SOLTI-VALENTINE (SOLTI-2103) Trial

[Slide 1] BRINGING THE WORLD U 3 SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO HER3-DXd showed pCR and ORR rates similar BREAST CANCER SYMPOSIUM to standard multi-agent chemotherapy UT Healek AACR December 10-13,2024 VALEN , TINE SOLTI HER3-DXd HER3-DXd + LET Chemotherapy Overall N=50 N=48 N=24 N=122 pCR rate N 2 1 % (95%Cl) 4.0% (0.5-13.7) 2.1% (0.1-11.1) 4.2% (0.1-21.1) 3.3% (0.9-8.2) ORR N 35 39 17 91 % (95%CP) 70.0% (55.4-82.1) 81.3% (67.4-91.1) 70.8% (48.9-87.4) 74.6% (65.9-82.0) PD N (%) 0 1 (2.1%) 1 (4.2%) 2 (1.6%) 4 -24 X --- [Slide 2] BRINGING THE WORLD OF EP TOGETHER SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 10-13, 2024 HENRY B. GONZALEZ CONVENTION CENTER . SAN ANTONIO, TX UT Health AACR - Mays Concer Comme to Neoadjuvant HER3-DXd alone or in combination with letrozole for high-risk HR+/HER2- early EBC: Primary results of the randomized phase II SOLTI VALENTINE trial Mafalda Oliveira, MD PhD Tomás Pascual Kepa Amiliano Parrage, Javier Salvador Bofill Santiago González-Santiago Clara Martinz Vila, Josefina Cruz. Xavier González- Farré, Elena Galve, Pilar Sanchez Henarejos, Juan Miguel Cejalvo, Maria-Eva Perez-Lopez Montse Munoz Serafin Morales Alba Gonzalez-Haba Maria Borrell Puy, Encamación González Juan A. Guerra Sergio Hoyos, Antonia Perello, Pablo Tolosa Ortega, Juan De a Haba, Yenk Zheteyava, David W. Stemberg, Fumitaka Suto, Esther Pang. Data Sellami Rodrigo Sanchez-Bayona, Guillermo Vilacampa, Samyukta Chillara. Mariana Paes Dias, Juan M. Ferrero-Cafiero, Aleix Prat Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain SOLTI Cancer Research Group, Barcelona, Spain Vall SOI TI Habron VHIO" Drag from top and touch the back button to exit full screen. DECEMBER 10 14. 2024 SAN ANTONIO --- [Slide 3] SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER Summary and conclusions SYMPOSIUM UT Health AACR December 10-13. 2024 VALEN TINE SOLTI Treatment with HER3-DXd +/- letrozole achieved comparable pCR rates and ORR estimates to those seen with multi-agent chemotherapy (E/AC-T). In high-risk HR+/HER2-negative EBC, HER3-DXd showed biological evidence of anti-tumor activity (drop in Ki67, switch to less proliferative PAM50 subtypes, decrease in ROR), and increase in CelTIL score that correlated with treatment response Treatment with HER3-DXd associated with a lower incidence of Grade >3 TRAEs and reduced rates of dose reductions, dose interruptions, and treatment discontinuations compared to multi-agent chemotherapy (E/AC-T). SOLTI VALENTINE supports the effectiveness of HER3-DXd in EBC and its potential incorporation in the treatment of high-risk HR+/HER2-negative breast cancer. This provider the of Miskelds Divisions ND PhD - - net by permission DECEMBER 10 14, 2024 . SANANTONIO --- [Slide 4] BRINGING THE WORLD OF EP TOGETHER SAN ANTONIO BREAST CANCER SYMPOSIUM HER3-DXd showed pCR and ORR rates similar SAN ANTONIO BREAST CANCER SYMPOSIUM to standard multi-agent chemotherapy UT Health AACR December 10-13,2024 VALEN TINE SOLTI HER3-DXd HER3-DXd + LET Chemotherapy Overall N=50 №48 N=24 N=122 pCR rate N 2 1 1 4 % (95%CI") 4.0% (0.5-13.7) 2.1% (0.1-11.1) 4.2% (0.1-21.1) 3.3% (0.9-8.2) ORR N 35 39 17 91 % (95%CI*) 70.0% (55.4-82.1) 81.3% (67.4-91.1) 70.8% (48.9-87.4) 74.6% (65.9-82.0) PD N (%) 0 1 (2.156) 1 (4.2%) 2(1.6%) - - 9 - I I Response I ! (1 FINDH NO This PhD DECEMBER 10 14, 2024 SAN ANTONIO --- [Slide 5] BRINGING THE WORLD OF EP TOGETHER SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER Safety and tolerability SYMPOSIUM LT Health AACR December 10-13. 