#1↓ AstraZeneca Investor science conference call: American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium 2022 Conference call for investors and analysts 24 January 2022#22 Forward-looking statements In order, among other things, to utilise the 'safe harbour' provisions of the US Private Securities Litigation Reform Act of 1995, AstraZeneca (hereafter 'the Group') provides the following cautionary statement: this document contains certain forward-looking statements with respect to the operations, performance and financial condition of the Group, including, among other things, statements about expected revenues, margins, earnings per share or other financial or other measures. 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Nothing in this document, or any related presentation/webcast, should be construed as a profit forecast. B#3Speakers 3 Dr Bruno Sangro Investigator, HIMALAYA and Professor Head Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra Susan Galbraith Executive Vice President, Oncology Research and Development Cristian Massacesi Chief Medical Officer & Oncology Chief Development Officer (for Q&A) Dr Arndt Vogel Steering Committee member, TOPAZ-1 and Professor - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Dave Fredrickson Executive Vice President, Oncology Business Unit Niko Andre Global Franchise Head, Immuno-Oncology and Haematology (for Q&A) 3#4Agenda 4 1 2 3 4 5 6 Introduction: AstraZeneca @ ASCO GI 2022 Imfinzi Phase III TOPAZ-1 trial Imfinzi + tremelimumab Phase III HIMALAYA trial Commercial opportunity What's next for AstraZeneca in GI? Closing and Q&A#51 Introduction Susan Galbraith Executive Vice President, Oncology R&D B#66 Comprehensive portfolio to combat cancer DENHERTUⓇ fam-trastuzumab deruxtecan-nxki 20 mg/mL INJECTION FOR INTRAVENOUS USE SIMFINZIⓇ durvalumab Injection for Intravenous Use 50 mg/mL Source: AstraZeneca. Lynparza™ olaparib TAGRISSOⓇ osimertinib CALQUENCE (acalabrutinib) 100 mg capsules Redirect local immunity Awaken dormant immune cells Infuse with engineered T cells Build synthetic immunity Cell therapy Targeted delivery of medicines that recruit immunity Build on PDx Overcome immune suppression Diverse pipeline with potential for orthogonal combinations Oncolytic virus Immune engagers Activate immune system Microenvironment Immuno-oncology "Ignore axis" "Defend axis" Tumour drivers and resistance Direct killing Tumour DNA damage response Oncogenic truncal drivers and mechanisms of resistance Synthetic lethality exploiting impaired DNA damage response Antibody drug conjugates Radioimmuno- conjugates Nanomedicines Replacing standard of care (i.e., chemo) with targeted delivery of toxic molecules Epigenetics Reprogramming tumour cells#7ASCO GI 2022 ASCO Gastrointestinal Cancers Symposium 7 21 abstracts with Four oral presentations Two Proffered paper oral presentations (late breakers) Two Mini oral presentations 17 Posters 21 Abstracts Source: ASCO GI 2022 accepted abstracts. Inclusive of externally sponsored research and partner-led trials. HCC = hepatocellular carcinoma; BTC = biliary tract cancer; CRC = colorectal cancer. ● Data highlights Imfinzi +/- tremelimumab in HCC HIMALAYA Study 22 Imfinzi in BTC TOPAZ-1 Enhertu DESTINY-Gastric01, DESTINY- Gastric03, DESTINY-CRC01 $#8Imfinzi and tremelimumab Phase II data in gastrointestinal cancers informed TOPAZ-1 and HIMALAYA designs Phase II trial in biliary tract cancer A Canon 2 Study 22¹ HCC T-cell proliferation data 31 2- -1 -2- -3 4 T75+ D -2 0 Canon 1: CD4+ populations Canon 2: CD8+ populations T300 + D 2 Canon 1 4 T 6 8 B 100- 80 60 20 0 T300 + D CR/PR SD PD Median 47 20.5 24 Count 9 18 19 CR/PR 38 3 D SD 12 9 Day 15 PD 13 23 CR/PR 35 1 T SD 26 7 PD 20 8 • 322 patients with advanced hepatocellular carcinoma randomised between arms T75+ D CR/PR SD PD 21.5 14 13 2 8 18 Median OS: T300+D - 18.7-mo; Imfinzi - 13.6-mo • 121 patients enrolled with 