ASCO 2023 HER2 gastrointestinal cancer SS2 Ku DL.pptx

her2 gastric cancer

1. HER2 Precision Therapy in Advanced Gastric/GEJ Cancer Supported by educational grants from AstraZeneca; Daiichi Sankyo, Inc.; and Seagen Inc.

2. Please feel free to use and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details About These Slides Slide credit: clinicaloptions.com

3. Faculty Geoffrey Ku, MD Associate Attending Physician Head, Esophagogastric Section, Gastrointestinal Oncology Service & Member, Cellular Therapy Service Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York Geoffrey Ku, MD: researcher: Adaptimmune, AstraZeneca, Bristol-Myers Squibb, CARsgen, Daiichi Sankyo, IMAB, Merck, Oncolys, Pieris, Zymeworks; consultant/advisor/speaker: AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, IMAB, Merck, Pieris, Zymeworks.

4. ToGA Study

5. 5 Mo Survival Probability 1.0 0.8 0.6 0.4 0.2 11.1 13.8 36 2 4 6 8 10 12 14 16 18 20 22 24 26 28 32 34 Trastuzumab + chemotherapy Chemotherapy alone 167 182 13.8 11.1 0.74 (0.60-0.91) .0046 Events P V alue HR (95% CI) Median OS, Mo ToGA: Chemotherapy ± Trastuzumab as First-line Therapy in HER2-Positive mGC Randomized phase III study of patients with HER2-positive gastric or GEJ cancer 594 patients randomly assigned to chemotherapy (fluoropyrimidine + platinum) with or without trastuzumab Significant improvement in OS in HER2-positive mGC with addition of trastuzumab to chemotherapy 5 Bang. Lancet. 2010;376:687.

6. ToGA: HER2 Subgroup Analysis Overall survival benefit of trastuzumab appeared to vary by HER2 subgroup Bang. Lancet. 2010;376:687. Trastuzumab regulatory approvals: US: IHC 3+ and/or FISH+ tumors (2010) Europe : IHC 2+/FISH+ or IHC 3+ (2022) HR (95% CI) HR (95% CI) N Median OS (months) 0.2 0.4 0.6 1 2 3 4 5 Favors chemotherapy alone Favors trastuzumab plus chemotherapy All Preplanned exploratory analysis IHC 0/FISH positive IHC 1+/FISH positive IHC 2+/FISH positive IHC 3+/FISH positive IHC 3+/FISH negative Post-hoc exploratory analysis IHC 0 or 1+/FISH positive IHC 2+/FISH positive or IHC 3+ 584 61 70 159 256 15 131 446 0.74 (0.60-0.91) 0.92 (0.48-1.76) 1.24 (0.70-2.20) 0.75 (0.51-1.11) 0.58 (0.41-0.81) 0.83 (0.20-3.38) 1.07 (0.70-1.62) 0.65 (0.51-0.83) 13.8 vs 11.1 10.6 vs 7.2 8.7 vs 10.2 12.3 vs 10.8 17.9 vs 12.3 17.5 vs 17.7 10.0 vs 8.7 16.0 vs 11.8

7. Subsequent Negative Phase III Studies in Advanced GC First-line Studies JACOB: capecitabine/cisplatin/trastuzumab ± pertuzumab (N = 780) OS: 17.5 vs 14.2 mo (HR: 0.84; P = .057) HELOISE: capecitabine/cisplatin + 2 dose levels of trastuzumab (N = 400) LOGiC: capecitabine/oxaliplatin ± lapatinib (N = 545) No difference in OS (12.2 vs 10.5 mo; HR: 0.91) Second-line Studies TyTAN: paclitaxel ± lapatinib (N = 261) GATSBY: paclitaxel or docetaxel vs T-DM1 (N = 415) T-ACT: paclitaxel ± trastuzumab (N = 91) Tabernero. Lancet Oncol. 2018;19:1372. Shah. JCO. 2017;35:2558. Randolph Hecht. JCO. 2016;34:443. Satoh. JCO. 2014;32:2039. Thuss-Patience. Lancet Oncol. 2017;18:640. Makiyama. JCO. 2020;38:1919.

