HERIZON-GEA-01 Trial

[Slide 1] Background • Zanidatamab is a bispecific HER2-directed antibody that binds to HER2 ECD 2 and 4 in a trans configuration, facilitating crosslinking associated with the formation of distinct HER2 clusters on the cell surface. It has several key mechanisms of action1: – Increasing HER2 internalisation; reducing phosphorylation of EGFR, HER2, and HER3 and blocking downstream signalling; and inducing immune-mediated effects (CDC, ADCC, and ADCP) • Tislelizumab is a high-affinity ICI targeting PD-1 and is specifically engineered to minimise Fcγ receptor binding on macrophages Adults with untreated, unresectable, locally advanced, recurrent or metastatic GEA • HER2 IHC 3+ or IHC 2+/ISH+ per central testing • ECOG PS 0 or 1 • No prior HER2-targeted agents or immunotherapy in any setting Stratification factors • Geographic region • HER2 status • ECOG PS R 1:1:1 N = 914 Trastuzumab + chemotherapy(a) Zanidatamab(b) + chemotherapy(a) Zanidatamab(b) + tislelizumab(c) + chemotherapy(a) Prophylaxis to prevent IRRs and diarrhoea was mandatory in the zanidatamab-containing arms Treatment until disease progression/death/unacceptable toxicity. Chemotherapy could be discontinued after 6 cycles Tumour imaging(d) Q6W Dual primary endpoints • PFS (per BICR) • OS Data cutoff for IA2: 15 July 2026 Here we report results from the planned second interim analysis of OS (IA2) from HERIZON-GEA-01 (a)Physician's choice of CAPOX (capecitabine plus oxaliplatin) or FP (5-fluorouracil plus cisplatin). Chemotherapy was administered for at least 6 cycles or until disease progression, unacceptable toxicity, or another criterion for treatment discontinuation was met. (b)Zanidatamab 1800 mg (<70 kg) or 2400 mg (≥70 kg) was administered IV Q3W. (c)Tislelizumab 200 mg was administered IV Q3W. (d)Computed tomography/magnetic resonance imaging scans were performed Q6W for the first 54 weeks, then every 9 weeks. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; BICR, blinded independent central review; CDC, complement-dependent cytotoxicity; ECD, extracellular domain; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; Fcγ, fragment crystallisable-gamma; GEA, gastro-oesophageal adenocarcinoma; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; IA2, planned second interim analysis of OS; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; IRR, infusion-related reaction; ISH, in situ hybridisation; IV, intravenously; OS, overall survival; PD-1, programmed cell death protein 1; PFS, progression-free survival; Q3W, every 3 weeks; Q6W, every 6 weeks; R, randomisation. 1. Weisser NE, et al. Nat Commun. 2023;14(1):1394. Kohei Shitara, MD [Slide 2] Zanidatamab + Tislelizumab + CT vs Zanidatamab + CT: OS in the ITT Population A consistent trend toward improved OS was observed irrespective of PD-L1 status Zanidatamab + tislelizumab + CT | Zanidatamab + chemotherapy Median OS (95% CI), mo: 27.0 (23.7–32.2) | 22.9 (19.9–27.6) ITT HR (95% CI): 0.81 (0.65–1.00); P = 0.0502 PD-L1 TAP <1% HR (95% CI): 0.76 (0.52–1.10) PD-L1 TAP ≥1% HR (95% CI): 0.77 (0.58–1.02) Y-axis: Overall survival (%); X-axis: Months from randomisation; + Censored Patients at risk (0,3,6,...,57 mo): Zani + TIS + CT: 302 267 246 228 207 185 168 148 129 101 72 64 53 42 35 28 11 6 2 0 Zani + CT: 304 278 256 228 202 182 162 142 122 94 71 51 42 28 22 18 5 3 1 0 Data cutoff: 15 July 2026. CT, chemotherapy; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; PD-L1, programmed death-ligand 1; TAP, tumour area positivity; TIS, tislelizumab; Zani, zanidatamab. Kohei Shitara, MD