POST ICML Indolent lymphomas relapse treatment Georg Hess University Medical School Johannes Gutenberg-University Mainz, Germany
Treatment of relapsed indolent lymphoma 2
General categories of second line approaches Standard patients re-treatment Intensive, curative approaches HDT, allogeneic SCT Novel agents moab, Pathway inhibitors, epigenetic modulation, immune modulators New combination therapies chemoimmunotherapy plus novel agents 3
High dose therapy 4
HDT for transformed indolent lymphoma Trial: NCIC CTG LY12 (8/2003 11/2011) Patients with rel aggressive lymphoma, < 3 lines R (R)-GCP x 3 (R)-DHAP x 3 HDT 619 patients, 89 with transformed lymphoma, 428 DLBCL Approx. 70% prior R-exposure, 30% R-refractory Median follow up 53 months Transformed DLBCL Response to salvage 54% 54% Transplantation rate 52% 52% EFS (4 yr) 26% 27% OS (4 yr) 38% 41% Kuravilla-J et al, ICML 2013, Abstr. 64 5
Novel Antibodies 6
Focus on: Antibody drug conjugates - Background An ADC is a drug delivery technology where drugs are linked to an antibody via a conditionally stable linker The antibody delivers drug to target cells by binding to antigen on cell surface The drug is released in target cells upon internalisation Achieving highly specific therapy with higher toxic dosis at the specific location Local delivery of high toxic chemo-agent to achive general lower adverse reactions Generating a targeted chemotherapy in combination with subcutaneous or oral given agents Senter PD. Curr Opin Chem Biol 2009;13:235 44.
Anti-CD22 Antibody-Drug Conjugate (ADC): DCDT2980S Anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker MMAE: potent microtubule disrupting agent CD22 is a cell-surface antigen whose expression is restricted to all mature B cells except plasma cells Expressed by nearly all B-cell hematologic malignancies Rapid internalization upon binding Potent anti-tumor activity in murine xenograft models of B-cell lymphoma 500 5 mg/kg Anti-CD22vcE 0 0 5 10 15 20 25 30 Genentech, Data on File Advani et al, ICML 2013, Abstr. 39 3000 2500 2000 1500 1000 Ramos (BL) 2 mg/kg Anti-CD22vcE R-CHOP
Patient Baseline Characteristics Demographics (N=43 patients) All Patients n (%) Histology Patients n (%) Age in years, median (range) 66 (30-85) Diffuse large B-cell lymphoma 22 (51) Sex Female Male ECOG status 0 1 2 No. systemic therapies, median (range) 1 2 3 20 (47) 23 (53) 19 (45) 20 (48) 3 (7) 4 (1-11) 5 (12) 4 (9) 34 (79) Follicular lymphoma 15 (35) Transformed follicular lymphoma 4 (9) Small lymphocytic lymphoma 2 (5) Prior rituximab therapy 43 (100) Autologous stem cell transplant therapy 7 (16)
Treatment Emergent Adverse Events * Per investigator assessment
Investigator-Assessed Best Responses in patients with at least 1 dose Best Response Efficacy-Evaluable Patients, 1.8 mg/kg (n=17) Objective response b 7 (41%) Partial Response Complete Response Histology DLBCL FL 6 (35%) c 1 (6%) b Stable disease 4 (24%) Progressive disease 5 (29%) Unable to evaluate 1 (6%) Lugano Update on inhl (n=16) Antibody only (n=11) 3(27%) Antibody plus rituximab (n=5) 1(20%) 5 (4 PR, 1 CR b) 2 (PR) Efficacy-evaluable patients defined as those patients who received at least one dose of study treatment and had at least one on-treatment tumor assessment. Disease measured by Cheson criteria. Advani et al, ICML 2013, Abstr. 39
Anti-CD79b Antibody-Drug Conjugate (ADC): DCDS4501A Anti-CD79b mab conjugated to monomethyl auristatin E (MMAE) via protease-cleavable peptide linker Rapid internalization upon binding Component of B-cell receptor restricted to mature B-cells except plasma cells Expressed by nearly all B-cell hematologic malignancies FL, MZL, MCL, DLBCL, CLL MMAE: microtubule disrupting agent Significant anti-tumor activity in mouse xenograft models of human CD79b+ NHL Tumor volume mm 3 2000 1500 1000 500 Granta MCL RTX CHOP R-CHOP 2 & 5 mg/kg Anti-CD79bvcE 0 0 5 10 15 20 25 30 Palanca-Wessels et al, ICML 2013, Abstr. 40
