DESTINY-Breast09 Trial

[Slide 1] ADCs will move to earlier lines (including neo/adjuvant) Neoadjuvant Adjuvant 1L cytotoxic, pre-ChT DESTINY-Breast11 DESTINY-Breast05 POSITIVE DESTINY-Breast09 T-DXd vs T-DXd/THP vs AC-THP T-DXd vs T-DM1 T-DXd +/- pertuzumab vs THP TROPION-Breast04 SURVIVE-HERoes TROPION-Breast02 Dato-DXd/Durva vs KN522 regimen T-DXd vs TPC Dato-DXd vs.TPC TROPION-Breast03 TROPION-Breast05 Dato-DXd +-/Durvavs. TPC Dato-DXd/Durva vs. chemo/pembro In the probable future, we will ASCENT-05/OptimICE-RD ASCENT-03 SG/pembro vs pembro +/- cape SG vs. TPC likely have more Topo1 ADCs approved in earlier indications NCT06393374 POSITIVE ASCENT-04 (curative setting, 1L setting) Sac-TMT/ pembro vs TPC SG/pembro vs. TPC/pembro SASCIA ASCENT-07 SG vs TPC SG vs. TPC HER2+ DYNASTY-Breast02 TNBC DB-1303 vs. TPC @PTarantinoMD HR+/HER2- TroFuse-010 Sac-TMT + pembro vs TPC

[Slide 1] Summary: T-DXd + P is a highly effective regimen in the 1L setting Optimal sequencing remains unclear Potential selection factors for 1L use of T-DXd + P: Clinical: brain metastases, significant visceral disease, recent progression after (neo)adjuvant therapy Biological: molecular markers of early progression (eg PIK3CAm), HER2 drivers (eg HER2DX low/med ERBB2 score), dynamic markers (eg lack of early drop in ctDNA) - need to be further validated Patient preference Could we achieve the same benefit with induction T-DXd + P till best response followed by maintenance HP? -- paucity of data Benefit of ET in maintenance phase in ER+ (PATINA) Ongoing trials evaluating improving outcome with maintenance therapy - HER2CLIMB-05 (Tucatinib): INAVO122 (Inavolisib for PIK3CAm) 2025 ASCO #ASCO25 PRESENTED Claudine Isaacs MD FRCPC ASCO 2025 ASCO ANNUAL MEETING

[Slide 1] Time without progression Duration of response Response to treatment The timepoint after randomization at which The length of time that at least half the The percentage of participants who had at least half of the participants had cancer people continued to respond to a 30% decrease in size of tumors (known as objective progression or died (known as median treatment (known as median duration response rate) was: progression-free survival) was: of response) was: 3 years ~9 in 10 (85%) of those in the T-DXd + pertuzumab arm manan T-DXd + 41 months 39 26 pertuzumab ~8 in 10 (79%) of those in the THP arm months months for people given for people given T-DXd + pertuzumab THP 58 (15.1%) people given T-DXd + pertuzumab and THP 27 months 33 (8.5%) people given THP had all signs of their cancer disappear (known as complete response) Safety What's next? Side effects possibly related to treatment that were experienced by at least 2 in 5 (40%) people in The study will continue to explore if T-DXd either treatment arm were: alone is superior to THP (once there is T-DXd + pertuzumab THP OF sufficient follow up to allow for this preplanned analysis) while also understanding if there is a further benefit of 71% Nausea 29% 46 (12%) people given T-DXd + pertuzumab with longer follow up T-DXd + pertuzumab 56% Diarrhea 54% and 4 (1%) people given How do the results of the THP developed interstitial 49% Neutropenia lung disease DESTINY-Breast09 study 45% (reduced white blood cells) (inflammation and/or help to improve the treatment scarring of the lungs); of cancer? 48% Fatigue 35% most cases were mild/moderate DESTINY-Breast09 potentially 46% Alopecia 50% establishes T-DXd with pertuzumab (hair loss) 2 (0.5%) people given as an effective new first-line treatment T-DXd + pertuzumab 42% Vomiting 13% died as a result option for people with HER2-positive metastatic/advanced breast cancer Where can I access more information? DESTINY-Breast09 ClinicalTrials.gov identifier NCT04784715 This summary is based on an oral presentation by Professor Sara M Tolaney at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Presentation ID LBA1008). This summary, and the results of this study, have not yet been peer reviewed. The authors would like to thank the patients and their families who participated in the DESTINY-Breast09 study, and the investigators, co-investigators, and study staff. Date of summary: May 2025. The DESTINY-Breast09 study was sponsored by AstraZeneca. In March 2019, AstraZeneca entered into a global and commercialization collaboration agreement with Daiichi Sankyo deruxtecan (T-DXd; DS-8201). This plain language summary was prepared --- [Slide 2] What is the purpose of the DESTINY-Breast09 study? DESTINY Breast09 Trastuzumab deruxtecan (T-DXd) is a recommended treatment for DESTINY-Breast09 is a clinical study of adults people whose breast cancer has a high level of the human epidermal who were given T-DXd alone, T-DXd + pertuzumab, growth factor receptor 2 protein (known as 'HER2-positive') and if the or THP as the first treatment for their HER2-positive cancer cells cannot be completely removed with surgery and have spread metastatic/advanced breast cancer. from where they started (known as metastatic/advanced cancer). T-DXd can currently only be given to these people if their breast cancer The study was designed to find out how well T-DXd has worsened (known as disease progression) while receiving the first worked with or without pertuzumab in delaying disease recommended treatment, which is a combination of a chemotherapy drug progression as compared with THP. The study also and two HER2-targeting drugs, known as THP (taxane + trastuzumab assessed the side effects participants experienced when + pertuzumab). receiving these treatments. What did the study show? This planned analysis of DESTINY-Breast09 showed that participants in the T-DXd + pertuzumab arm lived longer without their disease growing, spreading, or getting worse compared with participants in the THP (taxane + trastuzumab + pertuzumab) arm. Side effects of the treatments were manageable and as expected based on results of previous studies. How was the DESTINY-Breast09 study carried out? Start of study People included in the study had: 383 people were randomly assigned to Metastatic/advanced breast cancer T-DXd + pertuzumab 2 drugs Start of HER2+ HER2-positive tumors treatment* 387 people were randomly assigned to eeen No prior chemotherapy or HER2-targeted THP (taxane + trastuzumab + pertuzumab) therapy for metastatic/advanced breast cancer taxane options = paclitaxel or docetaxel 3 drugs One prior endocrine-based therapy for *At the time of this first analysis, the T-DXd alone arm remained blinded; metastatic/advanced breast cancer (optional) this will be evaluated at a subsequent analysis