1st-line biliary tract cancer • Imfinzi (+/- tremelimumab) in combination with gemcitabine and cisplatin • Combination was well tolerated ● Median OS: 18.1-mo for Imfinzi + gem/cis 8 1. Kelley et al J Clin Oncol 39, 27: 2021 2991-3001 2. D-Y Oh et al ASCO 2020 J Clin Oncol 38, 15 suppl: 2020 4520. OS = overall survival; T300 = tremelimumab 300mg; mo = months; gem - = gemcitabine; cis = cisplatin#92 Imfinzi TOPAZ-1 Dr Arndt Vogel Steering Committee Member, TOPAZ-1 Phase III trial B#10TOPAZ-1 trial design A double-blind, multicentre, global, Phase III trial Key eligibility Locally advanced or metastatic BTC (ICC, ECC, GBC) ● ● Previously untreated if unresectable or metastatic at initial diagnosis Recurrent disease >6 months after curative surgery or adjuvant therapy ECOG PS 0 or 1 Stratification factors Disease status - (initially unresectable versus recurrent) Primary tumor location - (ICC versus ECC versus GBC) R (1:1) (N=685) Durvalumab 1500 mg Q3W + GemCis (up to 8 cycles) ● Placebo Q3W + GemCis (up to 8 cycles) Primary objective Overall survival Secondary objectives Progression-free survival Objective response rate Duration of response Efficacy by PD-L1 status Safety GemCis treatment: gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 Q3W administered for up to 8 cycles. BTC, biliary tract cancer; ECC, extrahepatic cholangiocarcinoma; ECOG, Eastern Cooperative Oncology Group; GBC, gallbladder cancer; GemCis, gemcitabine and cisplatin; ICC; intrahepatic cholangiocarcinoma; PD, progressive disease; PD-L1, programmed cell death ligand-1; PS, performance status; QnW, every n weeks; R, randomization. Durvalumab 1500 mg Q4W until PD Placebo Q4W until PD#1111 Patient demographics and baseline characteristics Durvalumab + GemCis (n=341) 64 (20-84) 172 (50.4) Median age (range), years Sex, female, n (%) Race, n (%) Asian White Black or African American American Indian or Alaska Native Other Region, n (%) Asia Rest of the world ECOG PS 0 at screening, n (%) Primary tumor location at diagnosis, n (%) Intrahepatic cholangiocarcinoma Extrahepatic cholangiocarcinoma Gallbladder cancer Disease status at randomization, n (%) Initially unresectable Recurrent Disease classification at diagnosis,* n (%) Metastatic Locally advanced PD-L1 expression,* n (%) TAP ≥1% TAP <1% 185 (54.3) 131 (38.4) 8 (2.3) 0 17 (5.0) 178 (52.2) 163 (47.8) 173 (50.7) 190 (55.7) 66 (19.4) 85 (24.9) 274 (80.4) 67 (19.6) 303 (88.9) 38 (11.1) 197 (57.8) 103 (30.2) **Data missing for remaining patients. Unless otherwise indicated, measurements were taken at baseline. ECOG, Eastern Cooperative Oncology Group; GemCis, gemcitabine and cisplatin; PD-L1, programmed cell death ligand-1; PS, performance status; TAP, tumor area positivity. Placebo + GemCis (n=344) 64 (31-85) 168 (48.8) 201 (58.4) 124 (36.0) 6 (1.7) 1 (0.3) 12 (3.5) 196 (57.0) 148 (43.0) 163 (47.4) 193 (56.1) 65 (18.9) 86 (25.0) 279 (81.1) 64 (18.6) 286 (83.1) 57 (16.6) 205 (59.6) 103 (29.9) B#12Overall survival Probability of OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Number of subjects at risk Durvalumab + GemCis Placebo + GemCis 341 344 HR for time up to 6 months (95% CI) 0.91 (0.66-1.26) 309 317 6 268 261 Durvalumab + GemCis (n=341) Placebo + GemCis (n=344) Statistical significance cut-off for OS: p=0.03 HR for time after 6 months (95% CI) 0.74 (0.58-0.94) 208 183 12-mo OS: 54.1% 48.0% 135 125 Median OS (95% CI), months 12.8 (11.1-14.0) 11.5 (10.1-12.5) 15 18 12 Time from randomization (months) 79 49 65 29 12 Median duration of follow-up (95% Cl) was 16.8 (14.8-17.7) months with durvalumab + GemCis and 15.9 (14.9-16.9) months with placebo + GemCis. CI, confidence interval; GemCis, gemcitabine and cisplatin; HR, hazard ratio; mo, month; OS, overall survival. 