Constan'ne S Tam Victorian Comprehensive Cancer Center Melbourne, Australia

Transcription

1 Constan'ne S Tam Victorian Comprehensive Cancer Center Melbourne, Australia

2 BGB-3111: Kinase Selec.vity Rela.ve to Ibru.nib Equipotent against BTK compared to ibru.nib Higher selec.vity vs EGFR, ITK, JAK3, HER2 and TEC Targets Assays Ibru.nib IC 5 (nm) BGB-3111 IC 5 (nm) Ra.o (BGB-3111:Ibru.nib) BTK BTK-pY223 Cellular Assay Rec-1 Prolifera.on BTK Occupa.on Cellular Assay BTK Biochemical Assay EGFR p-egfr HTRF Cellular Assay A431 Prolifera.on ,21 ITK Occupancy Cellular Assay 189 3, ITK p-plc γ1 Cellular Assay 77 3, IL-2 Produc.on Cellular Assay ,536 ITK Biochemical Assay JAK3 JAK3 Biochemical Assay HER2 HER2 Biochemical Assay

3 BGB-3111 First-in-Human Study Part 2a (paired LN biopsy) Part 1 Dose Escala.on Cohort Dose n 1 Growth factor/ transfusion allowed 2 An'-coagula'on allowed RP2D # CLL/SLL Patients 1 4 mg QD mg QD mg QD 6 2 4a 32 mg QD 6 1 4b 16 mg BID 4 1 Eligibility: - WHO defined B cell malignancy - >1 prior therapy (relapsed cohorts only) - No available higher priority treatment - ECOG -2 - ANC >1,/ul, platelets >1,/ul 1 - Adequate renal and hepatic function - No significant cardiac disease 2 QD, 2 R/R MCL, MZL, FL, GCB DLBCL BID, 2 R/R MCL, MZL, FL, GCB DLBCL Part 2b BID, R/R non-gcb DLBCL, n=2 Part 2c BID, R/R CLL/SLL, n=2 Part 2d BID, R/R WM, n=2 Part 2e QD, R/R CLL/SLL, n=2 Part 2f QD, TN & R/R WM, n=2 Part 2g QD, R/R MCL, n=2 Part 2h QD, TN CLL/SLL, n=2 Part 2i QD, TN MCL, n=2 3

4 Plasma Exposure Comparison for BGB-3111 & Ibru.nib BGB-3111 Ibru.nib 7 7 Plasma Concentration (ng/ml) Plasma Concentration (ng/ml) Time post-dose (hours) Time post-dose (hours) 4mg QD 8mg QD 16mg QD 32mg QD Tam et al., ASH, mg Adapted from Advani et al., JCO, 213 C max and AUC of BGB-3111 at 8 mg is similar to those of ibru'nib at 56 mg Free drug exposure of BGB-3111 at 4 mg is comparable to that of ibru'nib at 56 mg 4

5 Complete and Sustained BTK Occupancy in PBMC and Lymph Node PBMC Lymph Node 12% BTK Occupancy 1% 8% 6% 4% 2% % CLL MCL FL DLBCL MZL WM mg QD 16mg BID Complete BTK occupancy in PBMCs at the star'ng dose (4 mg) Paired lymph node biopsies were collected during screening and pre-dose on day 3 Median trough occupancy: 1% (16mg BID) vs 94% (32mg QD), p=.2 Propor'on >9% trough occupancy: 94% (16mg BID) vs 58% (32mg QD), p=.27 5

6 Phase I CLL/ SLL: Patient Characteristics Characteristic Total (N = 69) Age, years, median (range) 68 (24-87) ECOG Performance Status, n (%) 1 2 Follow-up, months, median (range) Prior treatment status Treatment-naïve, n (%) Relapsed/refractory, n (%) Number of prior therapies, median (range) 34 (49) 33 (48) 2 (3) 1.3 ( ) 18 (26) 51 (74) 2 (1-7) Bulky disease,* n (%) 4 (6) Molecular risk factors, n (%) del17p/p53mut (n = 51) 11q- (n = 44) IgHV unmutated (n = 16) ECOG, Eastern Cooperative Oncology Group; LN, lesion. 2 (39) 14 (32) 11 (69) * Any lymph node >1 cm in maximum diameter. 6

7 CLL / SLL: Most Frequent Adverse Events (> 1%) Independent of Causality (N = 69) Adverse Event All Grade Grade 3-4 n (pts) % (N = 69) n (pts) % (N = 69) Petechiae/purpura/contusion 32 46% 1 1% Fatigue 2 29% % Upper respiratory tract infection 19 28% % Cough 16 23% % Diarrhea 15 22% % Headache 13 19% % Hematuria 1 15% % Nausea 9 13% % Rash 9 13% % Arthralgia 8 12% % Muscle spasms 8 12% % Urinary tract infection 8 12% % pts, patients. 7

8 CLL / SLL : Adverse Events of Interest Purpura (subcutaneous hemorrhage) SAE n (pts) % (N = 69) Grade Led to Treatment Discontinuation Y 1 1% G3 No Diarrhea Y 1 1% G2 No Atrial fibrillation N 1 1% G2 No A total of 18 SAEs were experienced by 13 patients Additional SAE s not listed in Table 4 (1 each) were also reported: CLL, delirium, febrile neutropenia, Invasive ductal breast carcinoma, lower respiratory tract infection, pleural effusion, renal colic, sepsis, splenectomy, splenomegaly, painful swelling in right neck, cardiac failure, coronary artery stenosis, ventricular extrasystole, pneumonia, and hemorrhoidal infection 8