[Slide 1] DESTINY-Breast09 Conclusions T-DXd + P demonstrated a statistically significant and clinically meaningful PFS benefit by BICR vs THP, which was consistently observed across subgroups PFS by BICR - Hazard ratio of 0.56 vs THP (P<0.00001) - Median PFS was 40.7 months (T-DXd + P) vs 26.9 months (THP) 44% Median DOR of >3 years with T-DXd + P. with CRs in 15.1% (T-DXd + P) Reduction in risk of vs 8.5% (THP) disease progression Early os data suggest a positive trend favoring T-DXd + P. or death with with a supportive hazard ratio of 0.60 for PFS2 T-DXd + P vs THP T-DXd + P safety data were consistent with known profiles of individual treatments T-DXd + P demonstrated a statistically significant and clinically meaningful PFS benefit vs THP and may represent a new first-line standard of care for patients with HER2+ a/mBC been DICR blended DOR duction of response human updermal growth factor incapital 3 positive os perfurume ASCO Tolaney MPH 2025 #ASCO25 ASCO MEETING KNOWLEDGE CONQUERS CANCER 2025 ASCO ANNUAL MEETING

[Slide 1] Enhertu plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival US. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer --- [Slide 2] DESTINY-Breast09 Phase III trial of AstraZeneca and Daiichi Sankyo's Enhertu is the first trial in more than a decade to demonstrate superior efficacy across a broad HER2-positive metastatic patient population versus current 1st-line standard of care Positive high-level results from a planned interim analysis of the DESTINY-Breast09 Phase III trial showed Enhertu (trastuzumab deruxtecan) in combination with pertuzumab demonstrated a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to a taxane, trastuzumab and pertuzumab (THP) as a 1st-line treatment for patients with HER2- positive metastatic breast cancer. The PFS improvement was seen across all pre- specified patient subgroups with Enhertu in combination with pertuzumab. The key secondary endpoint of overall survival (OS) was not mature at the time of this planned interim analysis; however, interim os data showed an early trend favouring the Enhertu combination compared with THP. The second arm assessing Enhertu monotherapy versus THP remains blinded to patients and investigators and will continue to the final PFS analysis. HER2-positive metastatic breast cancer is an aggressive disease driven by overexpression or amplification of HER2 affecting 15-20% of patients with metastatic breast cancer. 1 While HER2-targeted therapies have improved outcomes, prognosis remains poor, with most patients experiencing disease progression within two years of 1st-line treatment with THP, which has are for more