8. KEYNOTE-811

9. KEYNOTE-811 : Study Design Randomized, double-blind, placebo-controlled phase III study Primary endpoints: OS, PFS per RECIST v1.1 by BICR Secondary endpoints: ORR and DoR per RECIST v1.1 by BICR, safety Patients with HER2+ advanced gastric or GEJ adenocarcinoma, no prior therapy in advanced setting (N = 692) Pembrolizumab 200 mg IV Q3W + Trastuzumab 6 mg/kg IV Q3W + FP or CAPOX* Placebo IV Q3W + Trastuzumab 6 mg/kg IV Q3W + FP or CAPOX* Stratified by geographic region, PD-L1 CPS, chemotherapy choice Janjigian. Nature. 2021;600:727. Up to 35 cycles or until disease progression, unacceptable toxicity, or study withdrawal *Trastuzumab 8 mg/kg loading dose. FP: 5-fluorouracil 800 mg/m 2 IV Days 1-5 Q3W + cisplatin 80 mg/m 2 IV Q3W CAPOX: capecitabine 1000 mg/m 2 BID Days 1-14 Q3W + oxaliplatin 130 mg/m 2 IV Q3W

10. KEYNOTE-811: Pembrolizumab + Trastuzumab + Chemotherapy in Initial Therapy of HER2-Positive mGC 10 Efficacy analysis: first 264 patients enrolled; safety analysis: 433 patients who received ≥1 dose of study medication. Janjigian. Nature. 2021;600:727. Efficacy Population Outcome Pembrolizumab (n = 133) Placebo (n = 131) ORR, % (95% CI) 74.4 (66.2-81.6) 51.9 (43.0-60.7) ORR difference 22.7 (11.2-33.7); P = .00006 DCR, % (95% CI) 96.2 (91.4-98.8) 89.3 (82.7-94.0) Best response, n (%) CR PR SD PD Not evaluable Not assessed 15 (11) 84 (63) 29 (22) 5 (4) 4 (3) 64 (49) 49 (37) 7 (5) 2 (2) 5 (4) Duration of response Median, mo (range) ≥6 mo duration, % ≥9 mo duration, % (n = 99) 10.6 (1.1+ to 16.5+) 70.3 58.4 (n = 68) 9.5 (1.4+ to 15.4+) 61.4 51.1

11. KEYNOTE-811: 1L Pembrolizumab + Trastuzumab + Chemotherapy in HER2+ mGC Janjigian. Nature. 2021;600:727. Pembro + Trastuzumab n = 124 Any decrease 97% Decrease of ≥80% 32% Placebo + Trastuzumab n = 122 Any decrease 90% Decrease of ≥80% 15% Change From Baseline (%) 100 80 60 40 20 -20 -40 -60 -80 -100 Change From Baseline (%) 100 80 60 40 20 -20 -40 -60 -80 -100 Outcome Pembrolizumab (n = 133) Placebo (n = 131) ORR, % (95% CI) 74.4 (66.2-81.6) 51.9 (43.0-60.7) ORR difference 22.7 (11.2-33.7; P = .00006)

12. KEYNOTE-811 Survival data are pending FDA approved pembrolizumab + trastuzumab/chemotherapy as first-line therapy for HER2-positive GEJ/gastric cancer in May 2021 This combination is not approved outside of the US

13. Trastuzumab Deruxtecan

14. Trastuzumab Deruxtecan Antibody–drug conjugate of trastuzumab with a topoisomerase inhibitor Potential advantages: High potency payload High ratio of trastuzumab: payload molecules “ Bystander ” effect Humanized anti-HER2 IgG1 mAb Tetrapeptide-based cleavable linker Cysteine residue Drug/linker Topoisomerase I inhibitor (DXd) payload (exatecan derivative) Nakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039.

15. DESTINY-Gastric01: T-DXd in Previously Treated, HER2+ Gastric/GEJ Adenocarcinoma Randomized phase II study of T-DXd vs physician’s choice therapy (irinotecan or paclitaxel) for patients with HER2+ locally advanced or metastatic gastric or GEJ cancer that progressed on ≥2 prior regimens (N = 188) Shitara. Lancet Oncol. 2019;20:827. Shitara. NEJM. 2020 ;382:2419. Yamaguchi. ASCO GI 2022. Abstr 242. 3 6 9 12 15 18 21 24 100 80 60 40 20 Median OS , T-DXd vs PC: 12.5 vs 8.9 mo HR: 0.60 (95% CI: 0.42-0.86) Median PFS , T-DXd vs PC: 5.6 vs 3.5 mo HR: 0.47 (95% CI: 0.31-0.71) T-DXd PC Mo 21 30 43 Patients (%) 3 6 9 12 15 18 21 24 27 30 100 80 60 40 20 OS (%) Mo T-DXd PC ORR : 51% vs 14% (HR: 0.59 [0.39-0.88]; P <.0001)