9 CLL/ SLL: Response Response Treatment Naïve (n = 16) Relapsed/Refractory (n = 5) Total (n = 66) Median follow-up, mo (range) 7.6 ( ) 14. ( ) 1.5 ( ) Best Response ORR CR PR PR-L SD D/C prior to assessment 16 (1%) 1 (6%) 13 (81%) 2 (13%) 46 (92%) 1 (2%) 41 (82%) 4 (8%) 3 (6%) 1 (2%) 62 (94%) 2 (3%) 54 (82%) 6 (9%) 3 (5%) 1 (2%) CR, complete response; D/C, discontinuation; ORR, overall response rate; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease. The ORR in patients with del17p and/or 11q- (n = 22) was 96% 9

10 CLL/ SLL: Kinetics of ALC and SPD Response 1

11 CLL / SLL: Progression-Free Survival 11

12 Efficacy Summary in WM (n = 42) Total Median follow-up (range) 12.3 months ( ) Best Response (n = 42) CR VGPR PR MR SD IgM reduction (median, %) Hemoglobin change (median) Lymphadenopathy reduction by CT (n, range) Overall response rate * Major response rate 18 (43%) 14 (33%) 6 (14%) 4 (1%) 32.7 g/l to 6.1 g/l (81.3%) 9% ORR 14.5 g/l to 142 g/l 45.5% (median) (16, 18.2%-81.4%) 76% MRR* 12

13 IWWM Response Over Time on Treatment 1% 6% 28% 8% 53% Response Rate 6% 4% 59% 56% VGPR PR MR SD 2% 25% 4% 8% % 9% 8% 7% % Cycle 3 (n=32) Cycle 6 (n=25) Cycle 12 (n=15) 13

14 WM: Intrapa.ent Dose Escala.on S41: Ini.al dose 4mg QD S11: Ini.al dose 8mg QD IgM (g/l) Increase to 8mg QD Increase to 16mg QD IgM (g/l) Increase to 16mg QD Increase to 16mg BID 1 1 Screening W5D1 W9D1 W13D1 W17D1 W21D1 W25D1 W29D1 W33D1 W37D1 W41D1 W45D1 W49D1 W52D1 W6D1 W68D1 W76D1 W84D1 W92D1 W1D1 5 Screening W5D1 W9D1 W13D1 W17D1 W21D1 W25D1 W29D1 W33D1 W37D1 W41D1 W45D1 W49D1 W52D1 W6D1 W68D1 W76D1 W84D1 W92D1 W1D1 14

15 BGB-3111 Does Not Impair Rituximab-Induced ADCC Published preclinical data suggest that off-target effects of ibrutinib may be detrimental to CD2 mab-induced ADCC and the activity of the combination In a human MCL xenograft model, the combination of BGB-3111 and CD2 antibody demonstrated improved anti-tumor activity as compared to monotherapies and combination of ibrutinib and CD2 antibody 1 Li N, et al. Cancer Res. 215;75:2597 [abstract]. 15

16 Study Design: BGB-3111 in Combination with Obinutuzumab Cohort BGB-3111* (D1-28/28-day cycles) DOSE ESCALATION Obinutuzumab Patients Dosed 1a 32 mg QD Cycle 1 D2: 1 mg Cycle 1 D3: 9 mg Cycle 1 D9 and D16: 1 mg Cycles 2-6 D1: 1 mg 1b 16 mg BID 5 4 * BGB-3111 treatment continued until progression, death, or unacceptable toxicity. Cohort -1a and -1b will be opened if 2 or more DLTs are observed in Cohorts 1a and 1b. DOSE EXPANSION Eligibility: WHO defined B cell lymphoid malignancy 1 prior therapy (relapsed cohorts only) No available higher priority treatment ECOG -2 ANC >1,/µl, platelets >4,/µl Adequate renal and hepatic function No significant cardiac disease Growth factor/transfusion allowed. Anti-coagulation allowed. Pop Disease Planned TN CLL/SLL 2 R/R CLL/SLL 2 R/R non-gcb DLBCL 2 R/R FL, MCL, MZL, and WM 2 R/R FL 4 NCT

17 BGB GA11: Selected Adverse Events Event, n (%) CLL/ SLL (n = 45) FL (n = 17) Patients with at least one AE Grade 3 19 (42.2) 4 (23.5) Patients with at least one SAE 11 (24.4) 4 (23.5) Events leading to treatment discontinuation 1 (2.2)* * Patient with a history of squamous cell carcinoma discontinued due to squamous cell carcinoma AE of Special Interest, n (%) CLL/SLL (n = 45) FL (n = 17) All Grade Grade 3-4 All Grade Grade 3-4 Diarrhea 7 (15.6) 3 (17.6) Serious hemorrhage* Atrial fibrillation Infusion-related reactions 11 (24.4) 1 (2.2) 1 (5.9) * >Grade 3 hemorrhage, or central nervous system hemorrhage of any grade. 17

18 BGB GA11: Disease Response Follow-up and Response Median follow-up, mo (range) TN CLL/SLL R/R CLL/SLL FL (n = 18) (n = 25) (n = 15) 7. ( ) 8. ( ) 6.2 ( ) Best Response ORR 16 (88.9) 23 (92.) 11 (73.3) CR 4 (22.2) 4 (16.) 5 (33.3) PR 12 (66.7) 19 (76.) 6 (4.) PR-L N/A SD 2 (11.1) 1 (4.) 2 (13.3) PD 1 (4.) 2 (13.3) 18

19 Registration Studies WM : Phase 3 BGB-3111 vs Ibrutinib (1L/RR) CLL : Phase 3 BGB-3111 vs Benda-Ritux (1L) FL : Phase 2R BGB Obinutuzumab vs Obinutuzumab (RR) 19