Survival table Endpoint: OS (ITT) Arm | N | Median | Median CI Zanidatamab + tislelizumab + CT | 302 | 27.0 mo | 23.7–32.2 Zanidatamab + chemotherapy | 304 | 22.9 mo | 19.9–27.6 HR: 0.81 HR CI: 0.65–1.00 P: 0.0502 [Slide 3] Safety Summary The AE profile remained consistent with IA1, and no unexpected safety signals were observed Columns: Zanidatamab + tislelizumab + CT (n = 294)(a) | Zanidatamab + CT (n = 305)(a) | Trastuzumab + CT (n = 302) Duration of treatment, weeks Mean (SD): 64.1 (58.0) | 52.6 (52.6) | 42.3 (39.2) Median (IQR): 46.6 (17.6–101.4) | 31.1 (14.3–74.7) | 30.0 (18.1–54.1) Duration of zanidatamab or trastuzumab treatment, weeks Mean (SD): 60.2 (57.4) | 51.0 (52.9) | 40.8 (39.4) Median (IQR): 40.5 (14.4–97.1) | 30.1 (12.1–72.7) | 28.2 (16.3–52.1) Any-grade TEAE, n (%): 293 (99.7) | 301 (98.7) | 297 (98.3) TRAE, n (%): 289 (98.3) | 296 (97.0) | 291 (96.4) Grade ≥3: 213 (72.4) | 180 (59.0) | 181 (59.9) Serious TEAEs, n (%): 176 (59.9) | 155 (50.8) | 131 (43.4) Treatment-related: 124 (42.2) | 87 (28.5) | 62 (20.5) TEAEs leading to death, n (%): 30 (10.2) | 26 (8.5) | 22 (7.3) Treatment-related: 7 (2.4) | 1 (0.3) | 4 (1.3) Discontinuation due to TRAEs, n (%) Any component: 132 (44.9) | 107 (35.1) | 88 (29.1) Zanidatamab or trastuzumab(b): 35 (11.9) | 28 (9.2) | 7 (2.3) Tislelizumab(c): 49 (16.7) | — | — Any-grade diarrhoea, n (%): 244 (83.0) | 241 (79.0) | 161 (53.3) Grade ≥3: 74 (25.2) | 61 (20.0) | 39 (12.9) AESIs(d), n (%): 103 (35.0) | 94 (30.8) | 56 (18.5) IRRs: 74 (25.2) | 77 (25.2) | 40 (13.2) Noninfectious pulmonary toxicities: 22 (7.5) | 5 (1.6) | 4 (1.3) Left ventricular dysfunction: 27 (9.2) | 20 (6.6) | 13 (4.3) Immune-mediated AEs(d), n (%): 118 (40.1) | 44 (14.4) | 32 (10.6) • Diarrhoea occurred primarily in cycles 1 and 2, and the incidence was consistent with IA1 Data cutoff: 15 July 2026. (a)Five patients who were assigned to the zanidatamab + tislelizumab + CT arm did not receive tislelizumab. Data from these patients are summarized in the zanidatamab + CT arm. (b)Zanidatamab- or trastuzumab-related TEAEs that led to discontinuation of zanidatamab or trastuzumab. (c)Tislelizumab-related TEAEs that led to discontinuation of tislelizumab. (d)AESIs for zanidatamab were IRRs, non-infectious pulmonary toxicities, and left ventricular dysfunction; AESIs for tislelizumab were IRRs and immune-mediated AEs. Immune-mediated AEs are excluded from AESIs and reported separately. AESIs for zanidatamab and tislelizumab are reported in all treatment groups, even if the study agent was not administered in that group. AE, adverse event; AESI, AE of special interest; CT, chemotherapy; IA1, first interim analysis of OS; IQR, interquartile range; IRR, infusion-related reaction; TEAE, treatment-emergent AE; TRAE, treatment-related AE. Kohei Shitara, MD [Slide 4] Zanidatamab + CT: OS in the ITT Population Zanidatamab + CT demonstrated a statistically significant and clinically meaningful improvement in OS vs trastuzumab + CT (FFA criteria met) Zanidatamab + CT | Trastuzumab + CT Median OS (95% CI), mo: 22.9 (19.9–27.6) | 19.6 (16.9–22.2) HR (95% CI): 0.76 (0.62–0.93); P = 0.0088(a) Landmark labels: 24 mo: 49.6% (95% CI, 43.6–55.3) [Zani + CT]; 40.7% (95% CI, 34.9–46.5) [Tras + CT] 36 mo: 31.5% (95% CI, 25.4–37.8) [Zani + CT]; 22.9% (95% CI, 17.3–28.9) [Tras + CT] Y-axis: Overall survival (%); X-axis: Months from randomisation; + Censored Patients at risk (0,3,6,...,57 mo): Zani + CT: 304 278 256 228 202 182 162 142 122 94 71 51 42 28 22 18 5 3 1 0 Tras + CT: 308 284 261 227 199 171 147 121 95 70 48 39 33 21 15 12 5 