18-mo OS: 35.1% 25.6% 21 24 10 Hazard ratio (95% CI) 0.80 (0.66-0.97) 24 9 4 24-mo OS: 24.9% 10.4% p-value 27 1 0 0.021 30 12#13Progression free survival Probability of PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Number of subjects at risk Durvalumab + GemCis Placebo + GemCis 341 344 6-mo PFS: 58.3% 47.2% 258 255 6 189 149 Durvalumab + GemCis (n=341) Placebo + GemCis (n=344) Statistical significance cut-off for PFS: p=0.0481 9 100 71 9-mo PFS: 34.8% 24.6% 38 17 12-mo PFS: 16.0% 6.6% 12 15 18 Time from randomization (months) 13 Median duration of follow-up (95% CI) was 9.2 (0.0-24.0) months with durvalumab + GemCis and 6.9 (0.0-20.4) months with placebo + GemCis. CI, confidence interval; GemCis, gemcitabine and cisplatin; PFS, progression-free survival. Median PFS (95% CI), months 7.2 (6.7-7.4) 5.7 (5.6-6.7) 25 7 15 4 21 5 оu 0 Hazard ratio (95% CI) 0.75 (0.63-0.89) 24 0 27 p-value 0.001 30#14Tumour response ORR, % 40 35 30 25 20 15 10 5 0 26.7 ORR, n (%) CR, n (%) PR, n (%) DCR, n (%)* ORR* Odds ratio: 1.60 (95% CI, 1.11-2.31; p=0.011) Durvalumab + GemCis (n=341) Durvalumab + GemCis (n=341) 91 (26.7) 7 (2.1) 84 (24.6) 291 (85.3) 18.7 Placebo + GemCis (n=343) Placebo + GemCis (n=343) 64 (18.7) 2 (0.6) 62 (18.1) 284 (82.6) Proportion of patients still in response 1.0 0.9 0.8- 0.7 - 0.6 0.5- 0.4- 0.3 0.2 0.1 0.0 0 Number of subjects at risk Durvalumab + GemCis 91 Placebo + GemCis 64 3 79 56 6 49 31 Median DoR (quartile 1–3), months Median time to response (quartile 1-3), months DOR 22 14 Remaining in response 29 mo 32.6% 25.3% 9 12 15 Time from randomization (months) 13 5 Durvalumab + GemCis (n=91) 6.4 (4.6-17.2) 1.6 (1.3-3.0) *By investigator assessments using RECIST v1.1 based on patients in the final analysis set who had measurable disease at baseline. *Analysis of DCR was based on all patients in the full analysis set. *Analysis of DoR was based on 14 patients in the full analysis set who had an objective response and measurable disease at baseline. CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; GemCis, gemcitabine and cisplatin; mo, month; ORR, objective response rate; PR, partial response. Remaining in response ≥12 mo 26.1% 15.0% 11 1 18 5 0 21 1 0 Placebo + GemCis (n=64) 6.2 (3.8-9.0) 2.7 (1.4-4.1) 24 3#1515 Summary of adverse events and treatment exposure Median duration of exposure (range), months Durvalumab/placebo Gemcitabine Cisplatin Event, n (%) Any AE Any TRAE Any grade 3/4 AE Any grade 3/4 TRAE Any serious AE Any serious TRAE Any AE leading to discontinuation Any TRAE leading to discontinuation Any AE leading to death Any TRAE leading to death Any immune-mediated AE Durvalumab + GemCis (n=338) 7.33 (0.1-24.5) 5.19 (0.1-8.3) 5.13 (0.1-8.3) 336 (99.4) 314 (92.9) 256 (75.7) 212 (62.7) 160 (47.3) 53 (15.7) 44 (13.0) 30 (8.9) 12 (3.6) 2 (0.6) 43 (12.7) Placebo + GemCis (n=342) 5.77 (0.2-21.5) 5.03 (0.2-8.6) 4.88 (0.2-8.5) 338 (98.8) 308 (90.1) 266 (77.8) 222 (64.9) 149 (43.6) 59 (17.3) 52 (15.2) 39 (11.4) 14 (4.1) 1 (0.3) 16 (4.7)#1616 Conclusions • TOPAZ-1 is the first global Phase III trial to report positive results testing immunotherapy plus chemotherapy as first-line treatment for advanced BTC TOPAZ-1 met its primary endpoint at the prespecified interim analysis: durvalumab plus GemCis demonstrated statistically significant and clinically meaningful prolonged overall survival compared with placebo plus GemCis Durvalumab did not add additional toxicity to that observed with GemCis, and no new safety signals were identified from the known safety profiles of each individual treatment Durvalumab plus GemCis is an effective first-line therapy, and could become a new standard of care, for patients with advanced BTC BTC, biliary tract cancer; GemCis, gemcitabine and cisplatin.