Daiichi Sankyo Company, Limited · TSE:4568
Daiichi Sankyo — ASCO 2023 / ESMO Breast Cancer 2023
85 slides from Daiichi Sankyo's conference presentation, 2023
Slide 1: ASCO 2023/ESMO BC 2023 Presentation Materials (vol.2)
ASCO 2023/ESMO BC 2023 Presentation Materials (vol.2) ENHERTUⓇ ◆ DESTINY-PanTumor02 - Meric-Bernstam, FM. et al., ASCO 2023 #3000 Oral ◆ HERALD/EPOC1806 study - Taniguchi et al., ASCO 2023, #3014 Poster Dato-DXd ◆ TROPION-Lung02 - Goto, Y. et al., ASCO 2023 #9004 Oral HER3-DXd ◆ BRE-354 study - Hami
Slide 2: DESTINY-PanTumor02 interim results
Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY-PanTumor02 interim results Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Additional authors: Vicky Makker, Ana Oaknin, Do-Youn Oh, Susana Banerjee, Antonio
Slide 3: Trastuzumab Deruxtecan Designed with Seven Key Attributes
Trastuzumab Deruxtecan (T-DXd) was Designed with Seven Key Attributes T-DXd is an ADC with three components: Seven Key Attributes? 1. Ahumanized anti-HER2 lgG1 mAb with the same amino acid sequence as trastuzumab Payload mechanism of action: 2. Atopoisomerase | inhibitor payload, an exatecan derivat
Slide 4: Unmet Need in HER2-Expressing Tumors
Unmet Need in HER2-Expressing Tumors « T-DXd has become a standard of care in HER2-expressing unresectable/metastatic breast cancer, HER2-positive locally advanced/metastatic gastric/GEJ cancer and HER2 (ERBB2)- mutant unresectable/metastatic NSCLC*+ * Although testing is not routine, HER2 expressio
Slide 5: DESTINY-PanTumor02: A Phase 2 Study of T-DXd
DESTINY-PanTumor02: A Phase 2 Study of T-DXd for HER2-Expressing Solid Tumors An open-label, multicenter study (NCT04482309) Primary endpoint * Confirmed ORR Endometrial cancer (investigator)° » Advanced solid tumors not eligible VW? Cervical cancer for curative therapy * 2L+ patient population * HE
Slide 6: Patient Disposition
Patient Disposition Cervical | Endometrial Ovarian Pancreatic | Bladder Other" Patients treated, n 40 40 40 41 25 41 40 267 eee treatment atDCO, = 4g (26.0) 1435.0) «6 (15.0) —3(7.3) 1(4.0) 5 (12.2) 5 (12.5) 44 (16.5) Discontinued treatment, n(%) 30(75.0) 26(65.0) 34(85.0) 38(92.7) 24(96.0) 36(87.8)
Slide 7: Baseline Characteristics
Baseline Characteristics Pe All patients All patients Characteristic (N=267) (N=267) Age, median (range), years 62 (23-85) Local 205 (76.8) _ Female, n (%) 178 (66.7) HER2 testing for eligibility, White 163 (61.0) n(%)2 erennel CIeae) Race, 0 (%) wee ae # G28) Unknown? 10.4) ue i225) IHC 3+ 108 (40.
Slide 8: Efficacy endpoints: ORR, DCR and DOR
Efficacy endpoints: ORR, DCR and DOR Investigator assessment Cervical Endometrial Ovarian Bladdor (n=41) 99 (37.1) _ ORR, n (%) 20 (50.0) 23 (57.5) 18 (45.0) 9 (22.0) 1(4.0) 16 (39.0) 12 (30.0) Complete a rin 2 (5.0) 7 (17.5) 4(10.0) (2.4) ) 4 (2.4) 0 15 (5.6) Best overall Pattialresponse —18 (45.0)
Slide 9: Objective Response Rate by HER2 status
Objective Response Rate by HER2 status 100 - 90 80 = 70 & 60 56.3 56.3 ae ° E ° 39.0 on =° 5° 300 20 = Zi: = 10 40 53 0 : ! 0.0 my 0.0 SN n= 40 8 20 40 13 17 40 11 19 41 16 14 25 2 19 41 16 20 40 9 16 Cervical Endometrial Ovarian BTC Pancreatic Bladder Other All patients (N=99) IHC 3+ (n=46) . Media
Slide 10: Best Percentage Change in Target Lesion From Baseline
Best Percentage Change in Target Lesion From Baseline ¥ —., 120; 100 ° Mh. . lh li *, L.. J mq W Ti | 1 Maximum change in sum of diameters of target lesion from baseline, % —100- : ORR in Cervical Endometrial Ovarian BTC Pancreatic IHC 3+ (n=8) (n=13) (n=11) (n=16) (n=2) n (%) 6 (75.0) 11 (84.6) 7 (
Slide 11: Duration of Objective Response
