#1ASCO/ESMO BC Presentation Materials ENHERTU® 1. DESTINY-Breast04 data - Modi S et al., ASCO 2022 #LBA3 Plenary Session 2. Retrospective study to estimate the prevalence of HER2 low BC - Viale G et al., ASCO 2022 #1087 Poster 3. DESTINY-Breast03 safety follow up - Hamilton E et al., ASCO 2022 #1000 Oral 4. DESTINY-Breast03 patient-reported outcomes - Curigliano G et al., ESMO BC 2022 #1630 Oral 5. TUXEDO-1 primary analysis - Bartsch R et al., ESMO BC 2022 #165 Mini Oral 6. Primary analysis of Ph1b study in combination with nivolumab Hamilton E et al., ESMO BC 2022 #1620 Oral - 7. Preliminary results from DESTINY-Breast07 & 08 studies - Andre F et al., ASCO 2022 #3025 Poster Daiichi-Sankyo 1#2ASCO/ESMO BC Presentation Materials Dato-DXd Initial results of BEGONIA study - Schmid P et al., ESMO BC 2022 #166 Mini Oral HER3-DXd Results from Ph1/2 study in patients with HER3 expressing mBC - Krop I et al., ASCO 2022 #1002 Oral Results from Ph1 dose expansion study in patients with NSCLC without EGFR activating mutations - Steuer C et al., ASCO 2022 #9017 Poster DS-6000 Initial results from Ph1 study – Hamilton E et al., ASCO 2022 #3002 Oral DS-6157 Results from Ph1 study - George S et al., ASCO 2022 #11512 Poster Daiichi-Sankyo 2#3DESTINY-Breast04 Trastuzumab Deruxtecan (T-DXd) vs Treatment of Physician's Choice in Patients with HER2-low Unresectable and/or Metastatic Breast Cancer: Results of DESTINY-Breast04, a Randomized, Phase 3 Study Shanu Modi Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, USA Additional authors: William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto Ueno, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Xiaojia Wang, Binghe Xu, Dhiraj Gambhire, Lotus Yung, Gerold Meinhardt, Yibin Wang, Nadia Harbeck, David Cameron Daiichi-Sankyo ASCO 2022 #LBA3 Plenary Session On behalf of the investigators 3#4DESTINY-Breast04 Summary and Impact DESTINY-Breast04 Daiichi-Sankyo T-DXd treatment showed unprecedented improvement in efficacy for patients with HER2-low mBC Current mBC paradigm1,2 HER2+ HER2+ IHC 3+, 2+/ISH+ 15%-20% HER2- HR+/HER2- IHC 0, 1+, 2+/ISH- -65% HER2+ IHC 3+ IHC2+/ISH+ • HER2-low: IHC 1+ or IHC 2+/ISH- HER2-low IHC 1+ IHC2+/ISH- -50% · The new mBC paradigm T-DXd is the first HER2-targeted therapy to demonstrate improved efficacy in HER2-low mBC DESTINY-Breast04 establishes T-DXd as the new standard of care for HER2-low mBC HR-/HER2- (TNBC) -15% HER2- IHC <1 Potential improvement for ~50% of all mBC patients HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; T-DXd, trastuzumab deruxtecan; TNBC, triple-negative breast cancer; TPC, treatment of physician's choice. 1. Schettini F, et al. NPJ Breast Cancer. 2021;7(1):1. 2. Tarantino P, et al. J Clin Oncol. 2020;38(17): 1951-1962. ASCO 2022 #LBA3 Plenary Session 4#5HER2-low mBC: Unmet Clinical Need DESTINY-Breast04 10 Daiichi-Sankyo Current Standard of Care HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-) HR+a Endocrine therapy (ET) ET combinations PARP inhibitors (gBRCA+) HER2-low HR-b Checkpoint inhibitors (PD-L1+) PARP inhibitors (gBRCA+) Sacituzumab govitecan Chemotherapy ASCO 2022 #LBA3 Plenary Session HER2-low mBC is defined by IHC scores of 1+ or 2+/ISH- - This is a heterogenous population with a high prevalence of HR coexpression and without a distinct biology HER2-low mBC is treated as HER2- mBC, with limited options for later lines of therapy 1-4 Current HER2-targeted therapies are not effective for patients with tumors that express lower levels of HER2 Therapeutic options for patients with HR+/HER2- mBC after CDK4/6i progression have limited efficacy Real-world studies suggest a PFS of <4 months after progressive disease with CDK4/6i5 Limited benefit exists for patients who progress after multiple lines of chemotherapy In a pooled analysis of patients with HER2- mBC, eribulin and capecitabine provide minimal benefit, with a mPFS of ~4 months and MOS of ~15 months6 CDK4/6i, cyclin-dependent kinase 4/6 inhibitors; gBRCA+, germline breast cancer gene positive; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; mOS, median overall survival; PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death ligand 1; mPFS, median progression-free survival; T-DXd, trastuzumab deruxtecan. aImmunoreactive for estrogen or progesterone receptor in ≥1% tumor cell nuclei. "Immunoreactive for estrogen or progesterone receptor in <1% tumor cell nuclei. 1. Tarantino P, et al. J Clin Oncol. 2020;38(17):1951-1962. 2. Aogi K, et al. Ann Oncol. 2012;23:1441-1448. 3. Eiger D, et al. Cancers (Basel). 2021;13(5):1015. 4. Fehrenbacher L, et al. J Clin Oncol. 2019;38(5):444-453. 5. Mo H, et al. Clin Breast Cancer. 2022;22:143-148. 6. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601. 