Single Agent Activity of ZW25, a HER2-Targeted Bispecific Antibody, in Heavily Pretreated HER2-Expressing Cancers 1, Murali Beeram 2, Jose Mayordomo 3, Diana Hanna 4, Jaffer Ajani 1, Mariela Blum Murphy 1, Rashmi Murthy 1, Sarina Piha-Paul 1, Todd Bauer 5, Johanna Bendell 5, Anthony El-Khoueiry 4, Heinz-Josef Lenz 4, Michael Press 4, Nels Royer 6, Diana Hausman 6, Erika Hamilton 5 1 The University of Texas MD Anderson Cancer Center, Houston, TX, 2 START, San Antonio, TX, 3 University of Colorado, Aurora, CO, 4 University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, 5 Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; 6 Zymeworks Inc., Vancouver, BC 1
Unmet Need in HER2-Expressing Cancers HER2-targeted agents demonstrate the power of targeted therapy to dramatically improve outcomes in selected patients Despite this, medical need persists in a number of settings HER2 High gastroesophageal cancer after initial HER2-targeted therapy HER2 High breast cancer after multiple prior HER2-targeted regimens HER2 High colorectal and other cancers with no approved HER2-targeted agents Lower HER2-expressing cancers Challenge: overcome resistance and control disease without undue toxicity 2
ZW25: Azymetric Bispecific HER2-Targeted Antibody HER2 ECD2 HER2 ECD4 Designed using the Azymetric bispecific platform Biparatopic simultaneously binds two HER2 epitopes ECD4 (trastuzumab binding domain) ECD2 (pertuzumab binding domain) Unique binding results in novel mechanisms of action 3
Unique Binding Geometry Drives Additional Mechanisms of Action Increased Tumor Cell Binding HER2 Receptor Clustering Enhanced Internalization 5000 4000 JIMT1 (HER2 2+) 8000 6000 Internalization 37 C, 24h ZW25 Trastuzumab MFI 3000 2000 1000 ZW25 Trastuzumab 0 0 100 200 300 Concentration (nm) Single ZW25 Antibody ZW25-HER2 Cluster MFI 4000 2000 0 MCF7 JIMT-1 SKOV3 BT-474 HER2 IHC (0/1+) (2+) (2/3+) (3+) JIMT-1 (HER2 2+) Transmission Electron Microscopy Internalization 37 o C, 24h 4
Study Design Dose escalation and cohort expansion study of single agent ZW25 Objectives Identify maximum tolerated dose/ recommended dose (MTD/RD) and schedule Evaluate adverse events (AEs), left ventricular ejection fraction (LVEF), pharmacokinetics (PK), and anti-drug antibodies (ADA) Assess anti-tumor activity per RECIST 1.1 every 8 weeks Eligibility Advanced HER2-expressing cancer that progressed after standard of care therapies, including: HER2 High breast cancer: trastuzumab, pertuzumab, and T-DM1 HER2 High gastroesophageal cancer: trastuzumab ECOG performance status 0 or 1 No known untreated brain metastases Archived or new tumor biopsy for assessment (local and central) of HER2 status 1 1 HER2 High: IHC 3+ or 2+/FISH+; HER2 Intermediate: IHC 2+/FISH-; HER2 Low: IHC 1+/FISH-; HER2 Negative: IHC 0/FISH- 5
Study Design Weekly and every two week dosing regimens evaluated; Recommended dose and schedule: 10 mg/kg weekly or 20 mg/kg every two weeks 3+3 Dose Escalation (n=22) RD Expansion Cohorts (n=20) 1 Weekly 5 mg/kg IV QW (n=3) ZW25 IV Days 1, 8, 15, and 22 of 28 day cycle 10 mg/kg IV QW (n=6) No DLTs HER2 High breast cancer (n=9) HER2 High and Intermediate GEA (n=5) 15 mg/kg IV QW (n=7) HER2 High other cancers (n=6) Every 2 Weeks ZW25 IV Days 1 and 15 of 28 day cycle 20 mg/kg IV Q2W (n=6) 1 Enrollment ongoing. Data represents snapshot from unlocked database 18 April 2018 6
Patient Characteristics: Dose Escalation and Expansion Cohorts Total 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W N=42 1 n=3 n=13 n=7 n=19 Male/Female (n) 15/27 1/2 5/8 3/4 6/13 Median age (range) 63 (27-79) 61 (58-64) 62 (31-77) 52 (36-70) 67 (27-79) Median prior systemic regimens (range) Cancer Diagnosis (n) Heavily pretreated with median 5 prior systemic regimens Prior HER2 agents: trastuzumab (93%), pertuzumab (48%), and T-DM1 (43%) 5 (0-17) 4 (4-8) 4 (2-17) 6 (2-7) 5 (0-10) Breast 20 (48%) 2 6 4 8 Gastroesophageal 13 (31%) 1 5 2 5 Colorectal 5 (12%) - 1 1 3 Other 4 (9%) - 1-3 1 Enrollment ongoing. Interim analysis from unlocked database 18 April 2018 and subject to change. 7