16. DESTINY-Gastric01: Safety in Longer Follow-up Safety profile of trastuzumab deruxtecan was generally manageable The most common any-grade AEs in ≥30% of patients were hematologic or gastrointestinal Grade ≥3 TEAEs: 85.6% with T-DXd and 56.5% with chemotherapy Notable TEAE: Interstitial lung disease 16 Shitara. NEJM. 2020;382:2419. Trastuzumab Deruxtecan PI. Yamaguchi. ASCO GI 2022. Abstr 242. Safety Outcome (All Grade/Grade 3/4) T-DXd (n = 125) Chemotherapy (n = 62)* Neutropenia, % 65/51 36/24 Anemia, % 58/38 31/23 Decreased WBC count, % 38/21 36/11 Drug-related ILD, % 12.8/2.4 *Physician’s choice of irinotecan or paclitaxel.

17. DESTINY-Gastric01: Response by Prior ICI in mGC Under current treatment guidelines, more patients will receive ICI as first-line therapy in mGC Exploratory analysis by prior treatment with anti-PD-1 ICI T-DXd more effective than chemotherapy regardless of prior ICI Safety outcomes similar in patients with or without prior ICI, including rates of ILD Shitara. ASCO GI 2022. Abstr. 322. 17 Outcome T-DXd Chemotherapy* Prior ICI Yes n = 44 No n = 81 Yes n = 17 No n = 45 Confirmed ORR , % 56.8 34.7 18.5 10.0 Median OS, mo 95% CI 16.6 12.1-21.2 10.3 8.1-13.0 8.6 3.6-10.7 8.4 6.9-13.6 Any grade I LD, % 9.1 9.9 - - *Physician’s choice of irinotecan or paclitaxel.

18. DESTINY-Gastric01 Biomarker Analysis T-DXd in HER2+ Advanced Gastric/GEJ Cancer After ≥2 Prior Regimens Only 30% of new tumor samples obtained after/during trastuzumab therapy ORR slightly higher in patients with HER2+ tumor after/during first trastuzumab ORR: 57% vs 48% OS confounded by small sample size (same) High level of ERBB2 (mRNA or plasma) predicts high ORR Tissue mRNA >9.7: ORR 81% vs 23% (small sample size) Plasma ERBB2 detected in 64% of patients (Guardant360) ORR with ERBB2+ ctDNA : 76% vs 40% OS nearly doubled if ctDNA ERBB2 >6 copy: 21 vs 12 mo median OS Co-occurring EGFR/MET amplifications associated with worse outcome Shitara. ESMO World GI 2021. Abstr O14. FDA urges biopsy of all patients after trastuzumab progression ~20% of patients with esophagogastric cancer have loss of HER2 This analysis indicates that ctDNA can be used if biopsy is not feasible

19. DESTINY-Gastric02: Second-line Trastuzumab Deruxtecan for Advanced HER2+ GC/GEJ Cancers Ongoing, phase II, single-arm study of Western patients with HER2+ gastric/GEJ cancers Patients progressed while on or after first-line, trastuzumab-based therapy HER2+ by ISH 3+ or ISH 2+/ISH+ 1 (96.2%) or 2 (3.8%) prior lines of therapy Primary endpoint: Confirmed ORR 19 Ku. ESMO 2022. Abstr 1205M0. Outcome T-DXd (N = 79) Median follow-up duration, mo 10.2 Confirmed ORR, n (%) 33 (41.8) CR, n (%) PR, n (%) 4 (5%) 29 (37%) Median OS, mo (95% CI) 12.1 (9.4-15.4) 12-mo OS rate 50.6% Median DoR, mo (95% CI) 8.1 (5.9-NE) Median PFS, mo (95% CI) 5.6 (4.2-8.3)

