New Antibody Based Therapies in Hematologic Malignancies

Transcription

1 New Antibody Based Therapies in Hematologic Malignancies Leslie Popplewell, MD, FACP Associate Professor, City of Hope Department of Hematology and Hematopoietic Cell Transplantation Click to edit Master Presentation Date

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3 Characteristics of CD20 MoAb

4 Characteristics of Ab directed to lineage specific Ag

5 Non-lineage specific MoAb (approved) Alemtuzumab-- CD52(Campath) Daratumumab-- CD38(Darzalex) Elotuzumab SLAMF7 (CS1, CD319)(Empliciti) Mogalizumab CCR4--(Poteligeo)

6 Ab for non-lineage specific Ag

7 Ab targeting Immune Checkpoints

8 PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma Response Characteristics and Changes in Tumor Burden in Patients with Hodgkin's Lymphoma Receiving Nivolumab. Response onset and duration for the 20 study patients who had a response to treatment with nivolumab. Percentage reduction in tumor burden from baseline Ansell SM et al. N Engl J Med 2015;372: N Engl J Med Volume 372(4): January 22, 2015

9 Genetic and Immunohistochemical Analyses of PDL1 and PDL2 Loci, PD-L1 and PD-L2 Protein Expression, and Epstein Barr Virus Status in Patients with Hodgkin's Lymphoma. Ansell SM et al. N Engl J Med 2015;372:

10 Characteristics of the 23 Patients at Baseline. Ansell SM et al. N Engl J Med 2015;372:

11 Drug-Related Adverse Events in the 23 Patients. Ansell SM et al. N Engl J Med 2015;372:

12 Ansell SM et al. N Engl J Med 2015;372: Clinical Activity in Nivolumab-Treated Patients.

13 DAC currently on the market Gemtuzumab ozogamicin (Mylotarg) Inotuzumab ozogamicin (Besponsa) Brentuximab vedotin (Adcetris)

14 Brentuximab vedotin Brentuximab vedotin--approved for the treatment of classic Hodgkin s lymphoma after failure of autologous stem-cell transplantation or after two or more multiagent chemotherapy regimens in patients who are not candidates for transplantation. post-transplantation consolidation therapy for patients with Hodgkin s lymphoma who are at increased risk for relapse or progression.

15 Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma by Ajay K. Gopal, Robert Chen, Scott E. Smith, Stephen M. Ansell, Joseph D. Rosenblatt, Kerry J. Savage, Joseph M. Connors, Andreas Engert, Emily K. Larsen, Xuedong Chi, Eric L. Sievers, and Anas Younes Blood Volume 125(8): February 19, by American Society of Hematology

16 Patients who remain in remission per the investigator following treatment with brentuximab vedotin. Ajay K. Gopal et al. Blood 2015;125: by American Society of Hematology

17 OS following treatment with brentuximab vedotin. Ajay K. Gopal et al. Blood 2015;125: by American Society of Hematology

18 PFS following treatment with brentuximab vedotin. Ajay K. Gopal et al. Blood 2015;125: by American Society of Hematology

19 PFS relative to most recent prior therapy. Ajay K. Gopal et al. Blood 2015;125: by American Society of Hematology

20 Preliminary Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma Alex F Herrera, Nancy L Bartlett, Radhakrishnan Ramchandren, Julie M Vose, Alison J Moskowitz, Tatyana A Feldman, Ann S LaCasce, Stephen M Ansell, Craig H. Moskowitz, Keenan Fenton, Kazunobu Kato, Abraham Fong and Ranjana H Advani Blood :1105;

21 Modified Progression-free Survival in the Intention-to-Treat Population. Modified Progression-free Survival in the Intention-to-Treat Population. Panel A shows Kaplan Meier estimates of modified progression-free survival, by treatment group, according to the independent review committee. The hazard ratio for treatment with A+AVD versus ABVD and the 95% confidence intervals (CIs) were based on a stratified Cox proportional-hazards regression model, with treatment as the explanatory variable. Stratification factors included region and International Prognostic Score risk group at baseline. Connors JM et al. N Engl J Med 2018;378:

