymphoma: Survival in the pre-immunotherapy era Michael Gilbertson

6 Gabriel Caponetti, Wikipedia. Batlevi et al. Nat Rev Clin Oncol

7 The Economist, 2015 Green Shipp, Blood 2010

8 Hodgkin lymphoma: Amplification of 9p24.1 Green et al. Blood, 2010.

9 Hodgkin lymphoma: JAK-STAT signalling Green et al. Blood, 2010.

10 Hodgkin lymphoma: PD-L1 and JAK2 association Green et al. Blood, 2010.

11 Hodgkin lymphoma: Immune checkpoint inhibition Ansell et al. New Eng J Med 2015.

12 Hodgkin lymphoma: Immune checkpoint inhibition

13

14 Immune checkpoint inhibition: Acquired resistance 4 melanoma patients with delayed resistance Baseline biopsies +/- cell lines compared with relapse biopsies Zaretsky et al. NEJM, 2016.

15 Immune checkpoint inhibition: Acquired resistance Patient 1: Mutation and LOH in Jak1 Zaretsky et al. NEJM, 2016.

16 Immune checkpoint inhibition: Acquired resistance Patient 2: Mutation in Jak2 Zaretsky et al. NEJM, 2016.

17 Hodgkin lymphoma: Summary HL characterized by immuno-avoidant phenotype Immune-checkpoint inhibitors (PBS 1/5/18!) and JAK-STAT pathway inhibitors represent promising targets Batlevi et al. Nat Rev Clin Oncol

18 Nivolumab: DLBCL and Follicular NHL Phase I nivolumab in rrhaem malignancies: rrfl n=10; ORR 40% (including 1 CR) rrdlbcl n=11; ORR 36% (including 2 CR) Lesokhin et al. J Clin Oncol 2016; 34:

19 Type 2 mabs Cheah et al. Ann Oncol. 2016; 27:

20 Obinutuzumab: Type II anti-cd20 Ab Mechanism Type I Rituximab, Ofatumumab Type II Obinutuzumab, Tositumomab Complement-dependent cytotoxicity ++ Antibody-dependent cellular cytotoxicity Move CD20 into lipid rafts ++ Homotypic adhesion ++ Induce direct cell death ++ 20

21 Obinutuzumab: CLL (CLL11) CLL11: G-Chl superior to R- Chl for older patients with CLL and comorbidities Goede, N Eng J Med

22 Obinutuzumab: Follicular NHL (GALLIUM) Marcus, N Eng J Med

23 Obinutuzumab: DLBCL (GOYA) PFS-IA OS Vitolo et al. J Clin Oncol 2017; 35: Obinutuzumab is not approved for DLBCL in Australia

24 Obinutuzumab: Summary DLBCL Follicular NHL CLL

25 mab-conjugates Cheah et al. Ann Oncol. 2016; 27:

26 Inotuzumab-ozogamicin: anti-cd22 Ab conjugate Anti-CD22 mab conjugated to calicheamicin Isolated from Micromonospora echinospora Causes strand scission

27 Inotuzumab-ozogamicin: anti-cd22 Ab conjugate Phase II rr inhl N=81; 72=rrFL InO 1.8mg/m 2 IV q28 x4-8 ORR 71%; CR 35% Median PFS 12.7m; responders median DOR 24.8m Goy et al. British J Haematol. 2016; 174:

28 Polatuzumab vedotin: CD79b mab conjugated to vedotin Dorabella auricularia Forero-Torres et al. Blood 2017; Philibert Bidgrain. Waight et al. PLoS One 2016; 11:e

29 Polatuzumab vedotin: anti-cd79b Ab conjugate ROMULUS Phase II rrfl/dlbcl R-PoV (anti-cd79b) vs R-PiV (anti-cd22) Morschhauser et al. J Clin Oncol. 2014;

30 Background: CD79b expression in DLBCL Young & Staudt. Nat Rev Drug Disc. 2013; 12: Pfeifer et al. Leukemia 2015; 29:

31 Background: Polatuzumab phase I NHL & CLL Palanca-Wessels et al. Lancet Oncology 2015; 16: Polatuzumab vedotin is not approved for use in Australia