20. DESTINY-Gastric02: OS and PFS With T-DXd Cutoff date: November 8, 2021. *Analysis conducted in the full analysis set. † Analysis conducted in the full analysis set based on 51 events (44 PD, 7 deaths). Ku. Ann Oncol. 2022;33: Abstr 1205M0. Median OS : 12.1 mo (95% CI: 9.4 -15.4)* Median PF S : 5.6 mo (95% CI: 4.2-8.3) † 100 80 60 40 20 Patients (%) 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mo Patients at Risk, n 79 78 74 73 66 62 59 53 50 47 41 37 26 19 14 13 11 10 9 7 5 3 1 100 80 60 40 20 Patients (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mo Patients at Risk, n 79 77 60 49 44 35 27 25 22 19 11 9 5 5 4 3 3 3 3 3 1 1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

21. DESTINY-Gastric02 Additional T-DXd Results in HER2+ Adv Gastric/GEJ Cancer After First-Line Trastuzumab GEJ primary: 66% 1 vs 86% in DESTINY-Gastric01 2 Rebiopsy for HER2 mandated for all patients and centrally reviewed 1 vs 30% in DESTINY-Gastric01 2 ORR (primary endpoint): 38%; median PFS: 5.5 mo vs 27% ORR; median PFS: 4.2 mo with ramucirumab/paclitaxel 3 1. Van Cutsem. ESMO 2021. Abstr LBA55. 2. Shitara. NEJM. 2020 ;382:2419. 3. Wilke. Lancet. 2014;15:1224.

22. DESTINY-Gastric01 and -Gastric02 The results of DESTINY-Gastric01 and -Gastric02 led to these regulatory approvals for T-DXd: Approved in September 2020 Approved in January 2021 Approved in December 2022 Second-line or later therapy after prior trastuzumab-based regimen Third-line or later therapy after first-line trastuzumab-based regimen

23. Other DESTINY-Gastric Studies DESTINY-Gastric04: Phase III study of second-line T-DXd vs ramucirumab + paclitaxel (NCT04704934) DESTINY-Gastric03: Phase Ib/II study of T-DXd in combination with chemotherapy and/or immune checkpoint inhibitors in first line and second line (NCT04379596)

24. T-DXd: Interstitial Lung Disease

25. Management of ILD Associated With Trastuzumab Deruxtecan 25 Assessments should include: High-resolution CT Pulmonologist consult; if indicated, ID consult Blood culture and CBC; other blood tests as needed Consider bronchoscopy and BAL if indicated and feasible PFTs and pulse oximetry Arterial blood gases, if indicated As soon as ILD suspected, collect 1 blood sample for PK assessment, if feasible Rule out other causes of ILD (eg, progression, infection, other drugs, radiotherapy) All ILD events should be followed until resolution and after drug discontinuation Monitor Suspected ILD Interrupt drug Rule out ILD if the patient exhibits: Radiographic changes suggesting ILD Acute onset of new/worsening pulmonary or related symptoms (eg, cough, dyspnea, fever) Confirm Manage Grade 1: Hold until resolved to grade 0, consider corticosteroids (0.5 mg/kg/d prednisolone), then: If resolved ≤28 d from onset: maintain dose If resolved >28 d after onset: reduce dose by 1 level If grade 1 ILD occurs beyond cycle D 22 and has not resolved within 49 d from last infusion: discontinue drug Grades 2-4: Permanently discontinue treatment and promptly initiate systemic corticosteroid treatment , eg, ≥1 mg/kg/d prednisolone or equivalent for at least 14 d followed by taper for at least 4 wk Trastuzumab deruxtecan PI. Modi. NEJM. 2020;382:610.

26. Risk Factors for ILD With T-DXd: Pooled Analysis Adjudicated drug-related ILD events across 9 clinical trials with T-DXd in breast cancer, gastric cancer, NSCLC, colorectal cancer, and other tumor types. Across all tumor types, a total 15.4% of patients had an event; the majority of events were grade 1 or 2. Powell. ESMO Open. 2022;7:1. 26 Potential Risk Factor Age group <65 yr ≥65 yr Country Japan Non-Japan Lung comorbidities Yes No Baseline real function Normal Mild decrease Moderate/severe decrease Time since disease diagnosis 0 to ≤4 yr >4 yr Dose 5.4 mg/kg q3w 6.4 mg/kg q3w >6.4 mg/kg q3w Baseline SpO 2 ≥95% <95% Patients , n (N = 1150) 754 396 506 644 81 1069 470 458 196 624 403 315 808 27 1080 57 HR (95% CI) 1.56 (1.02-2.38) Ref 2.08 (1.45-2.98) Ref 1.75 (1.03-2.98) Ref Ref 1.24 (0.83-1.84) 2.73 (1.65-4.52) Ref 1.82 (1.20-2.75) Ref 1.30 (0.85-1.99) 2.92 (1.32-6.42) Ref 2.14 (1.11-4.13) HR (95% CI) 0.05 0.1 0.25 0.5 1 2 4 8 16 32 64