22 Gemtuzumab ozogamicin (Mylotarg) Final analysis of the ALFA0701 study Sylvie Castaigne et al. Blood 2014;124: by American Society of Hematology

23 Inotuzumab ozogamicin Inotuzumab ozogamicin consists of the humanized monoclonal antibody inotuzumab (against CD22), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin. [3][5] Ozogamicin is N-acetylgamma-calicheamicin dimethylhydrazide. [1] It includes the same linker, called "AcBut", and toxin, as gemtuzumab ozogamicin, which arose from the same collaboration. [6] The linker is a carbonyl-containing carboxylic acid. [7] Structure of AcBut linker used in inotuzumab ozogamicin and gemtuzumab ozogamicin The antibody, originally called G5/44, was created by grafting the complementaritydetermining regions and some framework residues from the murine anti-cd22 mab m5/44, onto human acceptor frameworks

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27 Figure 1 Clinical Lymphoma, Myeloma and Leukemia , e4DOI: ( /j.clml ) Copyright 2018 The Authors Terms and Conditions

28 Figure 2 Clinical Lymphoma, Myeloma and Leukemia , e4DOI: ( /j.clml ) Copyright 2018 The Authors Terms and Conditions

29 Figure 3 Clinical Lymphoma, Myeloma and Leukemia , e4DOI: ( /j.clml ) Copyright 2018 The Authors Terms and Conditions

30 Antibody Drug Conjugates in Clinical Trials for Treatment of B-lineage Malignancies Agent Sponsor Target Payload Status Coltuximab ravtansine (SAR3419) ImmunoGen CD19 DM4 Phase II a Denintuzumab mafodotin (SGN-CD19A) Seattle Genetics CD19 MMAF Phase II Loncastuximab tesirine (ADCT-402) ADC Therapeutics CD19 PBD dimer Phase I SGN-CD19B Seattle Genetics CD19 PBD dimer Phase I Inotuzumab ozogamicin (CMC-544) Pfizer CD22 Calicheamicin Phase III Pinatuzumab vedotin (DCDT2980S) Genentech CD22 MMAE Discontinued Camidanlumab tesirine (ADCT-301) ADC Therapeutics CD25 SG-3249, PBD Phase I Brentuximab vedotin (SGN-35) Seattle Genetics CD30 MMAE Approved Naratuximab emtansine (IMGN529) ImmunoGen CD37 DM1 Phase II AGS67E Agensys CD37 MMAE Phase I Lorvotuzumab mertansine (IMGN901) ImmunoGen CD56 DM1 Discontinued Vorsetuzumab mafodotin (SGN-75) Seattle Genetics CD70 MMAF Discontinued MDX-1203 (BMS936561) BMS CD70 MED-A Discontinued SGN-CD70A Seattle Genetics CD70 PBD Discontinued Milatuzumab doxorubicin (hll1-dox) Immunomedics CD74 Dox Phase II STRO-001 Sutro Biopharma CD74 Maytansinoid Phase I Polatuzumab vedotin (RG7596) Roche CD79b MMAE Phase III Iladatuzumab vedotin (DCDS0780A) Genentech CD79b MMAE Phase I Indatuximab ravtansine (BT062) Biotest CD138 DM4 Phase I/II GSK GlaxoSmithKline CD269 b MMAF Phase I ABBV-838 AbbVie CD319 MMAE Discontinued SGN-CD352A Seattle Genetics CD352 PBD dimer Phase I