[Slide 1] DESTINY-Breast09 Conclusions T-DXd + P demonstrated a statistically significant and clinically meaningful PFS benefit by BICR vs THP, which was consistently observed across subgroups PFS by BICR - Hazard ratio of 0.56 vs THP (P<0.00001) - Median PFS was 40.7 months (T-DXd + P) VS 26,9 months (THP) 44% Median DOR of >3 years with T-DXd + P, with CRs in 15.1% (T-DXd + P) Reduction in risk of vs 8.5% (THP) disease progression Early os data suggest a positive trend favoring T-DXd + P, or death with with a supportive hazard ratio of 0.60 for PFS2 T-DXd + P vs THP T-DXd + P safety data were consistent with known profiles of individual treatments T-DXd + P demonstrated a statistically significant and clinically meaningful PFS benefit vs THP and may represent a new first-line standard of care for patients with HER2+ a/mBC a/mBC, advanced/molastatic breast cancer; BICR, blinded independent central review CR complete response DOR duration of response HER2 human epidermal growth factor reception 2-positive, OS, overall survival P. portuzumab PFS, progression free survival PFS2, second progression-free survival, T-DXd, trashizumab deruxtecan, THP, laxane . trastuzumeb . partzzumab 2025 ASCO PRESENTED OT Sara M Tolaney, MD, MPH ASCO MERICAN SOCIETY #ASCO26 CLINICAL ONCOLO ANNUAL MEETING Preservation . property of the author and ASCO KHCWLEDGE CONQUERS CANC

[Slide 1] DESTINY-Breast09 DESTINY-Breast09 study design A randomized, multicenter, open-label,* Phase 3 study (NCT04784715) Eligibility criteria Endpoints n=387 HER2+ a/mBC T-DXd + placebo Primary PFS (BICR) Asymptomatic/inactive brain mets allowed Key secondary DFI >6 mo from last chemotherapy or R n=383 os HER2-targeted therapy in neoadjuvant/ adjuvant setting 1:1:1 T-DXd + pertuzumab Secondary One prior line of ET for mBC permitted PFS (INV) No other prior systemic treatment THP ORR (BICR/INV) n=387 for mBC Taxane (paclitaxel or docetaxel) DOR (BICR/INV) trastuzumabl + pertuzumabl PFS2 (INV) Stratification factors Safety and tolerability De-novo vs recurrent mBC HR+ or HR- If T-DXd was discontinued due to AEs (except Grade >2 ILD), patients could switch to trastuzumab** PIK3CAm (detected vs non-detected) Concurrent use of ET (AI or tamoxifen) was allowed for those with HR+ disease after six cycles of T-DXd or discontinuation of taxane in THP arm "Open THP arm Double blinded for pertuzumeb experimental arms THER2 targeted therapy chemotherapy 4 mgkg Q3W 1840 mg loading dose then 420 mg Q3W pacitaxel 80 mg/m? ow or 175 mg/m2 Q3W or docetaxel 75 mg/m2 Q3W of SDX cycles or until lg loading dose then dose AE DEL disease free interval DOR duration of response ET. endocrine therapy HER2 human epidemal growth factor mets metastases mo months ORR objective response rate OS overall survival PFS progression froo survival Q3W. every 3 weeks QW. once every week R randomization T-DXd. trastuzumab deruxlecan NCT04784715 Updated Mar 6 2025 Available from helps 2025) 2025 ASCO #ASCO25 Sara M Tolaney MD MPH ASCO AMERICAN SOCIETY or CLINICAL ONCOLDON ANNUAL MEETING . KNOWLEDGE CONQUERS CANCER --- [Slide 2] DESTINY-Brea PFS (BICR): primary endpoint T-DXd + P THP 93.0% (n=383) (n=387) 1.0 - (95% CI 89.9 95.2) 85.9% 40.7* 26.9 Median, mo (95% CI) (95% CI 81.9. 89.1) (36.5, NC) (21.8, NC 0.8 70.1% Hazard ratio (95% CI) 0.56 (0.44, 0.71) 87.8% (95% CI 64.8, 74.8) P-value <0.00001 (95% CI 84.0. 90.7) 0.6 72.4% (95% CI 67.4 76.8) + 52.1% 0.4 (95% CI 46.4, 57.5) 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time from randomization (months) No. at risk T-DXd 383 358 355 321 293 275 242 208 175 153 82 49 21 10 3 0 THP 387 353 312 273 241 215 187 160 124 106 51 32 12 5 1 0 Statistically significant and clinically meaningful PFS benefit with T-DXd + P (median A 13.8 mo) "Median PFS estimate for T-DXd P is likely to change at updated analysis 'stratified log rank test A P value of <0.00043 was required for interim analysis superiority BICR blinded independent central review CI confidence interval mo months (mJPFS (median) progression tree survival NG, not calculable T DXd trastuzumati deruxtecan THP taxane . trastuzumat . partuzumab 2025 ASCO Pid SENTED #ASCO25 Sara M Tolaney MD. MPH ASCO AMERICAN SOCIETY CUNICAL ONCOLD ANNUAL MEETING Presentation . KNOWLEDGE CONQUERS CANC --- [Slide 3] DESTINY-Breast09 Patient disposition Blinded until final PFS analysis Screened (N=1703) T-DXd + placebo (n=387) , Randomized 1:1:1 (N=1157) T-DXd + P (n=383) THP (n=387) Treated (n=380; 99.2%) Treated (n=383; 99.0%) Discontinuation reasons, %* Discontinued T-DXd (59.7%)* Discontinued taxane (96.3%)* Discontinued trastuzumab (66.6%)* PD 21.3 18.8 52.5 AE 20.8 25.8 3.4 Patient decision 11.1 7.3 5.7 Protocol deviation 0.3 0.3 0.3 Lost to follow up - 0.5 0.5 Other 2.4 43,6 3.7 Death 3.9 - 0.5 In the T-DXd + P arm, 8.7% (n=33/380) of patients switched to trastuzumab (+ P) after discontinuation of T-DXd for reasons other than PD Concurrent ET use was 13.5% (T-DXd + P) vs 38.3% (THP) among patients with HR+ disease" At DCO, 39.6% (n=302) of patients remained on any treatment: 45.8% (n=174) T-DXd + P vs 33.4% (n=128) THP* Median duration of follow up: 29.2 months Pertuzumab could not be continued as a single agent without T DX4 or trastuzumab THP was administered as per institutional standards "Percentages are based on the patients who started treatment 154 2% of patients discontinued all treatments 964 0% (n=250) of patients were assigned to docetaxol and 34 4% (n=133) were assigned to pacificate) 15-50% of patients completed the minimum of Six cycles of texase per protocol patients with HR+ disease could receive ET after Six cycles of T-DXd of discontinuation of tuxune AE adverse event DCD data outoff ET endocrine therapy HR+ hormone receptor-positive P. pertuzumab PD progressive disease; PFS progression from survival T DXd trastuzumati denutecan THP taxane trastuzumab pertuzumati 2025 ASCO PRE SENTED #ASCO25 Sara M Tolaney MD. MPH ASCO AMERICAN SOCIETY or CUNICAL ONCOLOGY ANNUAL MEETING Presentation . property of the author and A800 Permission required to reuse contact permissions@asco.or KNOWLEDGE CONQUERS CANCER