#173 Imfinzi+ tremelimumab HIMALAYA Dr Bruno Sangro Principal Investigator, HIMALAYA Phase III trial B#18Study population ● ● ● ● ● ECOG PS 0-1 ● ● HIMALAYA trial design HIMALAYA was an open-label, multicenter, global, Phase III trial ● ● Patients with confirmed uHCC BCLC B (not eligible for locoregional therapy) and C No prior systemic therapy Stratification factors Macrovascular invasion: Y / N Etiology of liver disease: HBV / HCV / others • Performance status: ECOG 0/1 18 Child-Pugh A No main portal vein thrombosis EGD was not required R N=1324 T300+D (n=393): Tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W* Durvalumab (n=389): Durvalumab monotherapy 1500 mg Q4W* Sorafenib (n=389): Sorafenib 400 mg BID* + T75+D (n=153): arm closed Tremelimumab 75 mg Q4W x 4 doses + durvalumab Q4W* Primary objective OS for T300+D vs sorafenib Key secondary objective OS for durvalumab vs sorafenib Additional secondary objectives PFS, ORR, and DoR as assessed by investigator per RECIST v1.1 Safety Multiple testing procedure OS superiority for T300+D vs sorafenib OS noninferiority for durvalumab vs sorafenib Noninferiority margin: 1.08 OS superiority for durvalumab vs sorafenib *Treatment continued until disease progression. Patients with progressive disease who, in the investigator's opinion, continued to benefit from treatment and met the criteria for treatment in the setting of progressive disease could continue treatment. The T75+D arm was closed following a preplanned analysis of a Phase 2 study. Patients randomized to this arm (n=153) could continue treatment following arm closure. Results from this arm are not reported in this presentation. BID, twice a day; EGD, esophagogastroduodenoscopy; Q4W, every 4 weeks. 3#19Baseline characteristics Characteristic Male sex, n (%) Median age (range), years Region, n (%) Asia (excluding Japan) Rest of world (including Japan) Viral etiology,*,* n (%) HBV HCV Nonviral ECOG PS, n (%) 0 1 BCLC, n (%) B C T300+D (n=393) 327 (83.2) 65.0 (22-86) 156 (39.7) 237 (60.3) 122 (31.0) 110 (28.0) 161 (41.0) 244 (62.1) 148 (37.7) 77 (19.6) 316 (80.4) Durvalumab (n=389) 323 (83.0) 64.0 (20-86) 167 (42.9) 222 (57.1) 119 (30.6) 107 (27.5) 163 (41.9) 237 (60.9) 150 (38.6) 80 (20.6) 309 (79.4) Sorafenib (n=389) 337 (86.6) 64.0 (18-88) 156 (40.1) 233 (59.9) 119 (30.6) 104 (26.7) 166 (42.7) 241 (62.0) 147 (37.8) 66 (17.0) 323 (83.0) Characteristic Child-Pugh classification, n (%) A B Missing ALBI grade, n (%) 1 2 3 MVI, n (%) EHS,+ n (%) PD-L1 positive, n (%) AFP ≥400 ng/ml,* n (%) T300+D (n=393) 392 (99.7) 0 1 (0.3) 217 (55.2) 174 (44.3) 1 (0.3) 103 (26.2) 209 (53.2) 148 (37.7) 145 (36.9) *HBV: patients who tested positive for HBsAg or anti-HBc with detectable HBV DNA; HCV: patients who tested positive for HCV or had history of HCV infection; Nonviral: no active viral hepatitis identified. *Determined at screening. *Defined as tumor area positivity score 21%. 19 T300+D, tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W. Durvalumab (n=389) 388 (99.7) 1 (0.3) 0 198 (50.9) 189 (48.6) 2 (0.5) 94 (24.2) 212 (54.5) 154 (39.6) 137 (35.2) Sorafenib (n=389) 386 (99.2) 3 (0.8) 0 203 (52.2) 185 (47.6) 1 (0.3) 100 (25.7) 203 (52.2) 148 (38.0) 124 (31.9) $#20Overall survival T300+D versus sorafenib Probability of overall survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. at risk T300+D Sorafenib 393 389 T300+D Sorafenib 6 308 283 12 235 211 18-mo OS: 48.7% 41.5% 18 190 155 OS events, n (%) Median OS (95% CI), months HR (96.02% CI) p-value (2-sided) 24-mo OS: 40.5% 32.6% I 24 Time from randomization (months) 158 121 20 Data cut-off: August 27, 2021. Median duration of follow-up was 33.18 (95% CI, 31.74-34.53) months for T300+D and 32.23 (95% CI, 30.42-33.71) months for sorafenib. CI, confidence interval; HR, hazard ratio; OS, overall survival; T300+D, tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W. 30 98 62 T300+D (n=393) 262 (66.7) 16.4 (14.2-19.6) 36-mo OS: 30.7% 20.2% 36 32 21 0.78 (0.65-0.92) 0.0035 Sorafenib (n=389) 293 (75.3) 13.8 (12.3-16.1) ## 42 1 1 48 OO 0 0 B#21Overall survival Durvalumab versus sorafenib Probability of overall survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 No. at risk Durvalumab 389 Sorafenib 389 HR for time up to 9 months (95% CI) 0.98 (0.77-1.24) Durvalumab Sorafenib 6 286 283 HR for time after 9 months (95% CI) 0.77 (0.61-0.97) 12 230 211 18 183 155 OS events, n (%) Median OS (95% CI), months HR (95.67% CI) Noninferiority margin-1.08 24 Time from randomization (months) 153 121 21 Data cut-off: August 27, 2021. Median duration of follow-up was 32.56 (95% CI, 31.57-33.71) months for durvalumab and 32.23 (95% CI, 30.42-33.71) months for sorafenib. CI, confidence interval; HR, hazard ratio; NI, noninferiority; OS, overall survival. 