31 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in B-cell Leukemia Target Phase Patients, a n Indication Treatment b Efficacy AEs CD19 I (NA) R/R B-ALL, > 12 y ADCT-402, q3w ORR NA, 4 BM CR Grade 3: febrile neutropenia (24%); decreased neutrophils (14%) I (55) R/R B-ALL, B-LBL, Burkitt LL SGN-CD19A, qw, q3w ORR, 35%; CRc, 35%; mdor, 27 wk II (17) R/R ALL SAR3419, qw 8 ORR 26%; mdor 1.9 mo Ocular symptoms (56%); pyrexia (54%); nausea (52%); fatigue (51%) Pyrexia (28%); ocular toxicity (25%); diarrhea (22%); thrombocytopenia (84%) and neutropenia (68%), both grade 3 CD22 II 21 5 (5) Pediatric relapsed InO; q3w, qw CRp, 40% Fever (60%) CD22 + B-ALL II (35) CD22 + 3L ALL InO, qw CR/CRi, 66%; MRD-, 51%; mos, 7.4 mo Grade 3: thrombocytopenia (31%), neutropenia (26%) II (90) R/R B-ALL InO, single-dose, qw ORR, 58%; CRc, 58%; mdor, 7 mo; mos, 6 mo Increased ALT/AST (40%); fever (26%) III (218) Adult 2L CD22 + ALL Arm 1, InO; qw 3 (21- d C1, 28-d C2-6); arm 2, FLAG or cytarabine + mitoxantrone or HD cytarabine I/II 25, c 47 (43) 60 y, 1L ALL InO, d3, q4w 4 + low intensity CVD II 26,c 59 (59) R/R adult ALL InO, d3, q4w 4 (C1-4) + low-intensity CVD Arm 1, CR/CRi 81%; mdor, 4.6 mo; mpfs, 5.0 mo; mos, 7.7 mo; arm 2: CR/CRi, 29%; mdor, 3.1 mo; mpfs, 1.8 mo; mos 6.7 mo CR/CRp/CRi, 98%; MRD-, 96%; 3-y OS 54% ORR, 78%; CR, 59%; mos 11 mo Grade 3, arm 1: febrile neutropenia (11%); SOS (11%); grade 3, arm 2: febrile neutropenia (18%); sepsis (5%) Prolonged thrombocytopenia (79%); grade 3: transaminase elevation (19%) SOS (15%), grade 3: prolonged thrombocytopenia (81%), infections (73%)

32 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in B-cell Lymphomas (CD19) Target Phase Patients, a n Indication Treatment b Efficacy AEs CD19 I (60) R/R B-NHL SGN-CD19A q3w, q6w I (35) R/R BCL SAR3419 q3w 6 ORR, 33%; CR, 22%; mdor, 40 wk ORR, 17% Blurry vision (65%); dry eye (52%) Grade 3: eye disorders (15%); neutropenia (10%) II 39 NA (41) CD19 + R/R DLBCL SAR3419 qw ORR, 44%; (W1-4), then CR 12% q2w Grade 3: neutropenia (26%); thrombocytopenia (10%) I (43) R/R B-NHL SAR3419 qw 12 ORR, 30%; Grade 3: 32%, including cholestasis (5%) and CR/CRu, paresthesia (5%) 15%; mdor, 10 wk I (68) R/R B-NHL ADCT-402 q3w B-NHL: ORR, 60%; CR, 35%; DLBCL: ORR, 55%; CR, 37% II 42,c 52 (45) R/R DLBCL SAR3419 qw ORR, 31%; (W1-4), then mpfs, 3.9 q2w (W5-8) + R mo; mos, 9.0 mo; mdor, 8.6 mo Grade 3: neutropenia (15%); increased GGT (15%) GI disorders (52%); asthenia (25%)