Patient Baseline Characteristics Demographics (N=47 patients) All Patients, n (%) Histology Patients, n (%) Age in years, median (range) 64 (20-85) Sex Female Male ECOG status 0 1 2 No. systemic therapies, median (range) 1 2 3 17 (36%) 30 (64%) 11 (23%) 26 (55%) 10 (21%) 4 (1-12) 1 (2%) 6 (13%) 40 (85%) Diffuse large B-cell lymphoma 21 (45%) Follicular lymphoma 17 (36%) Mantle cell lymphoma 4 (9%) Marginal zone lymphoma 3 (6%) Small lymphocytic lymphoma 1 (2%) Transformed follicular lymphoma 1 (2%) Prior rituximab therapy 45 (96%) Autologous stem cell transplant therapy 14 (29%)
Treatment Emergent Adverse Events * Per investigator assessment
Investigator-Assessed Best Responses in patients with at least 1 dose Best Response Efficacy-Evaluable Patients, 1.8 mg/kg (n=17) Objective response b 8 (47%) Histology MCL FL DLBCL Transformed FL Stable disease 3 (18%) Progressive disease 6 (35%) Lugano Update on inhl (n=21) Antibody only (n=12) 7 (58%) Antibody plus rituximab (n=9) 7 (78%) 4 3 0 1 Palanca-Wessels et al, ICML 2013, Abstr. 40
Pathway inhibitors 18
Targeting the B-Cell-Receptor Pathway Idelalisib GS-9973 Ibrutinib, Ino145 Wiestner, JCO, Doi: 10.1200/JCO.2012.44.4281 19
The class of PI3K inhibitors: Idelalisib 20
Final results of a phase I study of idelalisib, a selective inhibitor of PI3Kδ, in patients with relapsed or refractory indolent non-hodgkin lymphoma (inhl). Trial Outline Phase I MTD Dose 50-350mg QD/BID NCT00710528. Patients with rel indolent Idelasisb until PD 50-350mg Patients (n=64) Side effects efficacy Histology 38 FL 11 SLL 9 LPL/WM 6 MZL Patient characteristics Median Age: 64 Median pre Tx: 4 Refractory: 58% AE Grade total/>2 Diarrhea: 36/8% Fatigue: 36/3% Pneumonia: 17/16% AE disc. rate: 12.5% Responses ORR: Median DOR: Median PFS: FL 45% WM 56% MZL 33% All doses / > 100mg BID 48% (1CR)/67% 18.4 m/15.4 m 7.6m /16.6m Kahl et al, ICML 2013, Abstr. 296 21
Interim results of phase II study of idelalisib in inhl refractory to Rituximab and an alkylating agent Trial Outline Phase II MTD 150 mg/bid Patients with rel indolent R-refrac, Alkyl. Ref. Idelasisb 150 BID until PD Patients (n=125) Side effects efficacy Histology 72 FL 28 SLL 10 LPL/WM 15 MZL Patient characteristics Median Age: 64 Median pre Tx: 4 refr to >1 treat: 79% med time since last tx: 4.2m AE Grade total/>2 Diarrhea: 37/10% Fatigue: 28/2% Cough: 26/0% Dyspnoe: 17/3% AST Elev /26% Pneumonia: 17/16% AE disc. rate: 16% Responses ORR: 50.4% CR: 4% PR: 46% SD: 40% FL 49% SLL 64% WM 30% MZL 47% PFS 11.4 m DOR 11.9m Salles et al, ICML 2013, Abstr. 68 22
Interim results of phase II study of idelalisib in inhl refractory to Rituximab and an alkylating agent 23
Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with r/r lymphoma IPI-145: oral inhibitor of the PI3KEδ and PI3K-γ isoforms ongoing Phase 1 study 65 pts, 31 with lymphoma, 18 inhl neutropenia and increased ALT were the most common Grade 3 TRAEs MTD 75mg TRAE Pneumonitis, PCP-Pneumonie Median cycle number 4, 48% on treatment Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) Kahl et al, ICML 2013, Abstr. 66 24
Perspective: Chemo-free-multi-combinations of novel agents ALLIANCE (Abstract 563) Patients with relapsed FL, 3 + 3 Design R2 Plus Idelalisib 25
BTK-inhibition - Ibrutinib O N H 2 N N N N N O Fowler et al. ASH 2010 Abst. Honigberg, PNAS, 2010, 26