1 1 0 Data cutoff: 15 July 2026. (a)The critical 2-sided alpha was 0.0279. CT, chemotherapy; FFA, final formal analysis; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; Tras, trastuzumab; Zani, zanidatamab. Kohei Shitara, MD Survival table Endpoint: OS (ITT) Arm | N | Median | Median CI Zanidatamab + CT | 304 | 22.9 mo | 19.9–27.6 Trastuzumab + CT | 308 | 19.6 mo | 16.9–22.2 HR: 0.76 HR CI: 0.62–0.93 P: 0.0088 Landmark rates: 24 mo: Zanidatamab + CT 49.6% (CI 43.6–55.3) | Trastuzumab + CT 40.7% (CI 34.9–46.5) 36 mo: Zanidatamab + CT 31.5% (CI 25.4–37.8) | Trastuzumab + CT 22.9% (CI 17.3–28.9)

[Slide 1] Patient Disposition Median follow-up was 35.3 months at IA2, 9.4 months longer than at IA1 Randomised N = 914 Zanidatamab + tislelizumab + CT: n = 302; 299 patients treated^a Ongoing in study, n = 122 (40%): Ongoing study treatment, n = 67; Survival follow-up, n = 55 Discontinued study, n = 180 (60%): Death, n = 157; Withdrawal of consent, n = 20; Lost to follow-up, n = 3 Zanidatamab + CT: n = 304; 300 patients treated^a Ongoing in study, n = 103 (34%): Ongoing study treatment, n = 48; Survival follow-up, n = 55 Discontinued study, n = 201 (66%): Death, n = 178; Withdrawal of consent, n = 19; Lost to follow-up, n = 3; Investigator's decision, n = 1 Trastuzumab + CT: n = 308; 302 patients treated Ongoing in study, n = 75 (24%): Ongoing study treatment, n = 19; Survival follow-up, n = 56 Discontinued study, n = 233 (76%): Death, n = 211; Withdrawal of consent, n = 21; Lost to follow-up, n = 1 Data cutoff: 15 July 2026. ^aTreated includes all randomised patients who received any amount of any study treatment and does not necessarily reflect the safety analysis set. Five patients assigned to the zanidatamab-tislelizumab-CT arm did not receive tislelizumab and are included in the safety analysis set for the zanidatamab-CT arm. CT, chemotherapy; IA1, first interim analysis of overall survival; IA2, planned second interim analysis of overall survival Kohei Shitara, MD [Slide 2] Zanidatamab + CT: OS in the ITT Population Zanidatamab + CT demonstrated a statistically significant and clinically meaningful improvement in OS vs trastuzumab + CT (FFA criteria met) Median OS (95% CI), mo: Zanidatamab + CT 22.9 (19.9-27.6) | Trastuzumab + CT 19.6 (16.9-22.2) HR (95% CI): 0.76 (0.62-0.93); P = 0.0088^a Curve annotations: 49.6% (95% CI, 43.6-55.3) [24 mo, zanidatamab + CT]; 40.7% (95% CI, 34.9-46.5) [24 mo, trastuzumab + CT]; 31.5% (95% CI, 25.4-37.8) [36 mo, zanidatamab + CT]; 22.9% (95% CI, 17.3-28.9) [36 mo, trastuzumab + CT] Y-axis: Overall survival (%); X-axis: Months from randomisation (0-57); + Censored Patients at risk (partly obscured by camera): Zani + CT: [304] 278 256 228 202 182 162 142 122 94 71 51 42 28 22 18 5 3 1 0; Tras + CT: [308] 284 261 227 199 171 147 121 95 70 48 39 33 21 15 12 5 1 1 0 Data cutoff: [15] July 2026. ^aThe critical 2-sided alpha was 0.0279. CT, chemotherapy; FFA, final formal analysis; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; Tras, trastuzumab; Zani, zanidatamab Kohei Shitara, MD [partly obscured] Survival table Endpoint: OS (ITT) Arm | N | Median | Median CI Zanidatamab + CT | 304 | 22.9 mo | 19.9-27.6 Trastuzumab + CT | 308 | 19.6 mo | 16.9-22.2 HR: 0.76 HR CI: 0.62-0.93 P: 0.0088 (critical 2-sided alpha 0.0279) Landmark rates: 24 mo: Zanidatamab + CT 49.6% (CI 43.6-55.3) | Trastuzumab + CT 40.7% (CI 34.9-46.5) 36 mo: Zanidatamab + CT 31.5% (CI 25.4-37.8) | Trastuzumab + CT 22.9% (CI 17.3-28.9)