) Dalichi-Sankyn Duration of Objective Response ¥ Cervical (n=20) Endometrial (n=23) Ovarian (n=18) @ Censored 4 End of response * Patient with complete response BTC (n=9) Pancreatic (n=1) Bladder (n=16) Other (n=12) 0 3 6 9 12 15 18 21 24 Time, months Kaplan-Meier estimate of Cervical Endometrial O
Slide 12: Percentage Change in Target Lesions Over Time
—., ) Percentage Change in Target Lesions Over Time omen 7 Prolonged response and disease stabilization in many patients Change in target lesion from baseline, % Time since first dose, months Analyses were performed in patients who received 21 dose of T-DXd (n=267). ASCO 2023 #3000 Oral
Slide 13: Overall Safety Summary
Overall Safety Summary 4 nc one Any drug-related TEAEs 225 (84.3) Drug-related TEAEs Grade 23 103 (38.6) Serious drug-related TEAEs 32 (12.0) Drug-related TEAEs associated with dose discontinuations 22 (8.2) Drug-related TEAEs associated with dose interruptions 49 (18.4) Drug-related TEAEs associate
Slide 14: Drug-Related TEAEs in ≥10% of Patients
Drug-Related TEAEs in 210% of Patients 54.3 Nausea Fatigue* 37.8 Neutropenia? 32.6 Anemia Diarrhea Vomiting Decreased appetite Thrombocytopenia® Any grade Alopecia Hl Grade 23 Leukopenia® 30 40 50 60 70 Patients experiencing possibly-related TEAE, % Analyses were performed in patients who received 2
Slide 15: Adverse Events of Special Interest
Adverse Events of Special Interest ILD/pneumonitis adjudicated as T-DXd-related n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any grade All patients (N=267) 6 (2.2) 12 (4.5) 1 (0.4) 0 1 (0.4) 20 (7.5) Left ventricular dysfunction? n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any grade Ejection frac
Slide 16: Conclusions
— U Conclusions ww, e T-DXd demonstrated clinically meaningful activity across a broad range of HER2-expressing solid tumors, including those that are hard to treat: * Encouraging ORR: 37.1% in all patients and 61.3% in patients with IHC 3+ ¢ Durable responses: median DOR 11.8 months in all patients
Slide 17: HERALD/EPOC1806 study of T-DXd
HERALD/EPOCL806 was @ multicenter, investigator initiated phase 2 trial of T-OX¢ for patients with NERZ (ERESZ)-amplitied advanced solid tumors identified in efONA by Guardant360 (6360) as # part of the Nationwide Cancer Genome Screening Project (GOZILS study} in Japan Study design 4) Patients with
Slide 18: TROPION-Lung02: Dato-DXd Plus Pembrolizumab
TROPION-Lung02: Datopotamab Deruxtecan (Dato-DXd) Plus Pembrolizumab With or Without Platinum Chemotherapy in Advanced Non-Small Cell Lung Cancer Yasushi Goto, MD, PhD,1 Wu Chou Su, MD,2 Benjamin Levy, MD,3 Olivier Rixe, MD, PhD,4,5 Tsung Ying Yang, MD, PhD,6 Anthony Tolcher, MD,7 Yanyan Lou, MD, Ph
Slide 19: Introduction
Introduction * Dato-DXd is an antibody-drug conjugate composed of a TROP2-directed monoclonal antibody covalently linked to a highly potent cytotoxic payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linkert5 * Dato-DXd 6-mg/kg monotherapy demonstrated encouraging antitumor
Slide 20: Preclinical Rationale for TROPION-Lung02
Preclinical Rationale for TROPION-Lung02 a Preclinical data showed more potent antitumor activity of combinations of Dato-DXd and anti-PD-(L)1 antibodies than either agent alone, supporting their clinical investigation’ The phase 1b/2 BEGONIA trial (NCT03742102) showed the promising clinical activit
Slide 21: TROPION-Lung02: Phase 1b Study
TROPION-Lung02: Phase 1b Study —., U Daiichi-Sankyo + TROPION-Lung02 is the first study evaluating Dato-DXd + pembrolizumab + platinum CT? in advanced NSCLC without actionable genomic alterations® (NCT04526691) = The safety of the Dato-DXd + pembrolizumab doublet was established prior to evaluation