2024 VALEN TINE SOLTI HER3-DXd HER3-DXd LET Chemotherapy Grade 23 TRAEs less frequent in HER3-DXd arms N=50 N-48 N - 24 All treatment-related AEs (TRAEs) Less treatment reductions interruptions, and Any grade 45(56,0%) 47 (97 2%) 23(55.8%) discontinuations in HER3-DXd arms Grade 23 7 (14.0%) 7(14.8) 11(458%) Form No ILD cases were reported Treatment reduction (any) 3.(6.0%) 4(053%) 9.(37.5%) No treatment-related deaths (one non-related death in Treatment interruptions (arry) 6(120%) 2:(4.2%) 12(50.0%) Treatment discontinuation (any) 0 2:(4.2%) 2(6.3%) HER3-DXd arm due to a cerebrovascular accident) Non-Haematologic TRAEs in 220% of patients Haematologic TRAEs The us Treatment GITT All Grades Grade 23 - - HER3-OXd THE I I HER3-OXd Letrarche - ILS Cheractherapy ME BILD D.F. - - - are THE I 1 411 - " - - 11.2 - BI DU - a - - - - # - MP - - - - - 13 - : : - - - La 43 " : : " ** 43 41 18 I - I - Dates I I MO DECEMBER 10 14, 2024 SAN ANTONIO

[Slide 1] HER3-DXd showed pCR and ORR rates similar SAN ANTONIO BREAST CANCER SYMPOSIUM* to standard multi-agent chemotherapy UT Health AACR | December 10-13. 2024 - that - - VALEN TINE SOLTI HER3-DXd HER3-DXd + LET Chemotherapy Overall N=50 N=48 N=24 N=122 pCR rate N 2 1 1 4 % (95%CIᵃ) 4.0% (0.5-13.7) 2.1% (0.1-11.1) 4.2% (0.1-21.1) 3.3% (0.9-8.2) ORR N 35 39 17 91 % (95%CI) 70.0% (55.4-82.1) 81.3% (67.4-91.1) 70.8% (48.9-87.4) 74.6% (65.9-82.0) PD N (%) 0 1 (2.1%) 1 (4.2%) 2 (1.6%) 20 Treatment - 0 HER3-DX4 HER3-DX4 Letrurate Response ] $ I Chemotherapy Overall Response -33 CR . PR so from PO NE T stage or stage °N1 $12 0 N2 13 N3 . 14 -100 Overall Response cT stage CN stage 0 - asset confidence Day united - - É programise This presentation is the interfiection property of Metaids Others MD PhD Contact hist If - for - to -

[Slide 1] SAN ANTONIO HER3-DXd showed pCR and ORR rates similar BREAST CANCER SYMPOSIUM to standard multi-agent chemotherapy Health AACR December 10-13. 2024 VALEN TINE SOLTI HER3-DXd HER3-DXd + LET Chemotherapy Overall N=50 N=48 N=24 N=122 pCR rate N 2 1 1 4 % (95%CI") 4.0% (0.5-13.7) 2.1% (0.1-11.1) 4.2% (0.1-21.1) 3.3% (0.9-8.2) ORR N 35 39 17 91 % (95%CI") 70.0% (55.4-82.1) 81.3% (67.4-91.1) 70.8% (48.9-87.4) 74.6% (65.9-82.0) PD N (%) 0 1 (2.1%) 1 (4.2%) 2 (1.6%) be - - 0 : LATISON I I Response $ " HAM I # T2 *ID # 11 100 Charge CARE The provider is the intellectual property of Molata Diving IND PhD Context for at for permission distributo