27. Zanidatamab (ZW25)

28. Zanidatamab (ZW25): Biparatopic HER2 Ab ZWI-ZW25-201 is an open-label, 2-part, phase II study Ku. ESMO 2021. Abstr 1380. Primary endpoints: s afety (part 1); ORR (part 2) Secondary endpoints: ORR (part 1); safety, DCR, DoR, PFS (part 2) Patients with HER2+ unresectable, advanced/metastatic G/GEJ adenocarcinoma; no prior HER2-targeted therapy; no prior systemic therapy (adjuvant/neoadjuvant ≥6 mo prior allowed) (N = 36) Zanidatamab 30 mg/kg or 1800/2400 mg IV Q3W + CAPOX (n = 14) Zanidatamab 30 mg/kg or 1800/2400 mg IV Q3W + FP (n = 2) U ntil disease progression, unacceptable toxicity, or other discontinuation (patients who discontinue CT may continue zanidatamab alone) Zanidatamab 2 0 mg/kg or 1200/1600 mg IV Q2W + mFOLFOX6-1 or mFOLFOX6-2 (n = 20) Physician’s choice of CT Biparatopic trans binding: each HER2 can be targeted by 2 zanidatamab Abs binding to different domains

29. Zanidatamab + CT: TRAEs Ku. ESMO 2021. Abstr 1380. Diarrhea is a major toxicity but can be managed with a prophylactic antidiarrheal regimen Event, n (%) Zan + CAPOX (n = 14) Zan + FP (n = 2) Zan + mFOLFOX6 (n = 20) Total (N = 36) Grade Any ≥3 Any ≥3 Any ≥3 Any ≥3 TRAE 14 (100) 8 (57) 2 (100) 1 (50) 20 (100) 16 (80) 36 (100) 25 (69) Serious TRAE 2 (14) 2 (14) 1 (50) 1 (50) 4 (20) 4 (20) 7 (19) 7 (19) TRAE l eading to discontinuation 4 (20) 1 (6) 4 (11) 1 (3) TRAE in ≥20% and/or Grade 3 in >1 Diarrhea 13 (93) 5 (36) 2 (100) 1 (50) 19 (95) 9 (45) 34 (94) 15 (42) Nausea 11 (79) 1 (7) 1 (50) 15 (75) 1 (5) 27 (75) 2 (6) Peripheral neuropathy 10 (71) 9 (45) 19 (53) Fatigue 5 (36) 11 (55) 1 (5) 16 (44) 1 (3) Decreased appetite 5 (36) 1 (50) 9 (45) 15 (42) Hypokalemia 2 (14) 11 (55) 6 (30) 13 (36) 6 (17) Vomiting 3 (21) 1 (7) 9 (45) 2 (10) 12 (33) 3 (8) Hypomagnesemia 3 (21) 6 (30) 1 (5) 9 (25) 1 (3) Dysgeusia 4 (29) 4 (20) 8 (22) Stomatitis 2 (14) 6 (30) 8 (22) Neutrophil count decreased 2 (14) 5 (25) 3 (15) 7 (19) 3 (8) WBC decreased 6 (30) 2 (10) 6 (17) 2 (6) Acute kidney injury 1 (50) 1 (50) 1 (5) 1 (5) 2 (6) 2 (6) AESI in Any Patient, n (%) [All Grade <3] Zan + CAPOX (n = 14) Zan + FP (n = 2) Zan + mFOLFOX6 (n = 20) Total (N = 36) Infusion-related reaction 4 (29) 1 (50) 5 (15) Cardiac event 3 (15) 3 (9) Pneumonitis 1 (5) 1 (3)