Slide 22: Patient Baseline Characteristics
Patient Baseline Characteristics Triplet Characteristic Age, median (range), years 65 (44-83) Male, n (%) 48 (75) Histology, n (%) Adenocarcinoma 45 (70) Squamous 16 (25) History of brain metastases, n (%) 11 (17) PD-L1 expression, n (%)? <1% 23 (36) 1%-49% 28 (44) 250% 13 (20) Prior lines of therap
Slide 23: Patient Disposition
Patient Disposition Disposition Study duration, median (range), months Treatment status Ongoing on study treatment, n (%) Discontinued from study treatment, n (%) Duration of treatment, median (range), months No. of cycles received, median (range) Dato-DXd Pembrolizumab Cisplatin Carboplatin Primary
Slide 24: Antitumor Activity
=, Antitumor Activity ¥ All patients Patients in 1L Doublet Doublet Response® , (n=61)° (n=34)? + Inthe 1L setting, the ORR Confirmed + pending ORR, n (%)%" 23 (38) 35 (49) 17 (50) 30 (57) (confirmed and pending)* [95% Cl] [26-51] [37-61] [32-68] [42-70] was 50% in patients Confirmed + pending BOR,
Slide 25: Best Overall Tumor Change From Baseline
~~) Best Overall Tumor Change From Baseline All patients (n=124)@ Patients in the 1L setting (n=84)? 80 @ Doublet i Triplet + Treatment ongoing x Dato-DXd 6.0 mg/kg? 80 @ Doublet Bt Triplet + Treatment ongoing 2 Dato-DXd 6.0 mg/kg? 60 60 40 40 20 20 2 RIO ORR IO Ca eeneneND MC He HC IO sone ex SOOO
Slide 26: Depth and Duration of Response
—., U Depth and Duration of Response ee Doublet therapy, 1L subgroup Change from baseline, % PD-L1 status (n=34) m <1% (n=12) % 1%-49% (n=17) @ 250% (n=5) + Treatment ongoing Change from baseline, % Triplet therapy, 1L subgroup PD-L1 status (n=53) 60 m <1% (n=16) mi 1%-49% (n=22) ™ 250% (n=15) + Tre
Slide 27: Safety Summary
Safety Summary Event, n (%) TEAEs? 62 (97) Study treatment related’ 58 (91) Grade 23 TEAEs 34 (53) Study treatment related® 20 (31) Serious TEAEs 20 (31) Study treatment related 6 (9) TEAEs associated with: Deathf 3 (5) Dose reduction of any drug 14 (22) Dose reduction of Dato-DXd 14 (22) Discontinu
Slide 28: TEAEs Occurring in ≥20% of Patients
—., TEAEs Occurring in 220% of Patients wd Doublet therapy _ Triplet therapy Stomatitis To, Nausea 2 EY |, 2% 19% Fatigue 3% 8% Decreased appetite cya 30% 52% ¢ The most frequent TEAEs of Constipation any grade were stomatitis, Vomiting nausea, anemia, and fatigue Cough Platelet count decreased a *
Slide 29: Adverse Events of Special Interest
=, Adverse Events of Special Interest ¥. Triplet (n=72) a7 )a,b SES) * Oral mucositis/stomatitis was the most commonAESI and was predominantly grade 1/2 Allgrades Grade23 Allgrades Grade 23 Oral mucositis/stomatitis 37 (58) 5 (8) 31 (43) 4 (6) LER TOR? + No grade 5 AESIs have occurred ILD/pneumoniti
Slide 30: Conclusions and Ongoing Studies With Pembrolizumab
Conclusions and Ongoing Studies With © Pembrolizumab TROPION-Lung07 Dato-DXd + pembrolizumab + . . NCT05555732 cisplatin/carboplatin * In this study, Dato-DXd + pembrolizumab + ( ) platinum chemotherapy demonstrated Advanced/metastatic NSCLC encouraging antitumor activity in patients with Fee rape e
Slide 31: A Phase II Study of HER3-DXd in Metastatic Breast Cancer
A Phase II Study of HER3-DXd in Patients with Metastatic Breast Cancer Erika P. Hamilton, MD1,2; Ololade Dosunmu, MD, MPH1; Mythili Shastry, PhD1; Lindsey Finney, MS1; Dalila Sellami, MD3; David Sternberg, MD, PhD3; Vance Wright-Browne, MD4; Deborah Toppmeyer, MD5; William R. Gwin III, MD6; J. Thadd
Slide 32: Background
Background Overexpression of HER3, a member of the HER receptor tyrosine kinase (RTK) family, is associated with disease progression and increased invasion of cancer cells into the vessels in many solid tumors.1,2 HER3 forms heterodimers with other RTKs (most notably HER2) to promote tumorigenesis a