5#6T-DXD MOA, Bystander Effect, and Rationale for Targeting HER2-low mBC T-DXd1,2 1 T-DXd binds to HER2 Tumor Cell 8:1 drug-to- antibody ratio 2 T-DXd internalized Highly potent topoisomerase I Cleavable linker inhibitor payload 3 Linker cleaved, releasing topoisomerase I inhibitor 5 Tumor cell death Daiichi-Sankyo DESTINY-Breast04 Neighboring Tumor Cell 4 Topoisomerase I inhibitor enters nucleus 6 Membrane- permeable payload results in bystander effect Internalization of T-DXd leads to release of the DXd payload and subsequent cell death in the target tumor cell and neighboring tumor cells through the bystander effect1,2 T-DXd HER2 protein Topoisomerase I inhibitor payload Adapted with permission from Modi S, et al. J Clin Oncol 2020;38:1887-96. CC BY ND 4.0. · Results from a phase 1b study have reported efficacy of T-DXd in heavily pretreated patients (N = 54) with HER2-low mBC, with a mPFS of 11.1 months and an ORR of 37.0%³ HER2, human epidermal growth factor receptor 2; MOA, mechanism of action; mBC, metastatic breast cancer; mPFS, median progression-free survival; ORR, objective response rate; T-DXd, trastuzumab deruxtecan. 1. Nakada T, et al. Chem Pharm Bull. 2019;67:173-185. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22:5097-5108. 3. Modi S, et al. J Clin Oncol. 2020;38:1887-1896. ASCO 2022 #LBA3 Plenary Session 6#7DESTINY-Breast04: First Randomized Phase 3 Study of T-DXd for HER2-low mBC An open-label, multicenter study (NCT03734029) DESTINY-Breast04 Patientsa HER2-low (IHC 1+ vs IHC 2+/ISH-), unresectable, and/or mBC treated with 1-2 prior R lines of chemotherapy in the 2:1 metastatic setting HR+ disease considered 10 Daiichi-Sankyo T-DXd 5.4 mg/kg Q3W (n = 373) HR+ = 480 HR-= 60 TPC Capecitabine, eribulin, gemcitabine, paclitaxel, nab-paclitaxelc (n = 184) Primary endpoint • PFS by BICR (HR+) Key secondary endpointsb PFS by BICR (all patients) • OS (HR+ and all patients) endocrine refractory Stratification factors • Centrally assessed HER2 statusd (IHC 1+ vs IHC 2+/ISH-) 1 versus 2 prior lines of chemotherapy HR+ (with vs without prior treatment with CDK4/6 inhibitor) versus HR- ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; BICR, blinded independent central review; CDK, cyclin-dependent kinase; DOR, duration of response; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival; Q3W, every 3 weeks; R, randomization; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. "If patients had HR+ mBC, prior endocrine therapy was required. Other secondary endpoints included ORR (BICR and investigator), DOR (BICR), PFS (investigator), and safety; efficacy in the HR- cohort was an exploratory endpoint. "TPC was administered accordingly to the label. "Performed on adequate archived or recent tumor biopsy per ASCO/CAP guidelines using the VENTANA HER2/neu (4B5) investigational use only [IUO] Assay system. ASCO 2022 #LBA3 Plenary Session 7#8DESTINY-Breast04: Statistical Analysis and Hierarchical Testing Hierarchical testing PFS in HR+ PFS in all patients • • Daiichi-Sankyo DESTINY-Breast04 Primary analysis for PFS by BICR (planned after at least 318 events) At data cutoff (January 11, 2022), there were 321 and 370 BICR- assessed PFS events in the HR+ cohort and in all patients, respectively At data cutoff, 61 patients remained on treatment (58 on T-DXd and 3 on TPC), and median follow-up was 18.4 months OS analysis OS in HR+ OS in all patients • 199 events in the HR+ cohort and 239 events in all patients Stopping boundary for first interim OS analysis: - Efficacy boundary for superiority: P < 0.0075 BICR, blinded independent central review; HR, hormone receptor; OS, overall survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 8#9Patient Disposition Screened (N = 713) Randomized 2:1 (N = 557) TPC (n = 184) T-DXd (n = 373) Treated (99.5%) Ongoing study treatment (15.6%) • Discontinued study treatment (84.4%) . • Death (1.3%) Adverse event (16.2%) Progressive disease (59.3%) • Withdrawal by subject (3.2%) • Other (4.3%) 10 Daiichi-Sankyo DESTINY-Breast04 • Treated (93.5%) • Ongoing study treatment (1.7%) Discontinued study treatment (98.3%) • Death (1.2%) Adverse event (8.1%) Progressive disease (75.6%) Withdrawal by subject (6.4%) Othera (7.0%) T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. *Other includes clinical progression, physician decision, lost to follow-up, and other unknown reasons. ASCO 2022 #LBA3 Plenary Session Eribulin Chemotherapy, n (%) 94 (51.1) Capecitabine 37 (20.1) Nab-paclitaxel 19 (10.3) Gemcitabine 19 (10.3) Paclitaxel 15 (8.2) 6#10Baseline Characteristics Hormone receptor-positive T-DXD (n=331) TPC (n = 163) Age, median (range), years 57 (32-80) 56 (28-80) T-DXd (n=373) 58 (32-80) DESTINY-Breast04 All patients TPC (n = 184) 56 (28-80) Female, n (%) Region, n (%) Europe + Israel Asia 329 (99) 163 (100) 371 (99) 184 (100) 149 (45) 73 (45) 166 (45) 85 (46) 128 (39) 60 (37) 147 (39) 66 (36) 54 (16) 30 (18) 60 (16) 33 (18) North America HER2 status (IHC), n (%) 193 (58) 95 (58) 215 (58) 106 (58) 1+ 138 (42) 68 (42) 158 (42) 78 (42) 2+/ISH- ECOG performance status, % 187 (56) 95 (58) 200 (54) 105 (57) 0 144 (44) 68 (42) 173 (46) 79 (43) 1 Hormone receptor, n (%) 328 (99) 162 (99) 333 (89) 166 (90) Positive 3 (1) 1 (1) 40 (11) 18 (10) Negative Brain metastases at baseline, n (%) 18 (5) 7 (4) 24 (6) 8 (4) Liver metastases at baseline, n (%) 247 (75) 116 (71) 266 (71) 123 (67) Lung metastases at baseline, n (%) 98 (30) 58 (36) 120 (32) 63 (34) ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry: ISH, in situ hybridization; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. "Hormone receptor status is based on data collected using the interactive web/voice response system at the time of randomization, which includes misstratified patients. ASCO 2022 #LBA3 Plenary Session Daiichi-Sankyo 10#11Prior Therapies DESTINY-Breast04 Hormone receptor-positive T-DXD (n = 331) TPC (n = 163) All patients T-DXD (n=373) TPC (n = 184) Lines of systemic therapy (metastatic setting) Number of lines, median (range) 3 (1-9) 3 (1-8) 3 (1-9) 3 (1-8) Number of lines, n (%) 23 (7) 14 (9) 39 (10) 19 (10) 1 2 85 (26) 41 (25) 100 (27) 53 (29) 23 223 (67) 108 (66) 234 (63) 112 (61) Lines of chemotherapy (metastatic setting) Number of lines, median (range) 1 (0-3) 1 (0-2) 1 (0-3) 1 (0-2) Number of lines, n (%) 0 1 1 (0.3) 1 (0.6) 1 (0.3) 203 (61.3) 93 (57.1) 221 (59.2) 2 124 (37.5) 69 (42.3) 145 (38.9) ≥3 3 (0.9) 0 6 (1.6) 1 (0.5) 100 (54.3) 83 (45.1) 0 Lines of endocrine therapy (metastatic setting) Number of lines, median (range) 2 (0-7) 2 (0-6) 2 (0-7) 2 (0-6) Number of lines, n (%) 28 (8) 17 (10) 60 (16) 34 (18) 0 105 (32) 49 (30) 108 (29) 51 (28) 1 2 ≥3 110 (33) 53 (33) 115 (31) 54 (29) 88 (27) 44 (27) 90 (24) 45 (24) Prior targeted cancer therapy, n (%) Targeted therapy 259 (78) 132 (81) 279 (75) 140 (76) CDK4/6 inhibitor 233 (70) 115 (71) 239 (64) 119 (65) Based on derived data, which includes protocol deviations. CDK, cyclin-dependent kinase; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session Daiichi-Sankyo 11#12Progression-Free Survival Probability (%) 100 60 80 PFS in HR+ and All Patients Hormone receptor-positive Hazard ratio: 0.51 95% CI, 0.40-0.64 P<0.0001 60 A 4.7 mo T-DXd mPFS: 10.1 mo TPC mPFS: 5.4 mo Progression-Free Survival Probability (%) 10 Daiichi-Sankyo DESTINY-Breast04 100 All patients Hazard ratio: 0.50 95% CI, 0.40-0.63 P < 0.0001 80 60 A 4.8 mo T-DXd mPFS: 9.9 mo 40 40 20 TPC mPFS: 5.1 mo 0 0 T T T T T T T 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Months 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Months No. at Risk No. at Risk T-DXd (n = 331): TPC (n = 163): 331 324 290 265 262 248 218 198 182 165 142 128 107 89 78 73 64 48 37 31 28 17 14 12 7 4 4 1 1 0 163 146 105 85 84 69 57 48 43 32 30 27 24 20 14 12 8 4 3 2 1 1 1 1 1 0 1 T-DXD (n = 373): TPC (n=184): 373 365 325 295 290 272 238 217 201 183 156 142 118 100 88 81 71 53 42 35 32 21 18 15 8 4 4 1 1 0 184 166 119 93 90 73 60 51 45 34 32 29 26 22 15 13 9 5 4 3 1 1 1 1 1 1 0 PFS by blinded independent central review. HR, hormone receptor; mPFS, median progression-free survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 12#13Overall Survival Probability (%) OS in HR+ and All Patients 100 Hormone receptor-positive Hazard ratio: 0.64 95% CI, 0.48-0.86 P = 0.0028 80 60 40 40 20 20 TPC MOS: 17.5 mo T-DXd MOS: 23.9 mo A 6.4 mo Overall Survival Probability (%) DESTINY-Breast04 100 All patients Hazard ratio: 0.64 95% CI, 0.49-0.84 P = 0.0010 40 TPC MOS: 16.8 mo 10 Daiichi-Sankyo T-DXd MOS: 23.4 mo A 6.6 mo TT No. at Risk 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Months No. at Risk 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Months T-DXD (n = 331): 331 325 323319 314 309 303 293 285 280 268 260 250 228 199 190 168 144 116 95 81 70 51 40 26 14986621 TPC (n=163): 163 151 145 143 139 135 130 124 115 109 104 98 96 89 80 71 56 45 37 29 25 23 16 14 7 5 310 1110 T-DXd (n=373): TPC (n=184): 373 366 363357 351 344 338 326 315 309 296 287 276 254 223 214 188 158 129 104 90 78 59 48 32 20 14 12 10 8 31110 184 171 165 161 157 153 146 138 128 120 114 108 105 97 88 77 61 50 42 32 28 25 18 16 7 5310 HR, hormone receptor; mOS, median overall survival; OS, overall survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 13#14Progression-Free Survival Probability (%) PFS and OS in HR- (Exploratory Endpoints) 100 60 40 A 5.6 mo TPC mPFS: 2.9 mo PFS Hazard ratio: 0.46 95% CI, 0.24-0.89 T-DXd mPFS: 8.5 mo Overall Survival Probability (%) 10 Daiichi-Sankyo DESTINY-Breast04 100 OS Hazard ratio: 0.48 95% CI, 0.24-0.95 60 60 40 40 20 20 TPC MOS: 8.3 mo T-DXd MOS: 18.2 mo A 9.9 mo 0 0 0123 6 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Months 01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Months No. at Risk T-DXD (n = 40): 40 39 33 29 28 25 21 20 19 18 13 13 11 11 10 8 7 5 5 4 4 TPC (n = 18): 18 17 11 7 6 4 3 3 2 2 2 2 2 2 1111110 4 4 3 1 0 No. at Risk T-DXD (n = 40): 40 39 38 37 36 34 34 32 31 30 28 27 26 26 23 23 19 14 13 9 TPC (n = 18): 18 17 16 14 14 14 3 11 10 8 8 8 7 6 6 5 5 5 5 3 3 9 82 72 72 160 6 5 4 4 HR, hormone receptor; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. For efficacy in the hormone receptor-negative cohort, hormone receptor status is based on data from the electronic data capture corrected for misstratification. ASCO 2022 #LBA3 Plenary Session 14#15Subgroup Analysis: PFS in HR+ DESTINY-Breast04 Daiichi-Sankyo No. of Events/No. of Patients T-DXd TPC PFS, median (95% CI), mo T-DXd Hazard Ratio for Disease Progression or Death (95% CI) TPC Prior CDK4/6 inhibitors Yes No IHC status 149/233 74/115 10.0 (8.3-11.4) 5.4 (4.0-7.8) 0.55 (0.42-0.73) 60/96 35/47 11.7 (9.5-17.7) 5.9 (4.3-8.2) 0.42 (0.28-0.64) IHC 1+ 119/192 66/96 10.3 (8.6-12.3) 5.3 (4.1-7.8) 0.48 (0.35-0.65) IHC 2+/ISH- 92/139 44/67 10.1 (8.2-12.2) 5.9 (4.3-7.9) 0.55 (0.38-0.80) Prior lines of chemotherapy 1 129/203 63/93 10.9 (8.5-12.3) 6.8 (4.5-8.2) 0.54 (0.40-0.73) ≥2 81/127 47/69 9.9 (8.3-11.7) 4.6 (2.8-6.2) 0.47 (0.33-0.68) Age <65 years 170/260 79/120 9.8 (8.4-11.3) 5.4 (4.1-7.8) 0.51 (0.39-0.67) ≥65 years 41/71 31/43 12.0 (9.5-14.7) 5.6 (4.3-10.8) 0.47 (0.29-0.77) Race White 100/156 43/78 10.0 (8.5-12.2) 7.1 (4.0-10.0) 0.64 (0.44-0.91) Asian 83/131 54/66 11.0 (8.4-13.8) 4.8 (4.2-6.4) 0.40 (0.28-0.56) Other 25/37 11/16 6.0 (5.4-10.5) 7.0 (1.4-11.0) 0.83 (0.41-1.69) Region Asia 81/128 48/60 10.9 (8.4-14.7) 5.3 (4.2-6.8) 0.41 (0.28-0.58) Europe and Israel 90/149 44/73 10.8 (8.5-13.0) 7.1 (3.0-10.7) 0.62 (0.43-0.89) North America 40/54 18/30 8.5 (6.3-11.3) 4.5 (2.9-8.2) 0.54 (0.30-0.97) ECOG performance status 0 116/187 55/95 10.9 (9.5-13.0) 7.0 (4.2-8.5) 1 95/144 55/68 9.7 (7.3-11.5) 4.6 (2.9-6.2) Visceral disease at baseline Yes No 196/298 15/33 100/146 10/17 9.8 (8.5-11.1) 17.9 (10.9-26.4) 5.8 (4.4-7.1) 4.5 (1.6-12.4) 0.56 (0.40-0.77) 0.45 (0.32-0.64) 0.54 (0.42-0.69) 0.23 (0.09-0.55) 0.0 0.5 1.0 1.5 2.0 Favors T-DXd Favors TPC PFS by blinded independent central review. Based on derived data, which include protocol deviations. CDK, cyclin-dependent kinase; ECOG, Eastern Cooperative Oncology Group; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 15#16Confirmed ORR 60 50 50 F Confirmed Objective Response Rate Hormone receptor-positive | Hormone receptor-negative 52.6%a 3.6 50.0% Complete Response 2.5 Partial Response Percentage 40 40 30 30 49.2 16.3% 47.5 16.7% 20 20 0.6 5.6 10 10 15.7 11.1 0 T-DXD (n = 333) TPC (n = 166) Progressive disease, % 7.8 21.1 T-DXd (n = 40) 12.5 TPC (n = 18) 33.3 Not evaluable, % 4.2 12.7 7.5 5.6 Clinical benefit rate,b % 71.2 34.3 62.5 27.8 Duration of response, months 10.7 6.8 | 8.6 4.9 Hormone receptor status is based on data from the electronic data capture corrected for misstratification. ORR, objective response rate; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. 10 Daiichi-Sankyo DESTINY-Breast04 *The response of 1 patient was not confirmed. Clinical benefit rate is defined as the sum of complete response rate, partial response rate, and more than 6 months' stable disease rate, based on blinded independent central review. ASCO 2022 #LBA3 Plenary Session 16#17Best Change in Target Lesions (All Patients) 100. T-DXd (n = 348) 100 DESTINY-Breast04 Daiichi-Sankyo TPC (n = 156) Best % Change in Sum of Diameters From Baseline -100 -60 -40. -20 20. 40. * 60 60 80 80 *17 -80. IHC 1+ IHC 2+/ISH- *** **** *** ***** * 80 60 60 40 40 * 20 20 0 -20 -40 -60 ** ** -80 IHC 1+ IHC 2+/ISH- -100 **** * * *Patients with HR- disease Shown are the best percentage changes from baseline in the sum of the largest diameters of measurable tumors in patients for whom data from both baseline and postbaseline assessments of target lesions by independent central review were available. The upper dashed horizontal line indicates a 20% increase in tumor size in the patients who had disease progression, and the lower dashed line indicates a 30% decrease in tumor size (partial response). HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 17#18Drug-Related TEAEs in ≥20% of Patients Nausea 73 Fatiguea 48 Alopecia Vomiting Neutropeniab Anemiac Decreased appetite Thrombocytopeniad Transaminases increasede Leukopenia Diarrhea Constipation 5 0 24 5 42 38 34 34 33 33 33 29 29 24 24 14 8 8 5 00 10 10 2 1 5 16 1 9 80 60 40 33 33 41 51 23 23 24 24 3 8 23 23 23 22 6 19 31 22 1 2 18 21 00 13 20 0 20 40 60 10 Daiichi-Sankyo DESTINY-Breast04 T-DXd, Any Grade T-DXd, Grade ≥3 TPC, Any Grade TPC, Grade ≥3 80 80 60 Patients Experiencing Drug-Related TEAE (%) T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event; TPC, treatment of physician's choice. *This category includes the preferred terms fatigue, asthenia, and malaise. "This category includes the preferred terms neutrophil count decreased and neutropenia. This category includes the preferred terms hemoglobin decreased, red-cell count decreased, anemia, and hematocrit decreased. This category includes the preferred terms platelet count decreased and thrombocytopenia. "This category includes the preferred terms transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic function abnormal. This category includes the preferred terms white-cell count decreased and leukopenia. ASCO 2022 #LBA3 Plenary Session 18#19Overall Safety Summary 10 Daiichi-Sankyo DESTINY-Breast04 Safety analysis seta n (%) Total patient-years of exposure, yearsb T-DXd (n = 371) 283.55 63.59 TEAEs 369 (99) 169 (98) Grade ≥3 195 (53) 116 (67) TPC (n = 172) • Median treatment duration - T-DXd: 8.2 months (range, 0.2-33.3) ― TPC: 3.5 months (range, 0.3-17.6) • Most common TEAE associated with treatment discontinuation - T-DXd: 8.2%, ILD/pneumonitisc - - TPC: 2.3%, peripheral sensory neuropathy Serious TEAES TEAEs associated with dose discontinuations TEAEs