DESTINY-Breast05 Trial

[Slide 1] Invasive Disease-free Survival 100 90 3-Yr Invasive 80 Patients Disease-free 100 with Survival 70 Percentage of Patients Event (95% CI) 60 95 T-DXd no. (%) percent 50 90 T-DXd 51 (6.2) 92.4 (89.7-94.4) 40 85 T-DM1 T-DM1 102 (12.5) 83.7 (80.2-86.7) 30 80 Hazard ratio for invasive disease or 20 death, 0.47 (95% CI, 0.34-0.66) 0 10 P<0.001 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Months No. at Risk T-DXd 818 788 781 776 771 768 758 753 731 684 634 544 440 380 370 275 218 212 129 92 90 46 14 14 0 0 0 0 0 T-DM1 817 781 769 760 745 734 719 708 687 632 599 527 417 355 337 233 186 177 120 84 79 38 14 13 4 1 1 0 0

[Slide 1] A Invasive Disease-free Survival 100 90 3-Yr Invasive 80 Patients Disease-free 100 with Survival 70 Percentage of Patients Event (95% CI) 60 95 T-DXd no. (%) percent 50 90 T-DXd 51 (6.2) 92.4 (89.7-94.4) 40 85 T-DM1 T-DM1 102 (12.5) 83.7 (80.2-86.7) 30 80 Hazard ratio for invasive disease or 20 death, 0.47 (95% CI, 0.34-0.66) 0 10 P<0.001 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Months No. at Risk T-DXd 818 788 781 776 771 768 758 753 731 684 634 544 440 380 370 275 218 212 129 92 90 46 14 14 0 0 0 0 0 T-DM1 817 781 769 760 745 734 719 708 687 632 599 527 417 355 337 233 186 177 120 84 79 38 14 13 4 1 1 0 0 B Disease-free Survival 100 90 3-Yr 80 Patients Disease-free 100 with Survival 70 Percentage of Patients Event (95% CI) 60 95 T-DXd no. (%) percent 50 90 T-DXd 52 (6.4) 92.3 (89.5-94.3) 40 85 T-DM1 T-DM1 103 (12.6) 83.5 (79.9-86.4) 30 80 Hazard ratio for invasive disease, 20 noninvasive disease, or death, 0 10 0.47 (95% CI, 0.34-0.66) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 P<0.001 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Months No. at Risk T-DXd 818 788 781 776 771 768 758 753 731 683 633 543 440 380 370 275 218 212 129 92 90 46 14 14 0 0 0 0 0 T-DM1 817 779 767 757 743 733 718 707 686 631 598 526 416 354 336 233 186 177 120 84 79 38 14 13 4 1 1 0 0 C Distant Recurrence-free Interval 100 90 Patients 80 Patients Event-free 100 70 with at 3 Yr Percentage of Patients 60 95 T-DXd Event (95% CI) 50 90 no. (%) percent T-DM1 T-DXd 40 42 (5.1) 93.9 (91.4-95.7) 85 T-DM1 81 (9.9) 86.1 (82.5-89.1) 30 80 20 Hazard ratio for distant recurrence, 0 0.49 (95% CI, 0.34-0.71) 10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Months No. at Risk T-DXd 818 786 778 774 770 767 757 753 731 684 635 545 442 382 372 276 219 213 129 92 90 46 14 14 0 0 0 0 0 T-DM1 817 780 769 761 746 739 724 713 694 639 606 533 424 362 345 240 192 182 121 84 79 38 14 13 4 1 1 0 0 --- [Slide 2] 3-Yr Invasive Disease-free Hazard Ratio for Invasive Disease Subgroup T-DXd T-DM1 Survival (95% CI) (95% CI) T-DXd T-DM1 no. of patients with event/total no. percent All patients 51/818 102/817 92.4 (89.7-94.4) 83.7 (80.2-86.7) 0.47 (0.34-0.66) Age <65 yr 46/735 87/736 92.1 (89.2-94.3) 84.1 (80.2-87.2) 0.50 (0.35-0.71) >65 yr 5/83 15/81 94.9 (87.0-98.1) 79.2 (67.9-87.0) 0.31 (0.11-0.86) Race Asian 19/399 34/386 95.1 (91.9-97.0) 89.5 (85.3-92.6) 0.53 (0.30-0.93) Non-Asian 32/419 68/431 89.5 (84.5-93.0) 77.9 (72.1-82.7) 0.44 (0.29-0.67) Geographic region Asia 19/392 33/380 95.0 (91.9-97.0) 89.7 (85.4-92.7) 0.55 (0.31-0.96) Europe 13/222 30/223 93.1 (86.9-96.4) 82.9 (75.8-88.1) 0.40 (0.21-0.77) North America and Australia 5/57 10/72 85.8 (63.9-94.9) 80.7 (65.3-89.7) 0.56 (0.19-1.63) Rest of the world 14/147 29/142 85.1 (73.6-91.8) 69.2 (56.3-79.0) 0.43 (0.23-0.81) Central HER2 status