Slide 33: Background
Background • A previous Phase I/II study (NCT02980341) that evaluated patritumab deruxtecan in patients with heavily pretreated MBC demonstrated decreased tumor size irrespective of BC subtype and HER3 expression. a Membrane positivity for all patients with TNBC or HER2+ BC was ≥75%. HER3 expression
Slide 34: Study Design
Study Design • This Phase II study (NCT04699630) examines the efficacy and safety of patritumab deruxtecan administered in patients with locally advanced or metastatic BC. • Here, we present data for Part A. HER3 expression was not an enrollment criterion for Part A; HER3 expression was retrospectiv
Slide 35: Study Objectives
Study Objectives Primary Objective Evaluate objective response rate (ORR) and 6-month progression-free survival (PFS6 month) of single- agent patritumab deruxtecan in patients with HER2-negative MBC Secondary Objectives Assess safety and tolerability of patritumab deruxtecan in patients with HER2-ne
Slide 36: Key Enrollment Criteria (Part A)
Key Enrollment Criteria (Part A) Women and men ≥18 years of age and ECOG status of 0 or 1 Locally advanced or metastatic BC with ≥1 measurable lesion HER2-negative per ASCO-CAP guidelines (by immunohistochemistry) (includes zero and low expression) Hormone receptor positive (HR+) or negative (HR-) •
Slide 37: Patient Disposition
Patient Disposition (N=60) n (%) Patients Enrolled* 61 Patients Treated (Safety Set) 60 Treatment Status Receiving study treatment 21 (35.0) Discontinued from study treatment 39 (65.0) Primary reason for discontinuation from study treatment Adverse event** 8 (13.1) Clinical progression/objective dis
Slide 38: Demographics and Prior Systemic Therapies
Demographics and Prior Systemic Therapies (N=60) n (%) Sex/Age (Years) Male 1 (1.7) (N=60) Female 59 (98.3) n (%) >18 to <65 43 (71.7) Number of Prior Systemic Regimens in Metastatic ≥65 to <75 10 (16.7) Setting ≥75 6 (10.0) 1-2 prior regimens 24 (40.0) Race 3 or more prior regimens 36 (60.0) Median
Slide 39: Tumor Characteristics
Tumor Characteristics • Of the 60 patients who received treatment, 48 patients (80%) had baseline results available for both estrogen receptor (ER) and progesterone receptor (PR), and 47 patients (78.3%) had baseline results available for HER3. (N=48) n (%) Baseline ER (N=47) High (>10% expression)
Slide 40: Treatment Received and Dose Modifications
Treatment Received and Dose Modifications (N=60) Treatment Duration (Months) Median (range) 5.2 (0.7, 15.2) Patients with Treatment Duration ≥ 6 Months on Patritumab Deruxtecan, n (%) 26 (43.3) Dose Reduced, n (%) 9 (15.0) Adverse event* 9 (15.0) Number of Dose Reductions, n (%) 1 reduction 8 (13.3)
Slide 41: Duration on Study Treatment by HER3 Membrane Expression
Duration on Study Treatment by HER3 Membrane Expression Response legend CR PR PD Death Treatment Ongoing ≥75% Level of HER3 expression 25-74% <25% Unknown Tumor type legend ER+ TNBC 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Treatment duration (months) Data cutoff: September 6, 2022. ASCO 2023 #1004 Oral
Slide 42: Response – Investigator Assessment
Response – Investigator Assessment Unknown Membrane Membrane Membrane Membrane HER3 Total (N=60) HER3 ≥75% HER3 25%- 74% HER3 <25% Expression* N (%) (N=30) (N=13) (N=4) (N=13) Best Overall Response, n (%) Complete response (CR) 0 0 0 0 0 Partial response (PR) 10 (33.3) 6 (46.2) 2 (50.0) 3 (23.1) 21
Slide 43: Response by HER3 Expression Level and Clinical Subtype