30 87 62 Durvalumab (n=389) 280 (72.0) 16.6 (14.1-19.1) 36 27 21 Sorafenib (n=389) 293 (75.3) 13.8 (12.3-16.1) 0.86 (0.73-1.03) 42 6 1 48 O O 0#22Progression free survival T300+D vs sorafenib Probability of progression-free survival 1.0 0.8 0.6- 0.4 0.2- 0.0 No. at risk T300+D Sorafenib 0 393 389 T300+D Sorafenib 6 135 118 12 81 53 PFS for T300+D vs sorafenib 18 24 30 Time from randomization (months) 55 31 43 18 26 6 36 7 0 H 42 0 0 48 0 0 PFS events, n (%) Median PFS (95% CI), months PFS HR* (95% CI) Progression-free at DCO, n (%) Median TTP (95% CI), months Treated 21 cycle beyond progression, n (%) + 22 **Versus sorafenib. *Percent calculated from total patients in the safety analysis set: T300+D, N=388; durvalumab, N=388, sorafenib, n=374. CI, confidence interval; DCO, data cutoff; HR, hazard ratio; PFS, progression-free survival; T300+D, tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W; TTP, time to progression. T300+D (n=393) 335 (85.2) 3.78 (3.68-5.32) 0.90 (0.77-1.05) 49 (12.5) 5.42 (3.81-5.62) 182 (46.9) Durvalumab (n=389) 345 (88.7) 3.65 (3.19-3.75) 1.02 (0.88-1.19) 32 (8.2) 3.75 (3.68-5.42) 188 (48.5) Sorafenib (n=389) 327 (84.1) 4.07 (3.75-5.49) 19 (4.9) 5.55 (5.13-5.75) 134 (34.4) B#23Safety and tolerability Event, n (%) Any AE Any TRAE* Any grade 3/4 AE Any grade 3/4 TRAE Any serious TRAE Any TRAE leading to death Any TRAE leading to discontinuation T300+D (n=388) 378 (97.4) 294 (75.8) 196 (50.5) 100 (25.8) 68 (17.5) 9 (2.3)* 32 (8.2) Durvalumab (n=388) 345 (88.9) 202 (52.1) 144 (37.1) 50 (12.9) 32 (8.2) 0 16 (4.1) Includes AEs with onset or increase in severity on or after the date of the first dose through 90 days following the date of the last dose or the date of initiation of the first subsequent therapy. *Treatment-related was as assessed by investigator. *Nervous system disorder (n=1), acute respiratory distress syndrome (n=1), hepatitis (n=1), myocarditis (n=1), immune-mediated hepatitis (n=2), pneumonitis (n=1), hepatic failure (n=1), myasthenia gravis (n=1). #Hematuria (n=1), cerebral hematoma (n=1), hepatic failure (n=1). 23 AE, adverse event; SMQ, Standardized MedDRA Query; T300+D, tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W; TRAE, treatment-related adverse event. Sorafenib (n=374) 357 (95.5) 317 (84.8) 196 (52.4) 138 (36.9) 35 (9.4) 3 (0.8)* 41 (11.0) B#24Treatment-related hepatic or haemorrhage SMQ events Event, n (%) Patients with hepatic SMQ TRAE Patients with hemorrhage SMQ TRAE Alanine aminotransferase increased Aspartate aminotransferase increased Blood bilirubin increased Ascites Hepatic encephalopathy International normalized ratio increased Esophageal varices hemorrhage T300+D (n=388) All grades 66 (17.0) 7 (1.8) 18 (4.6) 22 (5.7) 6 (1.5) 1 (0.3) 0 4 (1.0) 0 Grade 23 27 (7.0) 2 (0.5) 4 (1.0) 9 (2.3) 1 (0.3) 0 0 1 (0.3) 0 Durvalumab (n=388) Grade 23 20 (5.2) 0 All grades 55 (14.2) 3 (0.8) 22 (5.7) 25 (6.4) 6 (1.5) 0 0 0 0 5 (1.3) 9 (2.3) 0 0 0 0 0 Sorafenib (n=374) All grades 46 (12.3) 18 (4.8) 8 (2.1) 10 (2.7) 10 (2.7) 2 (0.5) 2 (0.5) 0 0 Includes adverse events with onset or increase in severity on or after the date of the first dose through 90 days following the date of the last dose or the date of initiation of the first subsequent therapy. Treatment-related was as assessed by investigator. 