33 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in B-cell Lymphomas (CD22) CD22 I (73) R/R DLBCL, inhl, or CLL PiV q3w Refractory DLBCL: ORR, 25%; mpfs, 4.0 mo; inhl: ORR, 42%; mpfs, 7.6 mo; CLL: ORR, 0% II 16,c 63 (63) R/R DLBCL or FL PiV q3w + R DLBCL: ORR, 57%; CR, 24%; mpfs, 5.2 mo; FL: ORR, 62%; CR, 10% II (81) FL, MZL, or SLL refractory to R, R + CT, or RIT InO q4w 8 ORR, 67%; CR, 31%; mpfs, 13 mo I 45,c 10 (10) R/R CD22 + B-NHL InO q4w 8 + R ORR, 80%; CR/CRu, 70%; mdor, > 1 y I 46,c 48 (32) R/R CD22 + B-NHL InO q3w 6 + R-CVP inhl: ORR, 100%; CR, 24%; anhl: ORR, 57% I 47,c 55 (55) R/R B-NHL InO q3w 6 + R-GDP FL: ORR, 71%; DLBCL: ORR, 33%; MCL: ORR, 62% I/II 48, c 118 (111) R/R CD20 + CD22 + B-NHL with previous R InO q4w 8 + R II 49,c 63 (63) High-risk R/R DLBCL InO q3w 6 + R, then asct III 50, c 338 (332) CD22 + R/R and ab-nhl not candidates for HDT Arm 1: InO q4w + R; arm 2: R + bendamustine or gemcitabine FL: ORR, 87%; mdor, NR; DLBCL: ORR, 74%; mdor, 18 mo ORR, 29%; 2-y PFS, 61% for patients undergoing HDT-aSCT Arm 1: ORR, 41%; CR, 18%; mos, 9.5 mo; arm 2: ORR, 44%; CR, 16%; mos, 9.5 mo Grade 3: neutropenia; fatigue Grade 3: neutropenia (24%); diarrhea (6%) Thrombocytopenia (74%); neutropenia (56%) Grade 3: thrombocytopenia (70%); neutropenia (50%) Grade 3: neutropenia (74%); thrombocytopenia (50%) Thrombocytopenia (85%); neutropenia (69%) Grade 3: thrombocytopenia (31%); neutropenia (22%) Grade 3: thrombocytopenia; lymphopenia Arm 1 grade 3: thrombocytopenia (48%); neutropenia (24%); arm 2 grade 3: neutropenia (40%); leukopenia (23%)

34 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in B-cell Lymphomas (CD25 and CD30) CD25 I 9 86 (68) R/R HL or NHL ADCT-301 q3w HL: ORR, 71%; CR, 40%; B-NHL: ORR, 19%; CR, 9.5% CD30 II (52) R/R DLBCL with undetectable CD30 expression II (48) R/R DLBCL with detectable CD30 expression Grade 3: increased GGT (13%); decreased platelets (9%) BV q3w ORR, 31%; CR, 12% Peripheral neuropathy (57%); grade 3 neutropenia (23%) Cohort 1: BV q3w; cohort 2: BV q3w + R Cohort 1: ORR, 44%; CR, 17%; PFS, 4.0 mo; cohort 2: ORR, 46%; CR, 15% Cohort 1: fatigue (55%), diarrhea (43%); grade 3 neutropenia (37%); cohort 2: nausea (38%); peripheral sensory neuropathy (31%); grade 3 neutropenia (19%) I 53,c 18 (17) R/R DLBCL BV q3w + Len ORR, 53%; CR, 41% Anemia (50%); thrombocytopenia (33%) II 54,c 11 d (10) 1L DLBCL with IPI 1-3 or Part 1: BV q3w + R- Part 1 18-mo PFS: aaipi 2-3 CHOP; part 2: BV q3w + CD30 +, 79%; CD30, R-CHP 58%; 18-mo OS: CD30 +, 92%; CD30, 71%; part 2 ORR, 91%; CR, 82% I 55,c 13 (12) R/R HL BV q3w 16 + ipilimumab I 56,c 19 (18) R/R HL BV q3w 16 + nivolumab I/II 57, c 62 (60) 2L chl BV q3w 4 + nivolumab ORR, 67%; CR, 42%; mpfs, 8.9 mo ORR, 89%; CR, 50% ORR, 82%; CR, 61% Part 2: alopecia (73%); nausea (73%); fatigue (64%) Grade 3: rash (8%), vomiting (8%), peripheral sensory neuropathy (8%) Grade 3: typhlitis (11%), pneumonitis (11%), hypoxia (11%) Infusion-related reactions (44%), peripheral neuropathy (20%)