Response by HER3 Expression Level and Clinical Subtype HER3 Membrane Expression ≥75% HER3 Membrane Expression 25% to 74% ER+ TNBC ER+ TNBC (N=16) (N=11) (N=5) (N=5) ORR, n (%) 6 (37.5) 2 (18.2) ORR, n (%) 3 (60.0) 1 (20.0) 95% CI (15.2, 64.6) (2.3, 51.8) 95% CI (14.7, 94.7) (0.5, 71.6) CBR, n (%) 8
Slide 44: Majority of Patients Had Tumor Shrinkage
Majority of Patients Had Tumor Shrinkage Percent Change from Baseline in Sum of Diameters of Best Percent Change in Sum of Diameters from Target Lesions HR+ vs TNBC Baseline in Target Lesions Hormone receptor+ (ER+ or PR+) (N=29) TNBC (N=19) 25-74% HER3 expression % Change from Baseline in Sum of Di
Slide 45: Safety
Safety Treatment-Related Adverse Events Occurring in ≥10% of Patients by Highest Reported Grade* Any grade Grade 3/4 Treatment-Emergent Serious Adverse Events (N=60) (N=60) n (%) n (%) Treatment-related SAEs (N=60), n (%) Any Adverse Event (AE) 56 (93.3) 19 (31.7) Interstitial Lung Disease† 1 (1.7)
Slide 46: Conclusions
Conclusions Clinical activity of patritumab deruxtecan was observed across a broad range of HER3 membrane expression levels in patients with heavily pretreated ER+ and TN metastatic breast cancers. • This is consistent with emerging data: • SOLTI-TOT-HER3 reported an ORR of 30% irrespective of HR st
Slide 47: ICARUS-BREAST01: Exploratory Biomarker Analysis
ICARUS-BREAST01 A phase 2 Study of Patritumab Deruxtecan (HER3-DXd) in patients with advanced breast cancer: AN EXPLORATORY BIOMARKER ANALYSIS B. Pistilli, N. Ibrahimi, M. Lacroix-Triki, V. D'Hondt, C. Vicier, J.S. Frenel, F. Dalenc, T. Bachelot, M.A. Benderra, D. Loirat, A. Ducoulombier, D. Mayeur,
Slide 48: Declaration of Interests
DECLARATION OF INTERESTS =. Barbara Pistilli, MD Consulting fees: Astra Zeneca (institutional), Seagen (institutional), Gilead (institutional), Novartis (institutional), Lilly (institutional), MSD (institutional), Pierre Fabre (personal), Daiichi-Sankyo (institutional/personal) Research funding (to
Slide 49: Background I
BACKGROUND-I Human epidermal growth factor receptor 3 (HER3) is a key member of the ErbB family that lacks intrinsic protein tyrosine kinase activity and generally forms dimers with other HER family receptors (eg. HER2-HER3)'2 HER3 overexpression is associated with worse prognosis across different s
Slide 50: Background II
BACKGROUND-II A In the phase I/II U3-1402-J101 study, HER3-DXd showed promising activity in patients with heavily pretreated HER3-expressing advanced breast cancer (HR+/HER2-, TNBC, and HER2+); efficacy was observed across a broad range of HER3-positive expression levels’ Biomarkers of response and
Slide 51: ICARUS-PROGRAM
ICARUS-PROGRAM en Different clinical, basic/translational research teams to decipher mechanisms of action and the multiple parallel mechanisms of resistance to ADCs 5) weeks until PD or unacceptable Lease ll HER3-DXd 5.6 mghkg every 3 100 patients with \ Batis HRHHER2- ABC J toxicity 100 patients wi
Slide 52: ICARUS-BREAST01 Study Design
ICARUS-BREAST01 STUDY DESIGN Prospective, multicenter, single-arm study with multiple biomarker analyses KEY ELIGIBILITY CRITERIA*: Primary Endpoint: | -unresectable locally advanced/metastatic BC -Investigator-assessed ORR | -HR+/HER2-neg/ HER2-low HER3-DXd 5.6 mg/kg every 3 weeks Secondary Endpoin
Slide 53: Exploratory Biomarker Analysis
EXPLORATORY BIOMARKER ANALYSIS ee QUESTION: Can we identify potential markers of early treatment response (3-mos RR)* ? Total and HER3+ CTCs count at baseline and after 1s‘ HER3-DXd dose Gene alterations/expression at baseline/on-treatment C1D3 or C1D19 or C2D3 EOT CTCs, HER3+CTCs (planned in 35 pat
Slide 54: Baseline Characteristics