Safety Overview No dose-limiting toxicities Treatment-related AEs all Grade 1 or 2 except in one patient Reversible Grade 3 hypophosphatemia, arthralgia and fatigue (10 mg/kg QW) No treatment-related serious adverse events or discontinuations No LVEF decreases 10% during treatment No new detectable anti-drug antibodies Data cut-off date 18 April 2018; n=42 patients receiving <1 to 15+ treatment cycles (1 cycle = 28 days) 8
Incidence of Most Common Treatment Emergent Adverse Events QW Q2W Total (n=42) 5 mg/kg (n=3) 10 mg/kg (n=13) 15 mg/kg (n=7) 20 mg/kg (n=19) Grade Any 1 2 3 Any 1 2 3 Any 1 2 3 Any 1 2 3 Any 1 2 3 Adverse Event n (%) Infusion Reaction 23 (55%) 2 21-1 (33%) - 1-8 (62%) - 8-3 (43%) 2 1-11 (58%) - 11 - Diarrhea 22 (52%) 15 7-1 (33%) 1 - - 8 (62%) 7 1-2 (29%) 1 1-11(58%) 6 5 - Fatigue 16 (38%) 6 9 1 3 (100%) 2 1-5 (39%) - 4 1 3 (43%) 2 1-5 (38%) 2 3 - Nausea 11 (26%) 7 4-0 (0%) - - - 4 (31%) 3 1-3 (43%) 1 2-4 (21%) 3 1 - Anorexia 10 (24%) 7 3-2 (67%) 1 1-2 (15%) 2 - - 0 (0%) - - - 6 (32%) 4 2 - Rash 9 (21%) 9 - - 0 (0%) - - - 3 (23%) 3 - - 1 (14%) 1 - - 5 (26%) 5 - - Treatment emergent adverse events reported in 20% of patients regardless of relationship to study drug 9
Pharmacokinetics PK profile supports weekly and every 2 week dosing regimen 10 6 Single Dose PK 10 6 Multi-Dose PK Concentration (ng/ml) 10 5 10 4 10 3 0 1 2 3 4 5 6 7 Time (days) 20 mg/kg Q2W 15 mg/kg QW 10 mg/kg QW 5 mg/kg QW pmel pmel; predicted minimum efficacious level based on trastuzumab trough levels Concentration (ng/ml) 10 5 10 4 10 3 0 7 14 21 28 35 42 49 Time (days) 20 mg/kg Q2W 10 mg/kg QW pmel 10
Change in Target Lesions Across Cancer Types % Change in SLD 60 50 40 30 20 10 0-10 -20-30 Decrease in target lesions in majority of patients with measurable disease Breast Gastroesophageal Colorectal Cervical Salivary gland Gallbladder -40-50 -60-70 -80-90 SLD = sum of longest diameters 11/42 patients not evaluable for change in SLD: too early (n=3); no target lesions (n=4); CNS progression on Day 14 (n=1); clinical progression on Day 21 (n=1); withdrawal of consent (n=1); unrelated SAE (n=1). 11
Best RECIST 1.1 Response to Single Agent ZW25 Response- Evaluable Patients 1 Disease Control Rate Partial Response Stable Disease Progressive Disease Total (n=42) 33 18 (55%) 12 (36%) 6 (18%) 15 (45%) Breast cancer (n=20) 18 9 (50%) 6 (33%) 3 (17%) 9 (50%) Gastroesophageal cancer (n=13) 9 5 (56%) 4 (44%) 1 (12%) 4 (44%) Other cancers (n=9) 6 4 (67%) 2 (33%) 2 (33%) 2 (33%) Colorectal (n=5) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%) Other (n=4) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%) DCR: Disease control rate = best response of stable disease or partial response at any time 1 Response evaluable = measurable disease per RECIST 1.1 and at least one tumor restaging or unequivocal clinical progression. Not evaluable n=9, including: too early (n=3); no target lesions (n=4); withdrawal of consent (n=1); unrelated SAE (n=1). Data cut-off date 18 April 2018. 12
Breast Cancer: Single Agent Anti-tumor Activity All 20 patients with history of HER2 High breast cancer, and median 5 prior HER2-targeted regimens for metastatic disease Prior trastuzumab (T) = 100%; T-DM1 (K) = 95%; pertuzumab (P) = 85%; lapatinib (L) = 50%; investigational agent (I) = 35% % Change in SLD 40 30 20 10 0-10 -20-30 -40-50 -60 Change in Target Lesions at Time of Best Response 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W * # # # # * * PD due to new CNS lesion # PD due to new lesion TPKI TKL TPKI TKL TPK 1 TP TPKLI TKL TPKL TPKI TPK TPKL TPK TPKLI TPK TPKl TPKL 1 HER2 negative liver biopsy obtained at study entry; progressive disease in liver SLD = sum of longest diameters. 3/20 breast cancer patients not evaluable for change in SLD: no measurable disease (n=2); clinical progression on Day 21 (n=1). 13
Breast Cancer: Time on Treatment Breast Cancer Patients (n=20) TPKL TPK TPKI TPKL TPK TPKL TPKLI TPKI TPK TPKLI TPKI TP TLK TPK TLK TPKL TPKI TLK TPKLI TPK Non-CR/non-PD SD SD SD SD HER2 Neg 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W Active Patients PD due to CNS lesion 0 56 112 168 224 280 336 392 448 Days on Treatment 56 days = 2 cycles T = trastuzumab; P = pertuzumab; K = T-DM1; L = lapatinib; I = investigational CP clinical progression 14