[Slide 1] Zanidatamab + Tislelizumab + CT: OS in the ITT Population Zanidatamab + tislelizumab + CT continued to demonstrate an OS benefit vs trastuzumab + CT, with an improved HR from IA1 Median OS (95% CI), mo: Zanidatamab + tislelizumab + CT 27.0 (23.7-32.2) | Trastuzumab + CT 19.6 (16.9-22.2) HR (95% CI): 0.65 (0.52-0.80)^a Curve annotations: 55.8% (95% CI, 49.8-61.4) [24 mo, zanidatamab + tislelizumab + CT]; 40.7% (95% CI, 34.9-46.5) [24 mo, trastuzumab + CT]; 39.8% (95% CI, 33.2-46.3) [36 mo, zanidatamab + tislelizumab + CT]; 22.9% (95% CI, 17.3-28.5) [36 mo, trastuzumab + CT] Y-axis: Overall survival (%); X-axis: Months from randomisation (0-57); + Censored Patients at risk (0,3,6,...,57 months): Zani + TIS + CT: 302 267 246 228 207 185 168 148 129 101 72 64 53 42 35 28 11 6 2 0 Tras + CT: 308 284 261 227 199 171 147 121 95 70 48 39 33 21 15 12 5 1 1 0 Data cutoff: 15 July 2026. ^aAnalysis was descriptive, as prespecified criteria for significance were previously met. CT, chemotherapy; HR, hazard ratio; IA1, first interim analysis of OS; ITT, intent-to-treat; OS, overall survival; TIS, tislelizumab; Tras, trastuzumab; Zani, zanidatamab. Kohei Shitara, MD Survival table Endpoint: OS (ITT) Arm | N | Median | Median CI Zanidatamab + tislelizumab + CT | 302 | 27.0 mo | 23.7-32.2 Trastuzumab + CT | 308 | 19.6 mo | 16.9-22.2 HR: 0.65 HR CI: 0.52-0.80 Landmark rates: 24 mo: Zanidatamab + tislelizumab + CT 55.8% (CI 49.8-61.4) | Trastuzumab + CT 40.7% (CI 34.9-46.5) 36 mo: Zanidatamab + tislelizumab + CT 39.8% (CI 33.2-46.3) | Trastuzumab + CT 22.9% (CI 17.3-28.5) [Slide 2] Zanidatamab + Tislelizumab + CT vs Trastuzumab + CT: OS in Key Prespecified Subgroups The OS benefit with zanidatamab + tislelizumab + CT vs trastuzumab + CT was generally consistent across prespecified subgroups, including in patients with PD-L1-negative disease Subgroup | Category | Events/Patients Zanidatamab + tislelizumab + CT | Events/Patients Trastuzumab + CT | OS HR^a (95% CI) All patients | | 157/302 | 212/308 | 0.65 (0.52-0.80) Age | <65 years | 78/163 | 116/162 | 0.56 (0.42-0.74) Age | >=65 years | 79/139 | 96/146 | 0.79 (0.59-1.07) Geographic region | Asia | 70/159 | 111/165 | 0.55 (0.41-0.74) Geographic region | EU/NA | 60/95 | 65/93 | 0.84 (0.59-1.20) Geographic region | ROW | 27/48 | 36/50 | 0.69 (0.42-1.14) ECOG PS | 0 | 53/122 | 67/120 | 0.70 (0.49-1.00) ECOG PS | 1 | 103/179 | 145/188 | 0.64 (0.49-0.82) Prior gastrectomy | Yes | 21/51 | 34/56 | 0.61 (0.36-1.06) Prior gastrectomy | No | 136/251 | 178/252 | 0.65 (0.52-0.82) Anatomical subtype | Gastric | 96/208 | 155/226 | 0.55 (0.43-0.71) Anatomical subtype | GEJ | 51/74 | 45/60 | 0.98 (0.66-1.47) Anatomical subtype | Oesophageal | 10/20 | 12/22 | 0.73 (0.32-1.71) HER2 status | IHC 3+ | 127/251 | 172/255 | 0.65 (0.51-0.82) HER2 status | IHC 2+/ISH+ | 30/51 | 39/52 | 0.70 (0.43-1.13) PD-L1 status | TAP <1% | 47/90 | 75/98 | 0.50 (0.35-0.73) PD-L1 status | TAP >=1% | 90/187 | 121/188 | 0.68 (0.52-0.89) Forest plot axis: 0.1 - 1.0 - 10.0; Favours Zani + TIS + CT | Favours Tras + CT Data cutoff: 15 July 2026. ^aThe widths of the CIs were not adjusted for multiplicity and cannot be used to infer treatment effects. CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EU, European Union; GEJ, gastro-oesophageal junction; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridisation; NA, North America; OS, overall survival; PD-L1, programmed death-ligand 1; ROW, rest of the world; TAP, tumour area positivity; TIS, tislelizumab; Tras, trastuzumab; Zani, zanidatamab Kohei Shitara, MD [Slide 3] Zanidatamab + Tislelizumab + CT vs Zanidatamab + CT: OS in the ITT Population A consistent