associated with dose interruptions 103 (28) 60 (16) 143 (39) 43 (25) • Most common TEAE associated with dose reduction 14 (8) - T-DXd: 4.6%, nausea and fatigued - TPC: 14.0%, neutropeniad 72 (42) • Total on-treatment deathse TEAEs associated with dose reductions TEAEs associated with deaths 84 (23) 14 (4) 66 (38) - T-DXd: 3.8% 5 (3) - TPC: 4.7% ASCO 2022 #LBA3 Plenary Session ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event; TPC, treatment of physician's choice. aSafety analyses were performed in patients who received ≥1 dose of a study regimen. Patient-years of exposure are the treatment duration with year as unit. Grouped term. Fatigue includes the preferred terms fatigue, malaise, and asthenia; neutropenia included the preferred terms of neutropenia and neutrophil count decreased. "On-treatment death was defined as any death that occurred from the date of the first dose to 47 days after the last dose of study drug irrespective of the cause; the TEAEs associated with deaths represent a subset of on-treatment deaths reported by the investigators as adverse events. 19#20Adverse Events of Special Interest Adjudicated as drug-related ILD/pneumonitisa n (%) Grade 1 T-DXD (n = 371) 13 (3.5) TPC (n = 172) 1 (0.6) Left ventricular dysfunction n (%) Grade 2 Grade 3 Grade 4 24 (6.5) 0 5 (1.3) 0 0 0 Daiichi-Sankyo DESTINY-Breast04 Grade 5 3 (0.8) Any Grade 45 (12.1) 0 1 (0.6) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade Ejection fraction decreased T-DXd (n = 371) TPC (n = 172) 1 (0.3) 0 14 (3.8) 0 1 (0.3) 0 0 16 (4.3) 0 0 0 0 Cardiac failurec T-DXd (n = 371) 0 TPC (n = 172) 0 1 (0.3) 0 1 (0.3) 0 0 0 0 0 2 (0.5) 0 ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. "Median time to onset of ILD/pneumonitis for patients with T-DXd was 129.0 days (range, 26-710). "Left ventricular dysfunction was reported in a total of 17 (4.6%) patients in the T-DXd arm. One patient initially experienced ejection fraction decrease, then later developed cardiac failure. *Both patients with cardiac failure were reported to have recovered. ASCO 2022 #LBA3 Plenary Session 20 20#21• DESTINY-Breast04 Establishes T-DXd as the New Standard of Care in HER2-low, HR+/HR- MBC Daiichi-Sankyo DESTINY-Breast04 • T-DXd is the first HER2-targeted therapy to demonstrate unprecedented statistically significant and clinically meaningful improvement in PFS and OS versus TPC • Similar magnitude of benefit across all subgroups, including HER2 IHC status and prior CDK4/6i use • Safety is consistent with the known safety profile and showed an overall positive benefit-risk T-DXd € TPC DESTINY-Breast04 establishes HER2-low (IHC 1+, IHC 2+/ISH-) mBC as a new targetable patient population, with T-DXd as a new standard of care T-DXd TPC Median Efficacy in All Patients (HR+ and HR-) Progression-Free Survival 5.1 mo 9.9 mo Hazard ratio: 0.50, P < 0.0001 Overall Survival 23.4 mo 16.8 mo Hazard ratio: 0.64, P = 0.001 CDK4/61, cyclin-dependent kinase 4/6 inhibitors; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician's choice. ASCO 2022 #LBA3 Plenary Session 21#22Poster 465 Retrospective study to estimate the prevalence of HER2-low breast cancer (BC) and describe its clinicopathological characteristics Giuseppe Viale, MD, FRCPath'; Naoki Niikura, MD, PhD²; Eriko Tokunaga, MD3; Mark Basik, MD4; Naoki Hayashi, MD5; Joohyuk Sohn, MD, PhD; Ciara O'Brien, PhD; Gavin Higgins, PhD; Della Varghese, PhD; Gareth D. James 10; Akira Moh, MD, PhD11; Nana Scotto, MD12 'European Institute of Oncology IRCCS and University of Milan, Milan, Italy. "Tokai University School of Medicine, Kanagawa, Japan; *National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; *Jewish General Hospital, McGill University, Montreal, QC, Canada: $St. Luke's International Hospital, Tokyo, Japan; "Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 'The Christie NHS Foundation Trust, Manchester, UK; *Victoria Cancer Biobank, Melbourne, VIC, Australia; "AstraZeneca Pharmaceuticals LP, Gaithersburg, MD; Medical Statistics Consultancy Ltd, London, UK; 11Daiichi Sankyo Inc., Basking Ridge, NJ; 12AstraZeneca Pharmaceuticals, Cambridge, UK Objectives ⚫ The objectives were to (1) assess the prevalence of human epidermal growth factor receptor 2 (HER2)-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-; ie, HER2-low BC) among patients with unresectable/metastatic BC (mBC) originally scored as HER2 negative based on rescored HER2 IHC slides after training on low-end expression scoring; (2) describe characteristics, clinical presentation, treatment patterns, and clinical outcomes of patients with HER2-low vs HER2 IHC 0 mBC; and (3) characterize the concordance between HER2 IHC rescores and historical scores - Here we report interim analysis data with an expanded data set (392 of 800 planned patients) from that previously reported in the abstract (233 patients) Conclusions ⚫ In this study of mBC samples previously categorized as HER2-negative, the prevalence of HER2-low status was 61.2% - HER2-low prevalence was numerically higher among patients with hormone receptor (HR)-positive mBC compared with HR-negative mBC (66.4% and 46.0%, respectively) Data on HER2-low prevalence in BC are limited, but this estimated prevalence is similar to that in a previous study of HER2-negative BC samples (60%) 1 ⚫ The overall concordance rate for HER2 status classification between historical and rescored slides was 79.1% ( [95% CI], 0.554 [0.468-0.640]) indicating that historical scores were relatively accurate in identifying patients with HER2-low BC - Overall concordance was similar in the Ventana 4B5 and non-Ventana 4B5 cohorts (79.5% and 78.7%, respectively) ⚫ HER2-low and HER2 IHC 0 groups had similar demographic and baseline disease characteristics As HER2-targeted therapies such as trastuzumab deruxtecan (T-DXd) for the treatment of patients with HER2-low BC are emerging, 2-6 a greater understanding of patients with HER2-low expression who could benefit from these therapies is important Introduction ⚫ HER2-negative BC (IHC 0, 1+, or IHC 2+/ISH-) comprises -80% of all BCS7; however, -60% of BCS traditionally categorized as HER2 negative express low levels of HER2 (IHC 1+ or IHC 2+/ISH-)1 •⚫ HER2-targeted therapies for HER2-low mBC are under investigation (eg, T-DXd in the phase 3 DESTINY-Breast04 study [NCT03734029] and the phase 2 DAISY trial [NCT04132960]). 2-5 In DESTINY-Breast04, T-DXd demonstrated superior progression-free survival in previously treated patients with HER2-low mBC vs the standard of care; the safety profile of T-DXd was consistent with previous trials2 • As patients with HER2-low BC become a clinically relevant population and the HER2 paradigm shifts from binary categorization to more nuanced recognition of the continuum of HER2 expression, accurate identification of patients with HER2-low BC is important - HER2 assays currently used to select patients for approved anti-HER2 therapies are optimized for high HER2 expression and are not validated for HER2-low detection. A recent study found relatively poor concordance (19% of cases had <70% interrater agreement) in evaluation of IHC scores of 0 and 1+ using current HER2 assays, which underscores the need to understand the performance of HER2 assays for detection of HER2-low BC⁹ ⚫ Here we report the overall prevalence of HER2-low status among patients with unresectable/mBC identified as HER2 negative based on rescoring of historical HER2 IHC slides. We also describe patient characteristics, treatment patterns, and outcomes in HER2-low and HER2 IHC 0 mBC and the concordance between HER2 IHC rescores and historical scores Results and interpretation HER2-low prevalence within the HER2-negative population • HER2 rescores were available for 384 of 392 patients ⚫ HER2-low prevalence was 61.2% overall and numerically greater in the HR-positive subgroup vs HR-negative subgroup (66.4% vs 46.0%; Figure 1) - No notable differences in prevalence were seen when rescores were assessed using the Ventana 4B5 and other assays (P=.8524) Figure 1. HER2-low prevalence in the HER2-negative mBC population Assay Breast cancer 235/384 All (N=384) 188/283 46/100 61.2 66.4 46.0 Methods Study design This global, multicenter, retrospective study (NCT04807595) included patients with confirmed HER2-negative (HER2 IHC 0, 1+, or 2+/ISH-) unresectable/mBC diagnosed from 2014 through 2017 (date of mBC diagnosis was the index date) - Patients from Australia, Canada, France, Italy, Japan, Korea, and United Kingdom were included • Staff at local laboratories, blinded to historical HER2 scores, rescored HER2 IHC-stained slides - HER2 was assessed using Ventana 4B5 and other assays (eg, HercepTestTM [DAKO] or Bond Oracle™ [Leica]) ⚫ BCs were categorized as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 Patient demographics and clinicopathological characteristics ⚫ No notable differences in demographic or baseline disease characteristics between the HER2-low and HER2 IHC 0 groups were seen (Tables 1 and 2) At index date, most patients (291/392; 74.2%) were HR positive, most (75.3%) were ≥45 years of age, and most (79.6%) were Asian or White Visceral (58.9%) and bone (45.2%) metastases were commonly observed among reported metastatic sites; most patients (55.4%) reported 1 metastatic site Table 1. Patient demographics 12 (26.1) 13 (24.1) Outcomes • The prevalence of HER2-low BC among patients originally scored as HER2 negative was measured ⚫ Demographics, clinicopathological characteristics, treatment patterns, and outcomes were examined via medical charts/electronic health records - Data cutoff was December 31, 2020 (ie, >3 years of follow-up post index date) • Concordance between historical HER2 scores and rescores was also assessed using Cohen's kappa (k), with к describing the relative strength of agreement using the following scale: 10 ->0.8, almost perfect; 0.6-0.8, substantial; 0.4<x<0.6, moderate; 0.2<<0.4, fair; Oss0.2, slight; <0, poor • Time-to-event outcomes were estimated using Kaplan-Meier method and reported as medians and 95% CI Treatment patterns and outcomes • Most patients (50.0 % -78.2%) received monotherapy as their first treatment in the metastatic setting; 21.8% -50.0% had combination therapy, of whom 15% received