IHC 3+ 46/676 86/670 91.8 (88.7-94.1) 83.2 (79.2-86.5) 0.49 (0.34-0.70) ISH-positive 5/140 16/147 96.2 (91.0-98.4) 86.5 (78.1-91.8) 0.35 (0.13-0.97) Hormone-receptor status Positive 33/581 59/583 93.5 (90.6-95.6) 86.8 (82.9-89.9) 0.54 (0.35-0.82) Negative 18/237 43/234 89.4 (82.0-93.9) 75.6 (67.6-81.9) 0.37 (0.22-0.65) Operative status at disease presentation, before neoadjuvant therapy Operable disease 21/387 34/393 92.8 (88.0-95.7) 88.4 (83.8-91.8) 0.58 (0.34-1.01) Inoperable disease 30/431 68/424 92.0 (88.5-94.5) 79.4 (73.9-83.8) 0.41 (0.27-0.63) Pathological nodal status after neoadjuvant therapy Positive 40/660 87/658 92.5 (89.3-94.8) 82.5 (78.4-85.9) 0.43 (0.29-0.62) Negative 11/158 15/159 91.6 (85.3-95.3) 88.3 (80.6-93.0) 0.73 (0.33-1.59) HER2-targeted neoadjuvant therapy Single 13/176 27/171 87.5 (77.6-93.3) 77.9 (67.7-85.2) 0.43 (0.22-0.84) Dual 38/642 75/646 93.6 (90.9-95.5) 85.2 (81.4-88.2) 0.48 (0.33-0.71) Previous neoadjuvant therapy Anthracycline 32/423 61/399 90.6 (86.1-93.6) 80.3 (74.8-84.8) 0.45 (0.29-0.69) Platinum compound 20/386 37/392 93.9 (90.4-96.1) 87.3 (82.4-90.9) 0.54 (0.31-0.93) Radiotherapy treatment Sequential radiotherapy 15/326 34/279 93.8 (88.4-96.7) 83.2 (76.4-88.2) 0.35 (0.19-0.64) Concurrent radiotherapy 30/438 57/480 92.8 (89.7-95.0) 85.1 (80.6-88.6) 0.55 (0.35-0.85) No radiotherapy 6/54 11/58 81.0 (61.0-91.4) 73.4 (56.4-84.6) 0.57 (0.21-1.55) 0.06 0.12 0.25 0.50 1.00 2.00 T-DXd Better T-DM1 Better

[Slide 1] pCR (ypTO/is ypN0): primary endpoint ITT population+ (primary endpoint) HR-positive HR-negative 16.1% 11.2% (95% CI 3.0, 28.8) Д9.1% 100 (95% CI 4.0, 18.3; P=0.003*) (95% CI 0.2, 17.9) 83.1 80 67.1 67.3 61.4 56.3 52.3 pCR (%)* 60 40 20 216/321 180/320 145/236 123/235 69/83 57/85 0 T-DXd-THP ddAC-THP T-DXd-THP ddAC-THP T-DXd-THP ddAC-THP Neoadjuvant T-DXd-THP demonstrated a statistically significant and clinically meaningful improvement in pCR vs ddAC-THP Improvement was observed in both the HR-positive and HR-negative subgroups For the ITT population, treatment effects were estimated by the difference in pCR with 95% Cls and P values based on the stratified Miettinen and Nurminen's method, with strata weighting by sample size (ie Mantel-Haenszel weights) Patients with no valid records regarding pCR status for any reason were considered to be non-responders (including but not limited to withdrawal from the study, progression of disease or death before surgery, lack of surgical specimen, or defined as not evaluable by the central pathologist). Subgroup analyses were unstratified "By blinded central review; pCR responders were defined as patients who only received randomized study treatment (at least one dose) and had pCR; two-sided P-value crossed the 0.03 prespecified boundary IT. intent-to-treat Nadia Harbeck, MD DESTINY-Breast11 BERLIN congress Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. 2025 ESMO --- [Slide 2] EFS Hazard ratio 0.56 (95% CI 0.26, 1.17) 1.0 96.9% (95% CI 93.5, 98.6) At data cutoff (March 12, 2025), EFS event maturity was 4.5%; at final cutoff, maturity is predicted to be ~10%* Probability of EFS EFS events: 18/320 0.9 93.1% (95% CI 88.7, 95.8) H EFS events: 11/321 0.8 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Number of Time from randomization (months) patients at risk T-DXd-THP 321 315 313 305 248 220 208 189 141 93 50 14 2 0 ddAC-THP 320 303 296 285 231 199 187 163 124 72 35 14 1 0 An early positive trend in EFS was observed, favoring T-DXd-THP vs ddAC-THP The median duration of follow up was 24.3 months with T-DXd-THP and 23.6 months with ddAC-THP. "Predicted maturity assumes that the observed EFS hazard ratio continues after data cutoff (March 12, 2025) Nadia Harbeck, MD DESTINY-Breast11 BERLIN Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. 