BASELINE CHARACTERISTICS Patients, N = 56 Median age, years [range] 56 [28;82] Prior (neo)adjuvant chemotherapy, n (%) * 35 (64.8) Sex, n (%) Median number of systemic therapies for ABC, Female 56 (100.0) n [range]* 2 [1:4] HR status, n (%) ER-neg; PR-neg 4 (1.8); 12 (21.4) Prior treatment with CDK4
Slide 55: Patient Disposition
PATIENT DISPOSITION Patients, N = 56 HER3-DXd treatment status, n (%) Ongoing 24 (42.9) Discontinued 32 (57.1) Primary reason for discontinuation, n (%) Disease progression 23 (41.1) Adverse events 4 (7.1) Investigator’s decision 2 (3.6) Withdrawal by patient 2 (3.6) Other 1 (1.7) Median number of H
Slide 56: Safety Results
SAFETY RESULTS Overall safety profile, n (%)* TEAEs 2 25% of all patients,n(%) All grades Any grade TEAE 56 (100.0) Grade 23 27 (48.2) Fatigue 50 (89.3) 8 (14.3) * Leading to HER3-DXd discontinuation 7 (12.5)* Nausea 42 (75.0) 2 (3.6) * Leading to HER3-DXd interruption 9 (16.0) Diarrhea 26 (46.4) 2
Slide 57: Exploratory Biomarkers of Early Treatment Response
EXPLORATORY BIOMARKERS OF EARLY TREATMENT RESPONSE ee Tumor response by 3 months from treatment initiation, n (%) Partial response* 16 (28.6)* Stable Disease 30 (53.6) Progressive Disease 10 (17.8) BASELINE ON-TREATMENT (C1D3/C1D19/C2D3) WES/RNAseq RNAseq data cut-off: Feb 15", 2023; no patients had
Slide 58: CTC Count After First HER3-DXd Cycle
CTC COUNT AFTER FIRST HER3-DXD CYCLE CTC counts by CellSearch (31 patients, 69 blood samples) 250 200: 150 100. Count of CTCs/7.5mL of blood & Partial response . Stable Disease Progressive Disease 31 pts with evaluable CTC samples, n (%) 9 (29.0) 16 (51.6) 6 (19.3) . Median Baseline 2 C1D3 4 . C1D19
Slide 59: CTC Count After First HER3-DXd Cycle
CTC COUNT AFTER FIRST HER3-DXD CYCLE vy HER3- (cytokeratins+/-) CTCs by FACS* (31 patients, 74 blood samples) FACS 305 Median Baseline: 0 254 e c2p1: 0 2 3 EOT: 0 ws 204 =3 SE 154 a 58 e e e No substantial impact of the treatment on HER3- CTC count E 8 104 ° . No increase of HER3- CTC count at progr
Slide 60: HER3+ CTCs Dynamics and Treatment Response
HER3+ CTCs DYNAMICS AND TREATMENT RESPONSE © Dalichi-Sankyn HER3+ CTCs AT BASELINE HER3+ CTCs DECREASE FROM BASELINE TO C2D1 PRY ff) po f-~ | : PR 4 {fpecssssccanssessctereracrenssesccnc SD/PD: | sien | é ; SD/PD | i eee H 2» 0 60 80 100 o » 0 » 2» ww 0 HER3+ CTCs count by FACS* change in HER3+ CTCs
Slide 61: Tumor Genomic Alterations and Treatment Response
TUMOR GENOMIC ALTERATIONS AND TREATMENT RESPONSE U Dalichi-Sankyn 7 2 ss 2s | Matched DNA ow Matched normal 22 Mabiceal aliiellonsolils = === Matched DNA = ai Whole-exome sequencing from frozen samples of 18 patients Response cen PR . imepoini He! -> 17 baseline samples === PO -> 5 samples at progre
Slide 62: Transcriptomic Response to HER3-DXd in Early Responders
TRANSCRIPTOMIC RESPONSE TO HER3-DXD IN EARLY RESPONDERS RNAsegq from frozen samples of 24 patients -> 24 baseline samples and ->14 matched on-treatment samples (C1D3/C1D19/C2D1) RESPONDERS (n=7) NON-RESPONDERS (n=17) Downregulated:323 ee ee Upregulated: 19 Downregulated: 4°" “""" * "eer ___ Upregula
Slide 63: Key Findings and Perspectives
KEY FINDINGS AND PERSPECTIVES HER3-DXd showed a manageable safety profile and early signs of clinical activity in patients who progressed on CDK4/6inh and further lines of endocrine therapy +/- target therapies; these data are consistent with prior results of HER3-DXd in advanced breast cancer Total
Slide 64: HER3-DXd in HR+/HER2- and TNBC: Part B of SOLTI TOT-HER3
PATRITUMAB DERUXTECAN (HER3-DXD) IN HR+/HER2- AND TNBC: RESULTS OF PART B OF SOLTI TOT-HER3 WINDOW OF OPPORTUNITY TRIAL Mafalda Oliveira, T. Pascual, P. Tolosa, M. Margelí, J.M. Cejalvo, J. Cruz, F.J. Salvador Bofill, M. A. Arumi de Dios, M. Vidal, S. Pernas, S. Esker, P.-D. Fan, A. Santhanagopal, O