24 SMQ, Standardized MedDRA Query; T300+D, tremelimumab 300 mg x 1 dose + durvalumab 1500 mg Q4W; TRAE, treatment-related adverse event. Grade 23 18 (4.8) 6 (1.6) 3 (0.8) 6 (1.6) 2 (0.5) 0 1 (0.3) 0 0 3#25Conclusions 25 ● • A single priming dose of tremelimumab plus regular interval durvalumab with the STRIDE (T300+D) regimen statistically significantly improved overall survival versus sorafenib Median overall survival was 16.4 months for STRIDE (T300+D) and 13.8 months for sorafenib STRIDE (T300+D) appeared to provide a long-term survival benefit, with a landmark 36-month overall survival of 30.7% ● The HIMALAYA study was a large, Phase 3 study that included a global, heterogeneous population, representative of patients with uHCC ● ● ● Overall survival for durvalumab monotherapy was noninferior to sorafenib, with a favorable benefit-risk profile Both STRIDE (T300+D) and durvalumab monotherapy had manageable safety profiles, with lower rates of grade 3/4 TRAES and TRAEs leading to discontinuation than sorafenib and no increase in liver toxicity or bleeding risk The STRIDE (T300+D) regimen and durvalumab monotherapy may represent new treatment options for patients with uHCC#263 Commercial opportunity Dave Fredrickson Executive Vice President, Oncology Business Unit B#27TOPAZ-1 has the potential to become the first-ever IO therapy available for first-line, advanced biliary tract cancer patients Lack of innovation in biliary tract cancer 10+ years without innovation on top of standard of care 5% to 15% of all patients with BTC surviving only five years¹ 75% of BTC patients present with advanced, unresectable BTC² ~50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year³ TOPAZ-1 has practice-changing potential • Trial stopped early at an interim analysis due to clear efficacy, with almost 1 in 4 patients alive at two years versus one in 10 on chemotherapy alone ● • Potential new standard of care in this historically underserved cancer Regulatory submissions in H1 2022 • Safety: no AE-related increase in discontinuations First 10 therapy to demonstrate long-term survival in first-line advanced BTC 27 1. Turkes F, et al. Gastroenterol Res Pract. 2019; 2019:7698786. 2. Vienot A and Neuzillet C. Clin Res Hepatol Gastroenterol. 2020;44:810-824 3. Siegel R, et al. CA Cancer J Clin. 2020; 70: 7-30. and Nakachi K, et al. Japanese Journal of Clinical Oncology. 2018; 48(4): 392-395. and 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. AE = adverse events.#28HIMALAYA - an innovative IO regimen delivering survival benefit to patients with advanced, unresectable hepatocellular carcinoma Large unmet need in liver cancer 3rd leading cause of cancer death worldwide¹ 7% five-year survival in advanced HCC² At least 40% of treatment eligible first-line advanced HCC patients are at risk of bleeding³ ~80,000 people in the US, Europe and Japan and 260,000 people in China present with advanced, unresectable HCC each year Innovative STRIDE regimen with tremelimumab • First 10+10 combination in first- line advanced, unresectable HCC Only Phase III trial to show benefit of single, priming dose of CTLA-4 Impressive three-year landmark OS data with almost 1 in in 3 patients alive at three years on STRIDE regimen versus one in five on sorafenib ● Clear efficacy, safety and simplicity for patients Imfinzi monotherapy non- inferior to sorafenib, with numerical advantage in OS • No increased bleeding risk or severe liver toxicity seen in trials Exceptional safety profile Regulatory submissions in H1 2022 10-only combination strategy simplifies patient management 28 1. ASCO. Liver Cancer: Accessed January 2022. 2. Sayiner M, et al. Digestive Diseases and Sciences. 2019; 64: 910-917. 3. Boregowda et al. World J Gastrointest Pharmacol Ther. 2019 Jan 21; 10(1): 1-21. 4. AstraZeneca data on file. Kantar Health. 2021. STRIDE = single tremelimumab regular interval durvalumab; 10 = immuno-oncology; CTLA-4 = cytotoxic T-lymphocyte associated protein 4.