32 Polatuzumab: DLBCL Polatuzumab vedotin combined with Obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (G-CHP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL): Updated results of a phase 1b/2 study Andres Forero-Torres, 1 Kathryn S. Kolibaba, 2,7 Hervé Tilly, 3 Gilles Salles, 4 Lijia Wang, 5 Calvin Lee, 5 JeffSharman 6,7 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; 2 Compass Oncology, Vancouver; 3 Centre Henri Becquerel, University of Rouen, Rouen, France; 4 South Lyon Hospital Complex, Lyon, France 5 Genentech, Inc., South San Francisco, CA; 6 Willamette Valley Cancer Institute, Springfield, OR; 7US Oncology Research, The Woodlands, Texas Forero-Tores et al. Blood 2017; Obinutuzumab is not approved in DLBCL or in this combination

33 Study design: Polatuzumab DLBCL Pola + G-CHP in 1L DLBCL Pola Phase 1b/2 dose escalation and expansion combined 1.8 mg/kg N=21 Pola 1.4 mg/kg (n=6) Cycle (n=6) Cycle Cycle 3+ 1 Pola G-CHP Pola G-CHP Pola-G-CHP G=obinutuzumab 1000 mg IV on day 1, 8, 15 of Cycle 1; on day 1 of subsequent cycles C=cyclophosphamide 750 mg/m 2 IV on day1 H=doxorubicin 50 mg/m 2 IV on day 1 P=prednisone 100 mg/day po on days1 5 Pola administered on day 2 of cycles 1 and 2 (for pharmacokinetics); on day 1 of subsequentcycles Treatment was administered every 21 days for total of 6 or 8 cycles; granulocyte-colony stimulating factor (G-CSF) was allowed as primaryprophylaxis 1L, first line; DLBCL, diffuse large B-celllymphoma Forero-Tores et al. Blood 2017; Polatuzumab vedotin is not approved for use in Australia

34 Results safety: Polatuzumab DLBCL Adverse event profile, pola-g-chp (N=21) n (%) Any adverse event (AE) 21 (100) Grade 3/4 AE 15 (71) Serious AE 9 (43) AE leading to treatment discontinuation* 4 (19) AE leading to pola dose reduction 0 Peripheral neuropathy, all grades grade 2 8 (38) 2 (10) Deaths 1 (5) *AEs leading to treatment discontinuation included thrombocytopenia (cycle 1), coronary artery disease (cycle 4), septic shock (cycle 4), and recurrentneutropenic fever (cycle 4) Death due to septic shock, cycle4 AE, adverse event; PN, peripheral neuropathy Data cut-off 21 July, 2017 Forero-Tores et al. Blood 2017; Polatuzumab vedotin is not approved for use in Australia

35 Results efficacy: Polatuzumab DLBCL Forero-Tores et al. Blood 2017; Data cut-off 21 July, Polatuzumab vedotin is not approved for use in Australia

36 Ongoing studies: Polatuzumab in DLBCL A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Diffuse Large B-Cell Lymphoma (POLARIX) [NCT Monash] Phase III A Study of Obinutuzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory Follicular Lymphoma (FL) or Diffuse Large B-Cell Lymphoma (DLBCL) [NCT VCCC / Royal Hobart] Phase I 36

37 Proximal B-Cell Receptor Signaling Nodes Cheah et al. Ann Oncol. 2016; 27:

38 Targeting proximal BCR signaling: BTK inhibition BTK a critical node within BCR signaling pathway 1 Numerous specific inhibitors: Ibrutinib Acalabrutinib Zanubrutinib Young & Staudt, Nat Rev Drug Discov. 2013; 12:

39 BTK inhibition: Ibrutinib in DLBCL Phase I/2 study of ibrutinib 560mg daily PO, n=80 ORR 37% (14/38) ABC and 5% (1/20) GCB Wilson et al. Nature Med, 2015.

40 BTK inhibition: Ibrutinib in DLBCL Phase I study of ibrutinib & R-ICE dose expansion at 840mg ORR 90% (cf. historical approx. 50% in the CORAL study) Sauter, Blood 2018.