Slide 65: Declaration of Interests
DECLARATION OF INTERESTS aA Mafalda Oliveira MD, PhD Grant/Research Support (to the Institution): AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics Consultant: AstraZeneca, Daiichi-Sankyo / AstraZeneca, Gilead, iTEOS, MSD, P
Slide 66: Background
BACKGROUND e Patritumab deruxtecan (HER3-DXd; U3-1402) is a novel HER3-directed ADC composed of a human anti-HER3 mAb covalently linked to a topoisomerase | inhibitor payload via a stable, tumor selected, tetrapeptide-based, cleavable linker ¢ HER3-DXd has demonstrated antitumor activity and an acce
Slide 67: TOT-HER3 Study Design
TOT-HER3 STUDY DESIGN + Prospective, multicenter, window of opportunity trial Key eligibility criteria + Pre-and post-menopausal women, or men + Primary operable breast cancer 21 cm by US or MRI + HR-positive?/HER2- negative OR TNBC by local assessment * Ki67 =10% by local assessment + Noprevious an
Slide 68: Primary Endpoint: CelTIL Score
PRIMARY ENDPOINT: CELTIL SCORE ee « CelTlL score correlates with pCR across breast cancer subtypes'4 . Retrospective Analysis from PAMELA trial 100 TILS % -__,______, Baseline Day15 ‘Increased TiLs at Day 15 (No TILs increase at Day 15 1 Decreased TILs at Day 15 ESMO 2023 #1240 Oral R Baseline Day 1
Slide 69: Part A: CelTIL Increase After Dose of HER3-DXd
Oo PART A: CELTIL INCREASE AFTER 1 DOSE OF HER3-DXD Overall CelTIL Change from Baseline All patients (N=77) 8 =| P<0.001 Mean difference, +6.8 ° © = Decrease & = Increase @o = No change Qo4 3) on = Be. (S) o g4 of Baseline c1D21 CelTIL score, % 60 40 CelTIL Change by Clinical Response | ORR by physi
Slide 70: Study Objectives – Part B
STUDY OBJECTIVES — PART B ¢ Variation in CelTIL score between baseline and post-treatment (C1D21) tumor samples after 1 dose of HER3-DXd * Overall response rate (ORR) measured at C1D21 by ultrasound * Change in CelTIL score according to baseline expression levels of ERBB3 mRNA * Switch in PAM50 subt
Slide 71: Baseline Characteristics
BASELINE CHARACTERISTICS Assessed for eligibility (N=44) Excluded (N=7) * Molecular SF |__» | * Consent withdrawal * IC not met ¥ Included HR+/HER2- (N=20) TNBC (N=17) Efficacy population (N=37) Safety population (N=37) ESMO 2023 #1240 ERBB3 mRNA cohorts?(N = 37) HIGH (>-1.2) mm MEDIUM(>-1.9) m LOW
Slide 72: Patients' Characteristics
PATIENTS’ CHARACTERISTICS en ALL HR+/HER2- =TNBC ALL HR+/HER2- TNBC N= 37 N=20 N=17 N= 37 N =20 N=17 Age Nodal status N (%) oN 28(76) 17 (85) 1165) Median (Range 51 (30-81 51 (30-65) 50 (30-81 oN 9 (24 3(15 6 (35 Race N (%) KI67 local Caucasian 34 (92) 17 (85) 17 (100) Median, % (range) 30 (12-95) 2
Slide 73: Primary Endpoint: CelTIL Change After 1 Dose
PRIMARY ENDPOINT: CELTIL CHANGE AFTER1DOSE_ - ALL (N =37) Mean difference = +9.4, p=0.046 @ HR+/HER2- @ TNBC CeITIL score, % Baseline HR+/HER2- (N =20): Mean diff.= +2.2 TNBC (N =17): Mean diff. = +17.9 ESMO 2023 #1240 Oral The ORR by Ultrasound at C1D21 was 32% (35% in TNBC and 30% in HR+/HER2-) Re
Slide 74: CelTIL Variation by ERBB3 Cohort, PAM50 Subtype and ROR
CELTIL VARIATION BY ERBB3 COHORT, PAM50 SUBTYPE AND ROR Baseline PAM50 Subtypes (N=37) Baseline ERBB3 (N=37) HIGH N =2 75% Mean diff=-76 p=0.5 50% 25% = © Baseline ° ° o no = MEDIUM N =11 Ee Mean diff = -0.95 38 p=0.966 75% 50% 25% Ko m Increase ™ Decrease Baseline ESMO 2023 #1240 Oral cro21 LOWN =3
Slide 75: PAM50 Switch and Gene Expression Changes