#294 What's next in GI? Susan Galbraith Executive Vice President, Oncology R&D B#30FELLESSERTER Annual WW Incidence (000s) GI tumours are the next pillar for AstraZeneca in oncology complementing strong presence in lung & breast 7000 Annual worldwide incidence by cancer type Existing AstraZeneca presence ENHERTU fam-trastuzumab deruxtecan-nxki 20 mg/mL INJECTION FOR INTRAVENOUS USE Lynparza olaparib tabiateg FASLODEX fulvestrant breast SIMFINZIⓇ durvalumab the 50 mg TAGRISSO osimertinib lung Lynparza olaparib tatis omg Zoladex goserelin CALQUENCE (acalabrutinib) 100 mg capsules prostate leukaemia Lynparza olaparib ovarian pancreas oesophagus hepatobiliary gastric colorectal Levels of heterogenicity seen in Gl cancers shows the need for a varied arsenal of medicines across the GI cancer landscape GI Source: Globocan (Globocan 2020 Estimates of Incidence and Mortality Worldwide; GLOBOCAN Cancer Today, 2018). WW = worldwide; GI = gastrointestinal. Lynparza® olaparib ENHERTU fam-trastuzumab deruxtecan-mxki 20 ng/mL INJECTION FOR INTRAVENOUS USE#31AZ poised to become a leader in GI cancers Late-stage clinical programmes SIMFINZI durvalumab Injection for Intravenous Use 50 mg/mL ENHERTUⓇ fam-trastuzumab deruxtecan-nxki 20 mg/mL INJECTION FOR INTRAVENOUS USE EMERALD-1: locoregional HCC; data H2 2022 EMERALD-2: adjuvant HCC; data 2022 + MATTERHORN: resectable gastric / GEJ; data 2022+ KUNLUN: locally-advanced oesophageal; data 2022+ DESTINY-Gastric03: HER2+ gastric / GEJ; data 2022+ DESTINY-Gastric04: 2L gastric / GEJ; data 2022+ DESTINY-Gastric06: 3L HER2+ CN; data 2022+ DESTINY-CRC02: 3L HER2+ CN; data 2022+ DESTINY-PT01: CRC, liver and gastric; data 2022+ DESTINY-PT02: BTC and pancreatic; data 2022+ Selected early-stage 5 datopotamab deruxtecan (TROP2 ADC) HER2-ve gastric/GEJ and oesophageal AZD8205 (B7H4 ADC) cholangiocarcinoma oleclumab (CD73 mAb) pancreatic AZD0171 (LIF1 mAb) pancreatic 31 GEJ = gastroesophageal junction adenocarcinoma; HER2 = human epidermal growth factor receptor 2; CN = China; PT= pan-tumor; TROP2 = trophoblast cell surface antigen 2; HER2-ve = HER2-negative; B7H4 = v-set domain- containing T-cell activation inhibitor 1; ADC = antibody drug conjugate; CD73 = cluster of differentiation 73; mAb = monoclonal antibody; LIF1 = leukaemia inhibitory factor 1. 4#325 Closing and Q&A B#33Investor Relations 33 Chris Sheldon [email protected] Tom Waldron [email protected] Christer Gruvris [email protected] Lauren Swales [email protected] Josie Afolabi [email protected] Morgan Sanford [email protected] Philip Sparks [email protected] Jen Kretzmann [email protected] B#34A Appendix B#3535 TOPAZ-1 a#36Overall survival Subgroup analysis Subgroups All patients Sex Race Region ECOG PS at baseline Primary tumor location Disease status Disease classification PD-L1 expression <65 ≥65 Female Male Asian Non-Asian Asia Rest of the world 0 1 ICC ECC GBC Initially unresectable Recurrent Locally advanced Metastatic TAP ≥1% TAP <1% 0.1 0.5 1.5 1 Hazard ratio (95% CI) Favors durvalumab + Gem Cis Favors placebo + GemCis 36 Cl, confidence interval; ECC, extrahepatic cholangiocarcinoma; ECOG, Eastern Cooperative Oncology Group; GBC, gallbladder cancer; GemCis, gemcitabine and cisplatin; ICC, intrahepatic cholangiocarcinoma; OS, overall survival; PD- L1, programmed cell death ligand-1; PS, performance status; TAP, tumor area positivity. 2 Hazard ratio (95% CI) 0.80 (0.66-0.97) 0.80 (0.61-1.04) 0.79 (0.60-1.04) 0.82 (0.62-1.08) 0.78 (0.60-1.01) 0.73 (0.57-0.94) 0.89 (0.66-1.19) 0.72 (0.56-0.94) 0.89 (0.66-1.19) 0.90 (0.68-1.20) 0.72 (0.56-0.94) 0.76 (0.58-0.98) 0.76 (0.49-1.19) 0.94 (0.65-1.37) 0.84 (0.69-1.03) 0.56 (0.32-0.96) 0.49 (0.26-0.88) 0.83 (0.68-1.02) 0.79 (0.61-1.00) 0.86 (0.60-1.23) B#37Overall survival in subgroups by PD-L1 expression Subgroups All patients PD-L1 expression TAP >1% PD-L1 expression TAP <1% PD-L1 expression TAP 25% PD-L1 expression TAP <5% PD-L1 expression TAP >10% PD-L1 expression TAP <10% PD-L1 