[Slide 1] SAN ANTONIO BREAST CANCER SOLTI VALENTINE: Study Design SYMPOSIUM® UT Health AACR - - December 10-13, 2024 33ay Caron Live . - - VALEN TINE SOLTI Parallel, randomized, non-comparative, open-label, phase II trial (NCT05569811) Baseline Cycle 2 N=120 Surgery Day 1 Key eligibility criteria: HER3-DXd Pre- and post-menopausal Primary Endpoint: women, or men 5.6 mg/kg q21d X 6 cycles Rate of pCR (ypTO/is Primary operable breast ypN0) at surgery cancer 21 cm by MRI HER3-DXd + Letrozole HR+/HER2-negative" R 5.6 mg/kg q2 1d X 6 cycles pCR Follow up 2:2:1 5 years Secondary Endpoints: K67 ≥20%* and/or high letrozole 2 5mg QD +/- OFS ORR genomic risk (gene signature) Stratified by No prior treatment for the axilary nodal CelTIL score change, status Standard Multi-agent Chemotherapy Ki67 drop, PAM50, ROR current breast cancer EC or AC q14d or q21d X 4 cycles followed by Safety Available pre-treatment FFPE weekly paclitaxel 80mg/m2 X 12 weeks IDFS core-needle biopsy - HDL and 4057 determined by local accessment. AC Describe 43 age plus cyckphosphamide 600 mgt EDC Early breast cancer. ED 98 mg/m4 the - enghts), FIRE Female-bod Biopsy or Biopsy Surgery tissue 102. Homore - OF I archival tissue on treatment collection - and OFS: Organize lucins suppression part anatogy). - Rejective a $ Every by ⑈ Publical complete - COR: Rok If - This presentation is the intellectual property of Mafalda Oliveira, MD PhD. Contact her at moliveira@vhio net for permission to reprint and/or distribute --- [Slide 2] SAN ANTONIO BREAST CANCER Baseline Characteristics SYMPOSIUM® UT Health AACR - - - December 10-13, 2024 May Cannot - - - - VALEN HER3-DXd HER3-OXd + LET Chemotherapy Overall TINE SOLTI N=50 N=48 N=24 N=122 Age, median (range) 51 (29-77) 49 (32-82) 52 (31-73) 51 (29-82) Female 50 (100.0%) 48 (100.0%) 23 (05.8%) 121 (99.2%) Assessed for eligibility Pre/Perimenopausal 24 (48.0%) 28 (58.3%) 12 (52.2%)* 64 (52.9%) N=154 cT stage T1-T2 29 (58.0%) 29 (60.4%) 17 (70.8%) 75 (61.5%) T3-T4 Excluded (N=32) 21 (42.0%) 19 (39.6%) 7 (29.2%) 47 (38.5%) Consent withdrawal (N=9) Lymph node positive 38 (76.0%) 37 (77.1%) 18 (75.0%) 93 (76.2%) Stage Metastatic disease (N=9) II 32 (64%) 29 (60.4%) 17 (70.8%) 78 (64.0%) No pre-treatment biopsy (N=2) III 18 (36.0%) 19 (39.6%) 7 (29.2%) 44 (36.0%) Other (N=13) Histological Grade G1-G2 38 (82.6%) 35 (79.5%) 14 (66.7%) 87 (78.4%) Included Not available 4 4 3 11 N=122 HER2 HCS 0 20 (40.0%) 16 (33.3%) 9 (37.5%) 45 (36.9%) 1+ 18 (36.0%) 21 (43.8%) 8 (25.0%) 45 (36.9%) 2+ 12 (24.0%) 11 (22.9%) 8 (33.3%) 31 (25.4%) Local K167 median (range) 35 (20-85) 37 (18-80) 35 (20-90) 35 (18-90) HER3-DXd HER3-DXd 4 LET Chemotherapy HER3 IHC N=50 N=48 N=24 High 29 (80.6%) 31 (83.8%) 15 (88.2%) 75 (83.3%) Low 5 (13.9%) 4 (10.8%) 2 (11.8%) 11 (12.2%) Negative 2 (5.6%) 2 (5.4%) 0 4 (4.4%) Not available 14 11 7 32 Surgery Surgery Surgery Intrinsic subtype (PAM50) N=49 N=48 N=23 Basal-Like 0 1 (2.1%) 0 1 (0.8%) HER2-Enriched 1(2.0%) 2 (4.2%) 1 (4.3%) 4 (3.3%) F - PD new Baco Luminal A 21 (42.0%) 14 (29.2%) 10 (43.5%) 45 (37.2%) accident not related (tons metastisic) Luminal B 27 (54.0%) 29 (60.4%) 11 (47.8%) 67 (55.4%) Recruitment period: November 2022 to September 2023 Normal-Like 1 (2.0%) 2 (4.2%) 1 (4.3%) 4(3.3%) Not available 0 Data cut-off: April 22 2024 0 1 1 One male; One sample with HER2 HC NAISH negative in chemotherapy arm (4.2%); HER3 measured by membrane protein expression (%) using anti- PIC 15t - LET HERJ recombinant rabbit mAs done SP438 (Ventana Medical Systems). TOX: High275%, Low. <75% and 225%, Negative <25% This presentation is the intellectual property of Mafalda Oliveira, MD PhD. Contact her at moliveira@yhio net for permission to reprint and/or distribute --- [Slide 3] HER3-DXd showed pCR and ORR rates similar SAN ANTONIO BREAST CANCER SYMPOSIUM® to standard multi-agent chemotherapy UT Health AACR - December 10-13, 2024 ! VALEN TINE SOLTI HER3-DXd HER3-DXd + LET Chemotherapy Overall N=50 N=48 N=24 N=122 pCR rate N 2 1 1 4 % (95%CI*) 4.0% (0.5-13.7) 2.1% (0.1-11.1) 4.2% (0.1-21.1) 3.3% (0.9-8.2) ORR N 35 39 17 91 % (95%CI*) 70.0% (55.4-82.1) 81.3% (67.4-91.1) 70.8% (48.9-87.4) 74.6% (65.9-82.0) PD N (%) 0 1 (2.1%) 1 (4.2%) 2 (16%) 20 Treatment arm 0 HER3-DXd HER3-OXd Letrozole Response advance) I I I Chemotherapy $ Overall Response . CR PR SD I PD NE cT stage cN stage T1 N1 12 N2 T3 N3 T4 -100 Overall Response or stage CN stage 0 as and themis confidence Interved (b) Capper notice OR at importe - PER puthological complete response, PO: programs docume This presentation is the intellectual property of Matalda Civera, MD PhD Contact her at moliveira@vhio.net for permission to reprint and/or distribute --- [Slide 4] SAN ANTONIO BREAST CANCER Summary and conclusions SYMPOSIUM® UT Health AACR mhana / December 10-13, 2024 Mar License Just - VALEN TINE SOLTI Treatment with HER3-DXd +/- letrozole achieved comparable pCR rates and ORR estimates to those seen with multi-agent chemotherapy (E/AC-T). In high-risk HR+/HER2-negative EBC, HER3-DXd showed biological evidence of anti-tumor activity (drop in Ki67, switch to less proliferative PAM50 subtypes, decrease in ROR), and increase in CelTIL score that correlated with treatment response. Treatment with HER3-DXd associated with a lower incidence of Grade ≥3 TRAEs and reduced rates of dose reductions, dose interruptions, and treatment discontinuations compared to multi-agent chemotherapy (E/AC-T). ERC City - - - hospital ⑉ Aprilid response - и # - - RUS - of - TM - - advance - The presentation A the intellectual property of Malida Olivers, MD PND Contact her of for permission to reprint and/or distribute

[Slide 1] SAN ANTONIO BREAST CANCER Background SYMPOSIUM LT Health AAC - December 50-13, 2024 - Multi-agent chemotherapy improves survival outcomes in high-risk HR+/HER2-negative early breast cancer (EBC); however, there remains a need for more effective and tolerable strategies in this context. HER3-DXd is a potential first-in-class HER3-directed antibody-drug conjugate (ADC) with activity in multiple breast cancer subtypes¹. In SOLTI TOT-HER3, a single dose of HER3-DXd was essociated with increased CelTIL score and clinical response in patients with HR+/HER2-negative EBC²³, Hypothesis: HER3-DXd, either as single agent or in combination with letrozole, is an effective and safe neoadjuvant treatment option for women with treatment-naive, high-risk HR+/HER2-negative EBC. HR. Horroon Receptor, ESC: Carly Resured ORIGIN 01-82 4 Class X X Am Deas XIZ) Brest storidary at 9. No Common 2024 occes and/or - --- [Slide 2] SAN ANTONIO SOLTI VALENTINE: Study Design BREAST CANCER SYMPOSIUM IT Health AAGR December 10-13, 2024 - - - VALEN TINE SOLTI