2025 ESMO congress --- [Slide 3] Post-neoadjuvant treatments Patients with pCR* Patients without pCR* T-DXd-THP ddAC-THP T-DXd-THP ddAC-THP n (%) (n=226) (n=190) (n=95) (n=130) Any adjuvant treatment 224 (99.1) 187 (98.4) 85 (89.5) 107 (82.3) Any cytotoxic chemotherapy-containing regimen 13 (5.8) 11 (5.8) 10 (10.5) 12 (9.2) Any T-DM1-containing regimen 4 (1.8) 4 (2.1) 50 (52.6) 74 (56.9) Any trastuzumab-containing regimen 213 (94.2) 174 (91.6) 37 (38.9) 34 (26.2) Post-neoadjuvant treatments were generally well balanced between T-DXd-THP and ddAC-THP arms In both arms, more than half of patients without pCR received post-neoadjuvant T-DM1 Patients may have had at least one anti-cancer therapy and were counted once per therapy. "By local pCR result; excludes patients who withdrew consent or did not receive surgery; also excludes treatment given in the metastatic setting Nadia Harbeck, MD DESTINY-Breast11 BERLIN Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. 2025 ESMO congress

[Slide 1] San Antonio Breast Cancer Symposium®, December 9-12, 2025 SAN ANTONIO BREAST CANCER Conclusions SYMPOSIUM UT Health AAGR In DESTINY-Breast11, the safety profile of T-DXd-THP was manageable and less toxic than ddAC-THP Rates of adjudicated drug-related ILD/pneumonitis were low across arms, and there were fewer Grade ≥3 events with T-DXd-THP than ddAC-THP - Rates remained stable (T-DXd-THP) and were higher (ddAC-THP) in the THP phase (Cycles 5-8) VS Cycles 1-4 Rates of overall and Grade ≥3 left ventricular dysfunction were lower with T-DXd-THP than ddAC-THP - There were no events of cardiac failure in the T-DXd-containing arms Rates of nausea and vomiting were higher with T-DXd-THP than ddAC-THP, highlighting the importance of following guideline recommendations for antiemetics; however, events were generally low grade Rates of hematologic toxicities were lower in the T-DXd-THP arm than the ddAC-THP arm Most peripheral neuropathy events occurred during the THP phase (Cycles 5-8) and were non-serious and generally low grade DESTINY-Breast11 safety results support T-DXd-THP as a potential neoadjuvant treatment option for patients with high-risk HER2+ eBC This presentation is the intellectual property of the author/presenter. Contact giuseppe curigliano@ieo. it for permission to reprint and/or distribute DESTINY-Breast11 --- [Slide 2] San Antonio Breast Cancer Symposium®, December 9-12, 2025 SAN ANTONIO Adjudicated drug-related ILD/pneumonitis: treatment BREAST CANCER SYMPOSIUM Health AACR discontinuations, interruptions, reductions, and SAEs Adjudicated drug-related T-DXd-THP ddAC-THP T-DXd ILD/pneumonitis, n (%) (N=320) (N=312) (N=283) Leading to treatment discontinuation 6 (1.9) 7 (2.2) 9 (3.2) Grade 1 0 0 2 (0.7) Grade 2 5 (1.6) 4 (1.3) 7 (2.5) Grade 3 0 3 (1.0) 0 Grade 5 1 (0.3) 0* 0 Leading to treatment interruption 3 (0.9) 6 (1.9) 3 (1.1) Grade 1 1 (0.3) 2 (0.6) 0 Grade 2 1 (0.3) 0 3 (1.1) Grade 3 1 (0.3) 4 (1.3) 0 Leading to dose reduction 0 0 0 SAE 2 (0.6) 9 (2.9) 1 (0.4) The incidence of treatment discontinuations and interruptions due to ILD/pneumonitis were low across treatments, with no dose reductions, and there were more SAEs