[Slide 1] DESTINY-Breast09 Overall safety summary Safety analysis set* Median total treatment duration: T-DXd + P: 21.7 mo (range 0.3-44.5) T-DXd + P THP - T-DXd: 20.0 mos (n=381) (n=382) THP: 16.9 mo (range (0.7-41.7) Total exposure, patient years 659,7 564.0 Median treatment duration for taxanes: Any TEAE, n (%) 380 (99.7) 378 (99.0) Docetaxel: 5.5 mo (range (0.7-37.4) Possibly treatment-related TEAEs (investigator assessed), n (%) 373 (97.9) 369 (96.6) Paclitaxel: 4.4 mo (range 0.2-30.7) Grade >3 209 (54.9) 200 (52.4) Median number of cycles for taxanes: Serious TEAEs, n (%) 103 (27.0) 96 (25.1) Docetaxel: 8 (range 1-51) TEAEs associated with any treatment discontinuation, n (%) 79 (20.7) 108 (28.3) Paclitaxel: 6 (range 1-42) TEAEs associated with any dose interruptions, n (%) 262 (68.8) 187 (49.0) TEAEs associated with any dose reductions, n (%) 175 (45.9) 76 (19.9) TEAEs with outcome of death, n (%) 13 (3.4) 3 (0.8) Possibly treatment related (investigator assessed) 5 (1.3) 1 (0.3) "Safety analyses included all patients who received at least one dose of study treatment (at least one study drug); 'dose modifications or discontinuations relate to any component of each arm. Itreatment-related TEAEs with outcome of death were pneumonitis (n=1), sepsis (n=1), septic shock (n=1), febrile neutropenia (n=1), and dyspnea (n=1) in the T-DXd P arm, and anemia (n=1) in the THP arm excludes data from the 8.7% (33/380) of treated patients who received trastuzumab after discontinuing T-DXd due to TEAEs mo months P. pertuzumab; T-DXd. trastuzumab deruxtecan; TEAE treatment-emergent adverse event THP, taxane + trastuzumab . pertuzumab 2025 ASCO PRE SENTED BY: Sara M Tolaney, MD. MPH ASCO AMERICAN SOCIETY OF #ASCO25 CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse contact permissions@asco. KNOWLEDGE CONQUERS CANCER