Gastroesophageal Cancer: Single Agent Anti-Tumor Activity Median 4 prior systemic regimens, including prior trastuzumab in all patients % Change in SLD 60 50 40 30 20 10 0-10 -20-30 -40-50 -60-70 -80-90 Change in Target Lesions at Time of Best Response # HER2 Status HIGH HIGH 1 HIGH HIGH INT HIGH HIGH HIGH 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W # PD due to new lesion 1 IHC1+/FISH+; 5/13 patients GEA patients not evaluable for change in SLD: too early (n=1); no measurable disease (n=1); CNS PD Day 14 due to brain metastases (n=1); unrelated SAE (n=1); and withdrawal of consent (n=1). HER2 High: IHC 3+ or 2+/FISH+; HER2 Intermediate: IHC 2+/FISH-; HER2 Low: IHC 1+/FISH-; HER2 Negative: IHC 0/FISH- 15
Gastroesophageal Cancer: Time on Treatment HER2 Status 1 Gastroesophageal Cancer Patients (n=13) HIGH HIGH HIGH HIGH HIGH INT LOW HIGH 2 HIGH LOW HIGH HIGH SD PD 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W Active Patients PD due to CNS lesion Withdrew Consent Unrelated AE LOW 0 56 112 168 224 280 Days on Treatment 1 Discordance between local and central assessments; HER2 High status not confirmed in 5/9 patients with biopsies available for central review. 2 IHC1+/FISH+ HER2 High: IHC 3+ or 2+/FISH+; HER2 Intermediate: IHC 2+/FISH-; HER2 Low: IHC 1+/FISH- 16
Gastroesophageal Cancer: Anti-Tumor Activity 75 year old female with HER2 High metastatic gastric cancer Progression after prior FOLFOX, ramucirumab, FOLFIRI + trastuzumab Confirmed partial response including liver metastases Change in liver lesions 2.9 cm 1.3 cm 1.4 cm Baseline (Day 0) End Cycle 2 (-71% SLD) End Cycle 4 (-71% SLD) Baseline End Cycle 2 17
Other HER2 High Cancers: Single Agent Anti-Tumor Activity All patients with history of HER2 High cancer Median 4 prior systemic regimens Change in Target Lesions at Time of Best Response Time on Treatment % Change in SLD 50 45 40 35 30 25 20 15 10 5 0-5 -10-15 -20-25 -30-35 -40-45 5 mg/kg QW 10 mg/kg QW 15 mg/kg QW 20 mg/kg Q2W # # PD due to new lesion Colorectal 1 Cervical Colorectal Salivary Colorectal Gallbladder Colorectal Colorectal Salivary Gallbladder Colorectal 1 Cervical Adnexal Colorectal Colorectal SD TP SD SD T TP Active Patients T TPK TKLI 0 56 112 168 Days on Treatment 1 HER2 heterogeneous (HER2 High and HER2 Negative by central review) 3/9 patients not evaluable for change in SLD: too early (n=2); no measurable disease (n=1). T = trastuzumab; P = pertuzumab; K = T-DM1; L = lapatinib; I = investigational 18
Summary of ZW25 Single Agent Experience Well tolerated at all dose levels/schedules in heavily pretreated patients Recommended dose 20 mg/kg every two weeks Cytotoxin-free anti-tumor activity across multiple cancers HER2 High breast cancer with median 5 prior HER2-targeted regimens HER2 High and HER2 Intermediate gastroesophageal cancers after prior trastuzumab HER2 High colorectal, gall bladder and salivary gland cancers Validates Azymetric platform and biparatopic approach to overcome target resistance 19
ZW25 Ongoing Activities and Opportunities Continuing evaluation as single agent Late stage HER2 High gastroesophageal cancers HER2 High colorectal and other cancers Evaluating combinations with other agents in earlier lines of therapy Breast and gastroesophageal cancers Expanding early dataset in lower HER2-expressing cancers 20
Acknowledgements We sincerely thank all patients and their families Thanks to all the investigators and clinical trial personnel MD Anderson Cancer Center, Houston Sarah Cannon Research Institute, Nashville START, San Antonio University of Colorado Cancer Center, Denver UAB Comprehensive Cancer Center, Birmingham Ottawa Hospital Cancer Centre, Ottawa Hoag Family Cancer Institute, Los Angeles USC Norris Cancer Center, Los Angeles Rush University Medical Center, Chicago Northwest Medical Specialties, Tacoma Jewish General Hospital, Montreal Thanks also to Ms. Ivonne Villalobos at USC Medical Center Pathology Lab for support of HER2 testing and to Dr. Ronald Korn from Imaging Endpoints for PET imaging 21