in the ddAC-THP arm compared with T-DXd-THP and T-DXd arms Safety analyses included all patients who received at least one dose of any study treatment *One Grade 5 event in ddAC-THP arm, however, the patient died prior to decision to discontinue treatment SAE, serious adverse event DESTINY-Breast11 This presentation is the intellectual property of the author/presenter. Contact giuseppe curigliano@ieo it for permission to reprint and/or distribute --- [Slide 3] San Antonio Breast Cancer Symposium®, December 9-12, 2025 SAN ANTONIO BREAST CANCER SYMPOSIUM Conclusions Health AACR - IDFS improvement with T-DXd compared with T-DM1 was consistent across the following subgroups, regardless of: Prior NACT (anthracyclines or platinum-based therapy) HER2 status (IHC 3+ or HER2 IHC 2+/1+ and ISH+) Timing of adjuvant RT did not impact incidence or severity of adjudicated drug-related ILD Most patients who experienced ILD had recovered or were recovering by the DCO Adjudicated drug-related ILD and RP events were generally manageable with protocol-specific management guidelines While differences were observed in ILD/RP time to onset, duration, and outcomes between the sequential and concurrent RT groups, further analysis is needed to assess the impact of potential confounders such as race, comorbidities, regional variability in RT, and the use of steroids for managing ILD/RP Overall, T-DXd demonstrated a generally manageable safety profile with both sequential and concurrent adjuvant RT These additional analyses further characterize the clinical benefit and safety profile of T-DXd over T-DM1 in the post-neoadjuvant HER2+ eBC residual invasive disease setting, supporting T-DXd as a potential new standard-of-care eBC, early breast cancer; HER2, human epidermal growth factor receptor 2; IDFS, invasive disease-free survival; IHC, immunohlstochemistry; ILD, interstitial lung disease; ISH, in situ hybridization; NACT, neoadjuvant chemotherapy; RP, radiation pneumonitis; RT, radiotherapy; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. DESTINY-Breast05 This presentation is the intellectual property of the author/presenter. Contact sibylle loibl@gbg de for permission to reprint and/or distribute

[Slide 1] Primary endpoint: IDFSᵃ T-DXd T-DM1 n= 818 n= 817 Patients with events, n (%) 51 (6.2) 102 (12.5) 3-year IDFS, % (95% CI) 92.4 (89.7-94.4) 83.7 (80.2-86.7) HR (95 % CI) 0.47 (0.34-0.66) 1.0 P value <0.0001b Invasive Disease-Free Survival 0.8 Д8.7% 0.6 T-DXd (n = 818) T-DM1 (n = 817) Censor 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 Time, months Number at Risk: T-DXd 818 788 781 776 771 768 758 753 731 684 634 544 440 380 370 275 218 212 129 92 90 46 14 14 0 0 0 0 T-DM1 817 781 769 760 745 734 719 708 687 632 599 527 417 355 337 233 186 177 120 84 79 38 14 13 4 1 1 0 53% reduction in the risk of invasive disease recurrence or death for T-DXd compared with T-DM1 HR, hazard ratio; IDFS, invasive disease-free survival; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan Efficacy stopping boundary, P 0.0183. MDFS is defined as the time from randomization until the date of first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause. Two-sided Pvalue from stratified log-rank test. Hazard ratio and 95% CI from stratified Cox proportional hazards model with stratification factor of operative status at disease presentation Dr Charles E Geyer Jr Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. BERLIN DESTINY-Breast05 ESMO congress