BTK-inhibition in relapsed Lymphoma Advani et al, JCO 2012 DOI: 10.1200/JCO.2012.42.7906 27
Waldenström s Macroglobulinemia Treon, NEJM, 2012 28
A prospective, multicentre phase II study of the BTK Inhibitor Inbrutinib in patients with relapsed and refractory Waldenstrom's Macroglobulinemia Trial Outline Relapsed WM, at least 1 treatement Ibrutinib 420mg until progression (26 cycles) Patients Characteristics All 35 refractory 12 Median Age: 63 Median pre Tx: 2 Safety Side effects Grade 3/4 Thrombopenia 15.6% Neutropenia 9.3% Efficacy Responses (32pat) ORR (IWMWS) 81% VGPR 9,3% PR 47% MR 25% @24 weeks on study 94% Treon et al, ICML 2013, Abst. 67 29
Perspective: Ibrutinib in inhl: DAWN Ibrutinib in r/r FL (Abstract 556) Patients with relapsed AND refr inhl, at least 2 lines N=110 I until PD 30
Perspective: new targets: SYK Inhibition GS-9973 Phase I, healthy, n=120 Nausea, consipation, headache Grade 3: AST in 3, Grade 4 in 1 Garde 3 creatinin, amylase Abstract 286 Dose finding trial Abstract 548 GS-9973 single agent phase II CLL, inhl, MCL, DLBCL Abstract 551 GS-9973 combination with idelalisib phase II CLL, inhl, MCL, DLBCL Ramanathan et al, ICML 2013, Abstr. 286 31
Bcl-2-inhibition Davids and Letai, Cancer Cell, 2013 32
Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory NHL Trial Outline Phase I NHL 50-900mg Dose NCT01328626. Single dose 6 d rest Continous dosing Patients Side effects Efficacy Histology All 31 DLBCL 7 MCL 8 FL 7 MW 3 Patient characteristics Median Age: 68 Median pre Tx: 3 AE Grade > 15% Nausea 36% Diarrhea 36% Nausea 16% Vomiting 16% Fatigue 16% Pyrexia: 16% Responses (ORR/CR) 29 ev ORR: 55% DLBCL 3/7 MCL 8/8 WM 3/3 FL 2/7 Davids et al, ICML 2013, Abst 146 33
Best Percent Change from Baseline in Nodal Size by CT Scan N = 29 evaluable (at minimum, 6 week assessment) Median Time to 50% Reduction = 43 days (range 36 to 113) 34
Chemotherapy combination 35
Tolerability and activity of combinations of the PI3Kδ inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-hodgkin lymphoma (inhl): Updated results from a phase I study Trial Outline Phase I combo Dose 100/150mg BID NCT01732929. Idelalisib 100/150 Rituximab 375mg/m² (6x) Idelalisib 100/150 Bendamustin 90mg/m² (6x) I plus R (6x) plus B (6x) Resp I Patients Side effects Efficacy Histology 78 ind Patient characteristics Median Age: 62 Median pre Tx: 3 Refractory: 41% AE Grade All/ >2 Pyrexia: 56/4% Fatigue: 45/4% Rash: 40/8% Cough 37/0% Diarrhea 36/8% Pneumonia: 17/1% Responses (ORR/CR) ORR all: 71/28% ORR IR: 77/20% ORR IB: 85/29% ORR IBR: 79/43% 20mo PFS: 66% 20mo PFS-R: 73% Leonhard et al, ICML 2013, Abstr. 68 36
BeRT-Schedule Overall 4 cycles planned no mandatory maintenance
Dose escalation and treatment completion Phase I completed Defined dosage for Temsriolimus 50mg Entire Treatment completed : 11 patient Average cycle number: 3.47 Response in FL patients 4/4 Phase II ongoing now 16 patients in phase II recruited 38
Evolution continues Dep. of Hematology / Oncology / Pneumology
Active phase III trial(s) in relapsed inhl R +/- Idelalisib (Abstract 554) Patients with relapsed but not refr inhl, N=350, 2:1 Rando, placebo controlled R R8 plus I until PD R8 plus P until PD BR +/- Idelalisib Patients with relapsed but not refr inhl, N=450, 2:1 Rando, placebo controlled R RB x 6 plus I until PD RB x 6 plus P until PD 40
Summary For patients at risk novel drugs are under way moab B-cell-receptor pathway inhibitors Antiapoptotic drugs Value of these drugs in the overall treatment of relapsed indolent lymphoma remains to be determined Combination trials under way Single agent comparisons missing 41