—., PAM50 SWITCH AND GENE EXPRESSION CHANGES ¥ PAM50 Subtypes Switched (N=37) Gene Expression Changes (N=37) i Down-regulated atC1D21 Up-regulated at C1D21 “N=9) i nas ay Luminal B i | (N=4) Lumina 8 HB HeR2-E (N= 2) B64, 4 2 HER2- S =a ia Basal-Like Oo (N=8) wan 4 a © Basal-Like - (N=17) bie co 4 F
Slide 76: Safety Summary
SAFETY SUMMARY TEAEs TEAEs in >5% of patients, N (%)2 Nt) All grades 314 (84) 74 (96) Grade 4 0 4 (5) Nausea Grade 3 2 (5) 10 (13) Fatigue 17(48) | 0 | 3241) Grade 2 15 (41) 45 (58) Alopecia 10 (27) | NA | 28 (36) NA Grade 1 31 (84) 71 (91) Diarrhea 19 (24) ( SAEs, all grades 2 (5) 4 (5) Constipatio
Slide 77: Key Findings
U KEY FINDINGS ae In untreated HER2-negative early-stage breast cancer, a significant increase in CelTIL score is observed after one dose of HER3-DXd at 5.6 mg/kg ° A single dose of HER3-DxXd induced a ~30% ORR (measured by breast US), independently of HR status ¢ A lower incidence of hematological
Slide 78: HER2 expression and early response to HER3-DXd: TOT-HER3 correlative analysis
HER2 expression and early response to patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2- breast cancer: A correlative analysis from TOT-HER3 trial Fara Brasó-Maristany, Mafalda Oliveira, Pablo Tolosa, Mireia Margelí, Josefina Cruz, Salvador Bofill, Juan Miguel Cejalvo, Miriam Arumí de Dios, M
Slide 79: Declaration of Interests
DECLARATION OF INTERESTS Consultancy/speaker: Reveal Genomics Research funding (my institution): Novartis, Roche, AstraZeneca, Daiichi-Sankyo, PUMA Patents: HER2DX (filed), DNADX (filed) ESMO 2023 #3MO Oral Dalichi-Sankyn 79
Slide 80: Background (I)
BACKGROUND (I) HER3-DXd single dose Day 21 FFPE tumor sample —- YS CelTIL score Part B*: 5.6 mg/kg IV 0 HR+/HER2-, n=17 TNBC CeITIL score =-0.8 x tumor cellularity (%) +1.3 x TILs (%) v Patritumab deruxtecan (HER3-DXd) is Baseline FFPE a HER3-directed ADC composed of a tT" sample + Part A: 6.4mg/kg
Slide 81: Background (II)
BACKGROUND (Il) ome Y In our previous preliminary correlative analysis (n=45) of TOT-HER3 Part A*: v ERBB3/HER3 levels were not associated with CelTIL response Y_ High proliferation and non-luminal features were associated with CelTIL response v Intriguingly, low ERBB2 mRNA levels Do ERBB2/HER2 leve
Slide 82: Higher CelTIL response in tumors with low ERBB2 mRNA/HER2 protein
Higher CelTIL response to HER3-DXd in tumors with low ERBB2 mRNA/HER2 protein expression. Part A (n=77) ERBB2 mRNA (AUC=0.707) HER2 amplicon signature (AUC=0,742) HER2 IHC ERBB2 mRNA adjusted by HER2 IHC HER2 amplicon adjusted by HER2 IHC HER2 IHC adjusted by ERBB2 mRNA HER2 IHC adjusted by HER2 amp
Slide 83: Higher CelTIL response in tumors with low HER2 DNA copy-number signal
_ Higher CelTIL response to HER3-DXd in tumors with © low HER2 DNA copy-number signal ee Part A (n=49) 17q12 CN signal (AUC=0,797) HER2 DNA signature 1 (AUC=0.820) HER2 DNA signature 2 (AUC=0,843) HER2 IHC 17q12 CN signal adjusted by HER2 IHC § HER2 DNA signature 1 adjusted by HER2 IHC di 6 univaria
Slide 84: Conclusions
CONCLUSIONS v In pre-treatment HER2-negative tumors, low levels of HER2 IHC, ERBB2 mRNA and ERBB2 DNA copy-number signal are associated with early response to HER3-DxXd. ¥ Genomic tools may be better suited than IHC to capture HER2 expression levels which in turn can help better inform responses to
Slide 85: SOLTI-2103 VALENTINE trial (ESMO 2023 #155TiP)
A randomized phase 2 trial of neoadjuvant multi-agent chemotherapy or patritumab deruxtecan (HER3-DXd; U3-1402) +/- endocrine therapy for high- risk hormone receptor positive (HR+/HER2-) early breast cancer: SOLTI- 2103 VALENTINE trial V/ALEN TINE souTi? Background +The decision regarding Meoadjuanl
Daiichi Sankyo Company — ASCO 2023 / ESMO Breast Cancer 2023 on 6ix