41 BTK inhibition: Ibrutinib in Follicular NHL Phase II trial of ibrutinib 560 mg daily in rrfl (n=40) 2 ORR 37.5%; CR 12.5% Median PFS 14m; 2y PFS 20% Predictors of response: Rituximab sensitivity (52.6% vs 16.7%) CARD11 mutations (0% response) 1. Young & Staudt, Nat Rev Drug Discov. 2013; 12: Bartlett et al. Blood 2017; Adv online Oct 27: DOI /blood

42 BTK inhibition: Ibrutinib in Mantle Cell Lymphoma Phase II trial of ibrutinib 560 mg daily in rrmcl (n=111) ORR 68% Median PFS 14m Wang et al, New Eng J Med 2013

43 Targeting proximal BCR signaling: SYK inhibition SYK a critical node within BCR signaling pathway 1 Numerous specific inhibitors: Fostamatinib Entospletinib Young & Staudt, Nat Rev Drug Discov. 2013; 12:

44 SYK inhibition: Fostamatinib Phase I/II rrnhl including rrfl (n=21) Fostamatinib 200mg BD FL: ORR 9.5%; median PFS 4.6m (2-8.3) Friedberg et al. Blood 2010; 115:

45 SYK inhibition: Entospletinib Phase II rrnhl (n=69) including rrfl (n=41) Entospletinib 800mg BD All: ORR 13%; median PFS 5.5m ( ) Sharman et al. Blood 2015; 126:1545.

46 PI3K inhibition Cheah et al. Ann Oncol. 2016; 27:

47 PI3K inhibition: Idelalisib Phase 2 rr inhl (n=125) Idelalisib 150mg BD ORR 57%; median PFS 11m Gopal et al. N Eng J Med

48 BCL2-family targeting (apoptosis induction) Mcl1 Cheah et al. Ann Oncol. 2016; 27:

49 BCL2-family targeting (apoptosis induction)

50 BCL2 inhibition: Venetoclax Phase I rrnhl mg (n=106) Davids et al. J Clin Oncol 2017; 35:

51 MCL1 inhibition Kotschy et al. Nature MIK665 currently recruiting for Myeloma at Austin S64315 phase 1 MDS/AML currently recruiting at Alfred

52 Cyclin-dependent kinase inhibition Dinaciclib CDK9 Cheah et al. Ann Oncol. 2016; 27:

53 CDK inhibition: Dinaciclib Dinaciclib: potent inhibitor of CDKs 1,2,5,9,12 Potently represses transcription of MCL1 and MYC Phase Ib study in combination with pembrolizumab for DLBCL, CLL and MM Gregory et al. Leukemia 2015; 29: Quach et al. Lymphoma & Myeloma 2017.

54 Selective Inhibitors of Nuclear Export Cheah et al. Ann Oncol. 2016; 27:

55 SINE (Selective Inhibitor of Nuclear Export) XPO1 antagonist: forces retention of tumour suppressor proteins in the nucleus (eg p53) 1 Prevents escape of oncogenic mrnas such as cmyc 1 Tabe et al. PLoS ONE 2015; 10:e

56 SINE (Selective Inhibitor of Nuclear Export) XPO1 antagonist: Selinexor Phase I rrnhl; n=79 ORR 31% (22 of 70 evaluable patients) CR n=4 PR n=18 Phase 2 SADAL clinical trial (DLBCL) opening at numerous Australian sites Kuruvilla et al. Blood 2014; 124:396.

57 EZH2 inhibition Cheah et al. Ann Oncol. 2016; 27:

58 EZH2 inhibition: Tazemetostat EZH2: Enhancer of zeste homolog 2 Transcriptional repressor (methylates histones to form heterochromatin) reduced transcription of many genes including tumour suppressors 1 Gain of function mutations in 25% of FL 2 1. Kroken et al. Trends Parasitology 2012; 28: Bodor et al. Blood 2013; 122:

59 EZH2 inhibition: Tazemetostat Tazemetostat: oral inhibitor of EZH2 Phase II study of rrfl and DLBCL (n=210) ICML2017: FL ORR 92% (mutated) / 26% (wild-type) 1 Excellent tolerability: Dose reductions 3% / discontinuations 2% Morschhauser et al. ICML 2017.

60 BET inhibition BETi BRD4 Cheah et al. Ann Oncol. 2016; 27:

61 BET inhibition: RG6146 Phase 1 RG6146 Hogg et al. Mol Cancer Ther

62 DLBCL: High somatic mutational frequency Lawrence et al. Nature 2014.

63 Lymphoma panacea: Personalising the therapy to the mutations Zhang J. et al. Cell 2017 Cheah et al. Ann Oncol. 2016; 27:

64 Questions?