30. Zanidatamab + CT: Response Rates and DoR Ku. ESMO 2021. Abstr 1380. HER2+ Patients Zanidatamab + CAPOX (n = 12) Zanidatamab + FP (n = 2) Zanidatamab + mFOLFOX6 (n = 14) Total (N = 28) Confirmed ORR, % (95% CI) 92 (61.5-99.8) 100 (15.8-100) 57 (28.9-82.3) 75 (55.1-89.3) CR, % (n) 1 (7) 1 (4) PR, % (n) 11 (92) 2 (100) 7 (50) 20 (71) SD, % (n) 1 (8) 3 (21) 4 (14) PD, % (n) 3 (21) 3 (11) DCR, % (95% CI) 100 (73.5-100) 100 (15.8-100) 79 (49.2-95.3) 89 (71.8-97.7) Median DoR, mo (range) NR (2.7-15.2+) NR (6.8-12.5+) 16.4 (1.4-19.8+) 16.4 (1.4-19.8+)

31. 2 Zanidatamab + CT: PFS and OS in HER2+ Metastatic G/GEJ Cancer 31 PFS OS Elimova. ASCO GI 2023. Abstr 347. Median PFS: 12.5 mo (95% CI: 7.1 - NE) + Censored Patients (%) Mo 38 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 1.0 0.8 0.6 0.4 0.2 Patients at Risk, n 42 37 34 29 24 19 16 13 12 7 7 6 5 3 2 2 1 1 Median OS, mo: NE (95% CI: 23.6 - NE) 12-mo OS: 88% (95% CI: 73%-95%) 18-mo OS: 84% (95% CI: 68%-93%) Patients (%) Mo 38 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0.8 0.6 0.4 0.2 Patients at Risk, n 42 41 41 39 35 32 26 2 25 23 20 16 15 12 10 7 5 2 1.0 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

32. HERIZON-GEA-01: First-line Zanidatamab + CT Multicenter, randomized, open-label phase III study Taberno. Future Oncol. 2022;18:3255. NCT05152147. Primary endpoints: PFS (BICR), OS Secondary endpoints: ORR, DoR, safety, HRQoL Patients with HER2+ unresectable, advanced/metastatic G/GEJ adenocarcinoma; no prior HER2-targeted or ICI therapy; no prior systemic therapy; stable brain metastases allowed; ECOG PS 0/1 (Target N = 714 ) Trastuzumab 6 mg/kg IV Q3W + CAPOX † or FP ‡ (physician’s choice) Zanidatamab 1800/2400 mg IV Q3W + CAPOX † or FP ‡ (physician’s choice) U ntil disease progression, unacceptable toxicity, discontinuation, or death Zanidatamab 1800/2400 mg IV Q3W + Tislelizumab 200 mg IV Q3W + CAPOX † or FP ‡ (physician’s choice) Stratified by geographic region (Asia, EU/North America, or ROW), HER2 status (IHC 3+ or IHC 2+/ISH+) and ECOG PS (0 or 1) *8 mg/kg loading dose. † Oxaliplatin 130 mg/m 2 IV Q3W and capecitabine 1000 mg/m 2 PO BID. ‡ Cisplatin 80 mg/m 2 IV Q3W and fluorouracil 800 mg/m 2 /d IV x 5 days Q3W.

33. Evorpacept (ALX148)

34. Figure not available Evorpacept (ALX148): CD47-Blocking Protein CD47, a marker of self, is upregulated on tumor cells to evade the immune system CD47 engages SIRP⍺ and signals macrophages to ignore the cell on which it is expressed Lakhani. Lancet Oncol. 2021;22:1740. Molecular weight half the size of a targeted antibody I nactive Fc binds and blocks CD47-SIRP α interaction enhancing anti-cancer antibody’s ADCP activity Inactive Fc spares normal blood cells from CD47-targeted ADCP activity Activates dendritic cells and enhances cross-priming of T cells

35. ASPEN-01: Phase I Study of Evorpacept Combination Evorpacept + trastuzumab/ramucirumab/paclitaxel evaluated in ≥2L HER2+ gastric cohort (N = 18) Combination very well tolerated; no DLT or SAEs related to evorpacept Lee. SITC 2021. Abstr 498. Evorpacept + TRP (N = 18) AE, n (%) All Cause Evorpacept-Related Grade 1/2 3 4 1/2 3 4 Neutrophil count decreased 3 (17) 5 (28) 3 (17) Epistaxis 9 (50) Peripheral neuropathy 8 (44) 1 (6) Decreased appetite 8 (44) Fatigue 7 (39) 1 (6) 2 (11) Anemia 3 (17) 4 (22) 1 (6) Hypertension 6 (33) Abdominal pain 5 (28) 1 (6) Headache 5 (28) 1 (6) Stomatitis 5 (28) 1 (6) ALT increased 4 (22) Alopecia 4 (22) AST increased 3 (17) 1 (6) Asthenia 3 (17) 1 (6) Diarrhea 4 (22) 3 (17) Insomnia 4 (22) Evorpacept + TRP (N = 18) AE, n (%) All Cause Evorpacept-Related Grade 1/2 3 4 1/2 3 4 Rash/dermatitis 4 (22) 4 (22) Pruritus 3 (17) 2 (11) Urticaria 3 (17) 3 (17) Back pain 2 (11) 1 (6) Diverticulitis 1 (6) 1 (6) Dysphagia 1 (6) 1 (6) Hypophosphatemia 1 (6) 1 (6) Platelet count decreased 1 (6) 1 (6) Hydronephrosis 1 (6) Lymphocyte count decreased 1 (6) 1 (6) Noncardiac chest pain 1 (6) Urinary tract infection 1 (6) Vision blurred 1 (6) 1 (6)