Parallel, randomized, non-comparative, open-label, phase Il trial (NCT05569811) N=120 Baseline Cycle 2 Day 1 Surgery Key eligibility criteria: Pre- and post-menopausal HER3-DXd women, or men Primary Indpoint: 5.6 mg/kg q21d X 6 cycles Frimary operable breast Rate of pCR (ypTO/is cancer >1 cm by MRI ypN0) at surgery HER3-DXd + Letrozole R 2:2:1 5,6 mg/kg q21d x6 cycles pCR Follow up K157 20% and/or high ietrozole 2.5mg QD 41, OFS $ years Secondary Endpoints: genomic risk (gene signature) ORR Stratified by No prior treatment for the asillary hodal CelTIL score change, status current breast cancer Standard Multi-agent Chemotherapy K167 drop, PAM50, ROR Available pre-treatment FFPE EC or AC Q14d or g21d X4 cycles followed by Safety core-needle biopsy weekly pactitaxel 60mg/m2 X 12 weeks IDFS YNL BDC. and no determined by Use assessment AC Denetico 60 any Aa 405 a CBC Early treen cour cc) Linding 95 more (Au - - notest TM Biopsy or Biopsy no. insure register CFS Invoice Surgery issue anove OV $ Overat Name suppression archival bssee on treatment collection (LIGH bulings) ONR apdio FROM rate 00 Every - as KR Pathelogical camplete rewiver ROR Rea of distributo --- [Slide 3] SAN ANTONIO BREAST CANCER Safety and tolerability SYMPOSIUM UT Health AACH - December 10-13 2024 VALEN TINE SOLTI HER3-DXd HER3-DXd . LET Chemotherapy Grace z3 TRAEs less frequent in HER3-DXd arms N=50 No48 N = 24 All treatment-related AEs (TRAEs) Less treatment reductions, Interruptions, and Any grade 48 (00 0%) 47 (97 9%) 23 (95.0%) discontinuations in HER3-DXd arms Grade 23 7 (14 0%) 7 (14.6) 11 (45.0%) No ILD cases were reported Treatment reduction (any) 3 (6.0%) 4 (6.3%) 9 (37.5%) No treatment-related deaths (one non-related death in Treatment interruptions (any) 6(12.0%) 2 (4.2%) 12 (50.0%) Treatment discontinuation (any) 0 2 (4.2%) 2 (0.3%) HER3-DXd arm due to a cerebrovascular accident) Non-Haematologic TRAEs in 220% of patients Heematologic TRAEs - . - no. - Treatment orm All Gradez Grade 23 12M - 90.4 90.4 - HERG-DX# HERO-OXA . Letrozole % of bested patients with TRAE 4 NJ 47 NA NS - THE I % I - 5 Chemotherapy - - 41 41.7 RU ( . : - M 2 - ent IN . - L na E - 94 10 P - NS NA NJ 0 : THE : - C - C U 4.3 NT C 53 C LA C A1 AT " C : 47 CI $1 is 14 1 - - - fairly stipue have Aupeus Curree - - Condition linding Neurgers - National I - --- [Slide 4] SAN ANTONIO BREAST CANCER SYMPOSIUM Summary and conclusions UT Health AACR - December 10-13. 2024 - - VALEN TINE SOLTI Treatment with HER3-DXd 4/- letrozole achieved comparable pCR rates and ORR estimates to those seen with multi-agent chemotherapy (E/AC-T). In high-risk HR+/HER2-negative EBC, HER3-DXd showed biological evidence of anti-tumor activity (drop in Ki67, switch to less proliferative PAM50 subtypes, decrease in ROR), and increase in CelTIL score that correlated with treatment response. Treatment with HER3-DXd associated with a lower incidence of Grade >3 TRAEs and reduced rates of dose reductions, dose interruptions, and treatment discontinuations compared to multi-agent chemotherapy (E/AC-T). CEC Easty (6) Name CARD importe use you Exhangive united - SQB Plan - - Treatment added educative - not - Member to medical distribute