35 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in B-cell Lymphomas (CD 37, 70, 79b) CD37 I (50) R/R B- or T-cell lymphoma AGS67E q3w DLBCL: ORR, 23%; CR, 18% DLT grade 4 neutropenia; peripheral neuropathy (16%) I (31) R/R NHL IMGN529 q3w ORR, 13% Neutropenia (30%), fever (27%) CD70 I (26) CD70 + R/R B-NHL or ccrcc MDX-1203 q3w ORR, 0% e ; SD, 69% Fatigue (85%), nausea (54%) I (47) CD70 + R/R NHL or mrcc SGN-75 q3w, qw ORR, 6% e ; CR, 2% e Fatigue (40%), dry eye (32%), ITP (11% in NHL patients) CD79b I 62 7 (7) R/R B-NHL PoV q3w ORR, 43%; CR, 29% Peripheral sensory neuropathy (57%) I 63,c 95 (95) R/R B-NHL or CLL PoV or PoV + R q3w NHL PoV: ORR, 55%; mpfs, 5.7 mo; mdor, 6.2 mo; PoV + R: ORR, 78%; mpfs, 12.5 mo; mdor, 12.3 mo; CLL PoV: ORR, 0% II 16,c 59 (59) R/R DLBCL or FL PoV q3w + R DLBCL: ORR, 56%; CR, 15%; FL: ORR, 70%; CR, 40% PoV: peripheral sensory neuropathy (37%); grade 3 neutropenia (40%), anemia (11%); PoV + R: peripheral sensory neuropathy (67%); grade 3 neutropenia (56%), anemia (22%) Peripheral neuropathy (39%); grade 3 neutropenia (24%), diarrhea (6%) I/II 64, c 45 (45) 1L DLBCL PoV q3w 8 + R-CHP ORR, 91%; CR, 78% Grade 3 neutropenia (27%), febrile neutropenia (11%) I/II 65, c 70 (44) R/R DLBCL or FL PoV q3w 8 + G DLBCL: ORR, 52%; CR, 29%; FL: ORR, 78%; CR, 30% Grade 3 neutropenia (13%) I/II 66, c 21 (19) 1L or R/R DLBCL PoV q3w 8 + G-CHP ORR, 91%; CR, 81% Grade 3 neutropenia (58%), anemia (25%) I/II f (64) R/R DLBCL or FL not eligible for HSCT PoV q3w + B + (R or G) versus BR I (44) R/R B-NHL DCDS0780A q3w ± R DLBCL BR: CR, 15%; mos, 4.7 mo; for PoV + BR: CR, 40%; mos, 11.8 mo; FL for PoV + BR: ORR, 100%; CR, 67%; PoV + BG: ORR, 85%; CR, 65% All B-NHL; ORR, 57%; CR, 36%; DLBCL: ORR, 60%; CR, 43% Pov + BR: grade > 3: neutropenia (46%), thrombocytopenia (33%), anemia (26%) Grade 3: neutropenia (22%), hypercalcemia (5%), thrombocytopenia (5%), decreased WBC

36 Summary of Clinical Trial Data for Investigational Antibody Drug Conjugates in Multiple Myeloma Target Phase Patients, a n Indication Treatment b Response AEs CD56 I (28) CD56 + R/R MM IMGN901 D1, D8 (21-d cycle) I 106, c 41 (32) CD56 + R/R MM IMGN901 D1, D8, D15 (28-d cycle) + Len + Dex CD138 I/II (23) R/R MM failing previous imid and PI I/II 108, c 64 (43) R/R MM BT062 D1, D8, D15 (28-d cycle) + Dex + (Len or Pom) CD269 (BCMA) I (35) R/R MM with previous alkylator, PIs, imid, and SCT treatment ORR, 18%; CR 0% ORR, 59%; scr/cr, 6% BT062 D1, D8, ORR, 4%; CR, D15 (28-d cycle) 0%; DCR, 52%; mpfs (PR or SD), 112 d GSK q3w BT062/Len/Dex: ORR, 77%; mdor, 21 mo; BT062/Pom/De x: ORR, 79%; mdor, NR ORR, 60%; scr/cr, 9%; mpfs 7.9 mo Grade 3: fatigue, renal failure Peripheral neuropathy (16%); tumor lysis syndrome (11%) Anemia, diarrhea Diarrhea, fatigue Corneal events (63%), IRRs (23%); grade 3: thrombocytope nia (34%), anemia (14%)

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