36. ASPEN-01: Efficacy of Evorpacept + TRP Lee. SITC 2021. Abstr 498. Population N Evaluated ORR, % Median DoR, Mo (95% CI) Median PFS, Mo (95% CI) Median OS, Mo (95% CI) 12-Mo OS, % Median FU, Mo (95% CI) ≥2L GC treated with evorpacept 10 or 15 mg/kg + TRP 18 72.2 14.8 (3.9-NR) 17.1 (5.4-NR) 17.1 (9.8-NR) 79.0 14.5 (7.2-19.0) Best Change in Measurable Lesions From Baseline 40 30 20 10 -10 -20 -30 -40 -50 -60 Best % Change HER2 Score 3+ 2+ 2+ 3+ ND ND 2+ 3+ ND ND 3+ 2+ ND ND 2+ * * * ND Complete response partial response stable disease progressive disease Evorpacept 10 mg/kg Not Done * 60 40 20 -20 -40 -60 -80 100 200 300 400 500 Days % Change Evorpacept 10 mg/kg + TRP Evorpacept 15 mg/kg + TRP

37. ASPEN-06: Second-Line or Later Evorpacept + TRP International, randomized, open-label (phase II) or double-blind (phase III) study Primary Endpoint: ORR (phase II); OS (phase III) NCT05002127. Patients with HER2+ advanced gastric or GEJ adenocarcinoma; progressed on or after HER2-targeted therapy and fluoropyrimidine- or platinum-based CT (2 or 3L) (Target N = 450) Evorpacept 30 mg/kg IV Q2W + Trastuzumab 4 mg/kg* IV Q2W + Ramucirumab 8 mg/kg IV Q2W + Paclitaxel 80 mg/m 2 IV D1, 8, 15 (28-d cycle) Trastuzumab 4 mg/kg* IV Q2W + Ramucirumab 8 mg/kg IV Q2W + Paclitaxel 80 mg/m 2 IV D1, 8, 15 (28-d cycle) *Trastuzumab 6 mg/kg loading dose. Open-label phase II Evorpacept 30 mg/kg IV Q2W + Trastuzumab 4 mg/kg* IV Q2W + Ramucirumab 8 mg/kg IV Q2W + Paclitaxel 80 mg/m 2 IV D1, 8, 15 (28-d cycle) Ramucirumab 8 mg/kg IV Q2W + Paclitaxel 80 mg/m 2 IV D1, 8, 15 (28-d cycle) Double-blind phase III

38. Other Novel Anti-HER2 Therapies Tucatinib: HER2 TKI approved in BC and CRC Phase II MOUNTAINEER-02 study (NCT04499924) is fully enrolled PRS-343 (cinrebafusp alfa; HER2/4-1BB bispecific) Newer HER2 ADCs HER2/CD3 bispecific Abs HER2 cellular therapy

39. Summary: Treatment of HER2+ Advanced/Metastatic Gastric/GEJ Cancer The ToGA study established trastuzumab + chemotherapy as first-line SoC in HER2-positive mGC Addition of pembrolizumab was approved by the FDA based on response data from KEYNOTE-811; survival data are pending T-DXd can provide benefit in second-line or later setting, regardless of prior ICI exposure Monitoring and patient education are essential to mitigate risk of ILD with T-DXd Studies of T-DXd in combination with other agents, including ICI, are ongoing The phase III HERIZON-GEA-01 study of the biparatopic HER2 zanidatamab in first-line HER2-positive mGC is currently enrolling

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