trend toward improved OS was observed irrespective of PD-L1 status Median OS (95% CI), mo: Zanidatamab + tislelizumab + CT 27.0 (23.7-32.2) | Zanidatamab + chemotherapy 22.9 (19.9-27.6) ITT HR (95% CI): 0.81 (0.65-1.00); P = 0.0502 PD-L1 TAP <1% HR (95% CI): 0.76 (0.52-1.10) PD-L1 TAP >=1% HR (95% CI): 0.77 (0.58-1.02) Y-axis: Overall survival (%); X-axis: Months from randomisation (0-57); + Censored Patients at risk (0,3,6,...,57 months): Zani + TIS + CT: 302 267 246 228 207 185 168 148 129 101 72 64 53 42 35 28 11 6 2 0 Zani + CT: 304 278 256 228 202 182 162 142 122 94 71 51 42 28 23 18 5 3 1 0 Data cutoff: 15 July 2026 CT, chemotherapy; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; PD-L1, programmed death-ligand 1; TAP, tumour area positivity; TIS, tislelizumab; Zani, zanidatamab Kohei Shitara, MD Survival table Endpoint: OS (ITT) Arm | N | Median | Median CI Zanidatamab + tislelizumab + CT | 302 | 27.0 mo | 23.7-32.2 Zanidatamab + chemotherapy | 304 | 22.9 mo | 19.9-27.6 HR: 0.81 HR CI: 0.65-1.00 P: 0.0502

LBA79 - Zanidatamab (zani) + chemotherapy (CT) ± tislelizumab (TIS) for first-line (1L) HER2-positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (mGEA): Second interim analysis (IA) from HERIZON-GEA-01 Speakers Kohei Shitara (Kashiwa, Japan, Chiba) Lecture Time 16:15 - 16:20 [Abstract button] Background In the primary analysis of progression-free survival (PFS) and first IA (IA1) of overall survival (OS) of the phase 3 HERIZON-GEA-01 trial (NCT05152147), zani + CT ± TIS significantly prolonged PFS and, with TIS, provided a significant OS benefit (HR 0.72) vs trastuzumab (tras) + CT (Shitara, et al. NEJM. 2026), supporting the US approval of these regimens in 1L HER2+ mGEA. Here, we present the planned second IA of OS (IA2). Methods Patients (pts) with untreated HER2+ mGEA were randomized 1:1:1 to zani (1800 mg [<70 kg]/2400 mg [≥70 kg] IV every 3 weeks [Q3W]) + CT (capecitabine/oxaliplatin or 5-FU/cisplatin) ± TIS (200 mg IV Q3W) or tras + CT. PFS (by blinded independent central review) and OS were primary endpoints. At IA2, formal OS comparisons were tested in sequence: zani + CT vs tras + CT, then zani + CT + TIS vs zani + CT. Results 914 pts were randomized. With a median follow-up of 35.3 mo (data cutoff: 15 July 2026; 9.4 mo longer than IA1), zani + CT significantly improved OS vs tras + CT (HR 0.76 [95% CI: 0.62–0.93]; P = 0.0088; median OS, 22.9 mo [95% CI: 19.9–27.6] vs 19.6 mo [95% CI: 16.9–22.2]). A 4-mo longer median OS was observed with zani + TIS + CT (27.0 mo [95% CI: 23.7–32.2]) vs zani + CT (HR 0.81 [95% CI: 0.65–1.00]), although the difference was not statistically significant (P = 0.0502). The OS benefit of zani + TIS + CT vs tras + CT observed at IA1 (HR 0.72) was sustained at IA2 with an improved HR (0.65 [95% CI: 0.52–0.80]). Estimated 36-mo OS was 39.8% for zani + CT + TIS, 31.5% for zani + CT, and 22.9% for tras + CT. Median duration of treatment was 46.6 (40.5 for zani) wks with zani + CT + TIS, 31.1 (30.1 for zani) wks with zani + CT, and 30.0 (28.2 for tras) wks with tras + CT. The safety profiles were consistent with IA1. Conclusions At IA2, zani + CT led to a statistically significant and clinically meaningful OS improvement vs tras + CT. With longer follow-up, zani + CT + TIS showed improved OS benefit over tras + CT and there was a meaningful trend for OS improvement vs zani + CT. Unchanged safety profiles support the tolerability of prolonged treatment. These results continue to support zani combined with CT ± TIS as a new HER2-directed 1L standard of care in HER2+ mGEA.