expression TC >1% PD-L1 expression TC <1% 0.1 0.5 Hazard ratio (95% CI) 0.80 (0.64-0.97) 0.79 (0.61-1.00) 0.86 (0.60-1.23) 2 0.70 (0.50-0.99) 0.88 (0.69-1.13) 0.75 (0.47-1.19) 0.83 (0.66-1.03) 1 1.5 Hazard ratio (95% CI) Favors durvalumab + GemCis Favors placebo + GemCis 0.70 (0.49-0.99) 0.87 (0.68-1.11) 37 CI, confidence interval; IC, immune cell; OS, overall survival; PD-L1, programmed cell death ligand-1; TC, tumor cell; TAP, tumor area positivity 1 2 3 1 Tumor Area Positivity (TAP) score using the Ventana PD-L1 (SP263) Assay Tumor area TC area TC area with PD-L1 expression IC area IC area with PD-L1 expression 3 TC: proportion of TCs with PD-L1 membrane staining at any intensity IC: proportion of tumor-associated ICs with PD-L1 cytoplasmic/ membrane staining at any intensity Combined TCs and ICs: Proportion of tumour area occupied by TCs with membrane and ICs with cytoplasmic/membrane PD-L1 staining at any intensity (TAP score)#38Grade 3/4 adverse events 38 Event, n (%) Any grade 3/4 AE (25%) Anemia Neutrophil count decreased Neutropenia Platelet count decreased Cholangitis Thrombocytopenia White blood cell count decreased Any grade 3/4 TRAE (≥2%) Neutrophil count decreased Neutropenia Anemia Platelet count decreased White blood cell count decreased Thrombocytopenia Fatigue Leukopenia Asthenia Durvalumab + GemCis (n=338) 80 (23.7) 71 (21.0) 68 (20.1) 33 (9.8) 22 (6.5) 16 (4.7) 15 (4.4) 70 (20.7) 65 (19.2) 64 (18.9) 27 (8.0) 14 (4.1) 12 (3.6) 9 (2.7) 7 (2.1) 4 (1.2) Placebo + GemCis (n=342) 77 (22.5) 88 (25.7) 72 (21.1) 29 (8.5) 11 (3.2) 18 (5.3) 20 (5.8) 87 (25.4) 69 (20.2) 64 (18.7) 26 (7.6) 20 (5.8) 18 (5.3) 8 (2.3) 2 (0.6) 7 (2.0)#3939 HIMALAYA 4#40Forest plot of overall survival T300+D versus sorafenib in patient subgroups All patients Sex Age Region Viral etiology* ECOG PS* BCLC score MVI* EHS MVI and/or EHS PD-L1 status AFP Male Female <65 yr ≥65 yr Asia (except Japan) Rest of world (includes Japan) HBV HCV Nonviral 0 1 B C Yes No Yes No Yes No/no Positive+ Negative <400 ng/ml >400 ng/ml 0.25 40 Stratification factor. *Defined as tumor area positivity score 21%. T300+D, tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W. 0.5 T300+D vs sorafenib Favors T300+D 1 HR (95% CI) Favors sorafenib 2 HR (95% CI) 0.78 (0.66-0.92) 0.73 (0.61-0.88) 1.02 (0.67-1.56) 0.82 (0.65-1.04) 0.73 (0.58-0.93) 0.71 (0.54-0.92) 0.82 (0.66-1.02) 0.64 (0.48-0.86) 1.06 (0.76-1.49) 0.74 (0.57-0.95) 0.79 (0.63-0.98) 0.74 (0.57-0.95) 0.87 (0.57-1.33) 0.76 (0.63-0.91) 0.78 (0.57-1.07) 0.77 (0.63-0.93) 0.67 (0.53-0.84) 0.87 (0.67-1.11) 0.73 (0.59-0.89) 0.79 (0.58-1.06) 0.85 (0.65-1.11) 0.83 (0.65-1.05) 0.82 (0.63-1.05) 0.64 (0.45-0.91) B#41Immune-mediated adverse events. 41 Event, n (%) Patients with immune- mediated event Hepatic events Diarrhea/colitis Dermatitis/rash Pancreatic events Adrenal insufficiency Hyperthyroid events Hypothyroid events Pneumonitis Renal events All grades 139 (35.8) 29 (7.5) 23 (5.9) 19 (4.9) 9 (2.3) 6 (1.5) 18 (4.6) 42 (10.8) 5 (1.3) 4 (1.0) T300+D (n=388) Grade 3 or 4 49 (12.6) 16 (4.1) 14 (3.6) 7 (1.8) 7 (1.8) 1 (0.3) 1 (0.3) 0 0 2 (0.5) Received high-dose steroids 78 (20.1) 29 (7.5) 20 (5.2) 12 (3.1) 7 (1.8) 1 (0.3) 2 (0.5) 1 (0.3) 4 (1.0) 3 (0.8) Leading to discontinuation 22 (5.7) 9 (2.3) 5 (1.3) 2 (0.5) 0 0 0 0 1 (0.3) 2 (0.5) All grades 64 (16.5) 26 (6.7) 3 (0.8) 3 (0.8) 2 (0.5) 6 (1.5) 4 (1.0) 19 (4.9) 3 (0.8) 0 Durvalumab (n=388) Grade 3 or 4 25 (6.4) 17 (4.4) 1 (0.3) 1 (0.3) 1 (0.3) 3 (0.8) 0 0 1 (0.3) 0 Received high-dose steroids 37 (9.5) 25 (6.4) 2 (0.5) 3 (0.8) 2 (0.5) 3 (0.8) 0 0 3 (0.8) 0 Leading to discontinuation 10 (2.6) 5 (1.3) 1 (0.3) 1 (0.3) 0 0 0 0 2 (0.5) 0 B#4242 Use of AstraZeneca slides from conference calls and webcasts The AstraZeneca webcast, conference call and presentation slides (together the 'AstraZeneca materials') are for your personal, non-commercial use only. 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