CDK4/6 inhibitors (Figure 3) ⚫ Median time to first subsequent treatment and overall survival (OS) were numerically greater for HER2-low than for HER2 IHC 0 with 1 exception (OS in patients who were HR positive and did not receive CDK4/6 inhibitors; Figures 4 and 5) Patients, % The magnitude of the differences in median OS between HER2-low and HER2 IHC 0 was generally larger among HR-negative than HR-positive groups Figure 3. First treatment received in the metastatic setting 50.0 47.2 50.0 47.2 HR+ HER2-low (n-150) HR+ HER2 IHC 0 (n-78) HR-HER2-low (n-36) HR-HER2 IHC 0 (n-36) HR positive HR negative Total HER2-low (N=188) HER2 IHC 0 Total" (N=95) (N=291) HER2-low (N=46) HER2 IHC 0 Total (N=54) (N=392) (N=100) 100.0- Female, n (%) 187 (99.5) 94 (98.9) 288 (99.0) 46 (100.0) 54 (100.0) 100 (100.0) 389 (99.2) 90.0 Median age at Index date, median (range), years 60 (27-93) 56 (28-90) 59 (27-93) 57 (31-80) 51 (35-92) 53 (31-92) 57 (27-93) 78.2 80.0 Total Age group at Index date, n (%)* 70.0 18 to 44 years 23 (12.2) 11 (11.6) 36 (12.4) 9 (19.6) 16 (29.6) 25 (25.0) 61 (15.6) 61.5 75/126 Primary (n=126) 66/104 59.5 63.5 HR positive 45 to 64 years 82 (43.6) 48 (50.5) 134 (46.0) 23 (50.0) 20 (37.0) 43 (43.0) 177 (45.2) 60.0- 52.8 52.7 ≥65 years 66 (35.1) 27 (28.4) 93 (32.0) 25 (25.0) 50.0 118 (30.1) 9/22 40.9 HR negative 50.0 Not reported/missing 1 (0.5) 2 (0.7) 0 0 0 2(0.5) 40.0 157/255 61.6 Smoking status "never." n (%) 110 (58.5) 61 (64.2) 178 (612) 30 (65.2) 34 (63.0) 64 (64.0) 242 (61.7) Metastatic (n=255) 119/176 67.6 Race, n (%) 30.0 Aslan 82 (43.6) 38 (40.0) 125 (43.3) 14 (30.4) 23 (42.6) 37 (37.0) 163 (41.6) 37/78 47.4 20.0 White 67 (35.6) 34 (35.8) 101 (34.7) 23 (50.0) 25 (46.3) 48 (48.0) 149 (38.0) Black or African American 1 (0.5) 1 (1.1) 2 (0.7) 1 (2.2) 0 1 (1.0) 3 (0.8) 10.0 6.0 5.1 Other 2(1.1) 0 2 (0.7) 0 0 2 (0.5) 0.0 36 (19.1) 22 (23.2) 60 (20.6) 8 (17.4) 5 (11.1) 14 (14.0) 75 (19.1) Any Endocrine therapy Chemotherapy Any Monotherapy Not reported/missing *Includes patients with missing HER2 category. Includes patients with missing HR status. Index date was the date of mBC diagnosis 0 0 21.8 20.0 16.7 Aromatase inhibitors + CDK4/6 inhibitors Combination therapy 118/193 61.7 Ventana 4B5 (n=193) 101/149 67.8 18/44 40.9 Plain language summary Why did we perform this research? Breast cancers can have high levels of the HER2 protein (HER2-positive breast cancer), low levels of the HER2 protein (HER2-low breast cancer), or no HER2 protein (HER2-negative breast cancer). About 60% of breast cancers historically classified as HER2 negative are HER2-low breast cancers. Some anticancer like trastuzumab deruxtecan (T-DXd), are designed to target and kill cancer cells that express drugs, HER2.2.3 T-DXd may be able to treat HER2-low breast cancer, but the tests to detect HER2 are not sensitive for low amounts of HER2.47 We wanted to find out how many patients who were historically categorized as having HER2-negative breast cancer should actually be considered as having HER2-low breast cancer. We also wanted to describe the differences between characteristics of patients with breast cancer that was identified as HER2-low and characteristics of patients with breast cancer that had no HER2 expression detected (immunohistochemistry [IHC] score of 0). How did we perform this research? Patients who were diagnosed with HER2-negative unresectable or metastatic breast cancer from 2014 through 2017 were included. Staff at local laboratories, who did not know how the tissue biopsies were scored when the patients were diagnosed, reevaluated the tissue samples after being trained. The samples were then categorized as either HER2-low or HER2 IHC 0. The number of patients who were recategorized as HER2-low among all patients reevaluated was calculated, and information about the patients (such as age, race, and aspects of disease and treatment) was examined. We also looked at how well the new HER2 category matched with the first category the patients were given. What were the findings of this research and what are the implications? We found that 61.2% f patients with HER2-negative breast cancer were actually HER2-low. We did not see notable differences in the characteristics of patients with HER2-low and patients with HER2 IHC 0 breast cancer. The majority (79.1%) of HER2 tests that were rescored as HER2-low matched historical HER2 results. This research helps us understand how many patients have HER2-low breast cancer and differences between patients with HER2-low and HER2 IHC 0 breast cancer. Where can I access more information? ClinicalTrials.gov. Estimation of the prevalence of HER2-low and describe the standard of care, treatment patterns, and outcome in real-world practice among unresectable and/or metastatic breast cancer patients with HER2-low status. https://clinicaltrials.gov/ct2/show/NCT04807595 This study is sponsored by AstraZeneca Pharmaceuticals and Dalichi Sankyo Inc. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Dalichi Sankyo for trastuzumab deruxtecan (T-Oxd; D0-8201). ..... References: 1. Schettini F, et al. NPJ Breast Cancer. 2021;7(1):1. 2. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 3. Oglani Y, et al. Clin Cancer Res. 2016;22(20) 5097-5108. 4. Modi 3, et al. J Can Oncol. 2020;38(17):1887-1896. 5. Modi 3, et al. Presented at San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract OT1-07-02. 6. Pauletti G, et al. Oncogene. 1996;13(1):63-72. 7. AstraZeneca. Enhertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2-low metastatic breast cancer. Accessed May 4, 2022 https://www.astrazeneca.com/media-centre/press-releases/2122/enhertu-improve-of-and-os-incher2-low-bc.html • The concordance rate between historical and rescored slides for HER2 status classification was 79.1% (Figure 2) - Overall, positive agreement was 81.6% and negative agreement was 74.6% - Overall concordance was similar in the Ventana 4B5 and non-Ventana 4B5 cohorts (79.5% and 78.7%, respectively) Figure 2. Concordance between rescores and historical scores Ventana 4B5 assayab Overall concordance: 163/205 (79.5%) HER2 IHC 0 Non-Ventana 4B5 assaya.b.c Overall concordance: 140/178 (78.7%) K (95% CI): 0.534 (0.406-0.661) HER2-low HER2 IHC 0 * (95% CI): 0.572 (0.457-0.686) HER-low 118/191 60.7 Non-Ventana 4B5 (n=191) 87/134 64.9 Table 2. Patient clinical characteristics Figure 4. Time to first subsequent treatment 28/56 50.0 HR positive HR negative Total HR+ HER2-low (n=102) HER2-low (N=188) HER2 IHC 0 Total* (N=95) HER2-low (N=291) (N=46) HER2 IHC 0 Total" (N=54) (N=392) (N=100) HR+ HER2 IHC 0 (n=58) 0 20 40 60 80 100. Time from Initial BC diagnosis to mBC diagnosis, n (%) <2 years 76 (40.4) 35 (36.8) 116 (39.9) 21 (45.7) 28 (51.9) 49 (49.0) 165 (42.1) Patients, % 2 to 5 years 39 (20.7) 22 (23.2) 63 (21.6) 14 (30.4) 10 (18.5) 24 (24.0) 87 (22.2) *Only patients with avaliable HER2 score (HER2-low or HER2 HCD) contributed to prevalence calculations. Patents with presently unknown HR status included in total category only. *Ventana and non-Ventana groups based on the rescore results. >5 years 57 (30.3) 28 (29.5)) 85 (29.2) 9 (19.6) 11 (20.4) 20 (20.0) 105 (26.8) *Includes Hercep Test, Bond Oracle, or unknown. Not reported/missing 16 (8.5) 10 (10.5) 27 (9.3) 2 (4.3) 5 (9.3) 7 (7.0) 35 (8.9) HR-HER2-low (n=23) HR-HER2 IHC 0 (n=31) HR+ HER2-low (n=28) HR+ HER2 IHC 0 (n=18) 9.5 (7.5-15.3) 7.0 (6.0-10.5) 7.6 (4.1-8.4) 5.0 (4.2-8.0) HER2 testing concordance Location of metastasis/metastases, n (%) Bone 96 (51.1) 47 (49.5) 150 (51.5) 13 (28.3) 13 (24.1) 26 (26.0) 177 (45.2) HR+ HER2-low (n=74) Brain 7 (3.7) 5 (5.3) 13(4.5) 6 (13.0) 4 (7.4) 10 (10.0) 23 (5.9) Liver 48 (25.5) 30 (31.6) 81 (27.8) 18 (39.1) 14 (25.9) 32 (32.0) 113 (28.8) Lung 46 (24.5) 23 (24.2) 73 (25.1) 10 (21.7) 17 (31.5) 27 (27.0) 101 (25.8) Visceral 103 (54.8) 61 (64.2) 171 (58.8) 29 (63.0) 30 (55.6) 59 (59.0) 231 (58.9) HR+ HER2 IHC 0 (n=40) HR-HER2 IHC 0 (n=31) HR-HER2-low (n=23) Number of metastatic locations, n (%) 1 113 (60.1) 49 (51.6) 162 (55.7) 26 (56.5) 29 (53.7) 55 (55.0) 217 (55.4) 18.6 (8.5-21.3) 13.1 (6.1-15.3) 8.3 (6.0-13.3) 6.4 (3.8-10.0) 7.6 (4.1-9.4) 5.0 (4.2-8.0) 12 18 24 2 36 (19.1) 18 (18.9) 56 (19.2) 7 (15.2) 14 (25.9) 21 (21.0) 77 (19.6) 23 39 (20.7) 20 (29.5) 73 (25.1) 13 (20.3) 11 (20.4) 24 (24.0) 90 (25.0) Metastatic or locally advanced at Index date, n (%) All assaysa Metastatic 169 (89.9) 85 (89.5) 261 (89.7) 43 (93.5) 47 (87.0) 90 (90.0) 351 (89.5) Kaplan-Meler estimate, median (95% CI), months *Data for Hire-negative subgroups not reported (no; ie, use of corals intors not indicated for patiens with HR-egative BC). Figure 5. Overall survival Overall concordance: 303/383 (79.1%) Locally advanced 1 (0.5) 0 1 (0.3) 0 2(3.7) 2(2.0) 3 (0.8) Both 3(1.5) 1 (1.1) 4 (1.4) 1 (2.2) 2 (3.7) 3 (3.0) 7 (1.8) x (95% CI): 0.554 (0.468-0.640) HER2-low HR+ HER2-low (n=150) Not reported/missing 15 (8.0) 9 (9.5) 25 (8.6) 2 (4.3) 3 (5.6) 5 (5.0) 31 (7.9) HER2 IHC 0 Stage at Initial BC diagnosis, n (%) 14 (7.4) 6 (6.3) 20 (6.9) 7 (15.2) 7 (13.0) 14 (14.0) 34 (8.7) Π 62 (33.0) 34 (35.8) 97 (33.3) 11 (23.9) 17 (31.5) 28 (28.0) 125 (31.9) 30 (16.0) 20 (21.1) 52 (17.9) 13 (28.3) 13 (24.1) 26 (26.0) 78 (19.9) IV 27 (14.4) 14 (14.7) 44 (15.1) 1 (2.2) 9 (16.7) 10 (10.0) 54 (13.8) Other/not reported/missing 55 (29.3) 21 (22.1) 78 (26.8) 14 (30.4) 8 (14.8) 22 (22.0) 101 (25.8) HR+ HER2 IHC 0 (n=78) HR-HER2-low (n=36) HR-HER2 IHC 0 (n=38) HR+ HER2-low (n=42) HR+ HER2 IHC 0 (n=23) 43.9 (38.7-52.7) 41.7 (32.5-53.7) 31.1 (20.6-41.9) 11.5 (8.6-20.5) 66.0 (43.7-NC) 46.1 (32.4-NC) Positive agreement 81.6% Negative agreement 74.6% Includes patients with missing HER2 category. Includes patients with missing HR status. Reported over the course of patients' metastatic disease. HR+ HER2-low (n=108) Index date was the date of mBC diagnosis. Poster Plain language summary Supplementary material (HER2-low prevalence by country, overall reported treatments in the metastatic setting, time to treatment failure) Please scan this quick response (QR) code with your smartphone camera or app to obtain a copy of these materials. Alternatively, please click on the link below. https://bit.ly/3Fh087C Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster. This presentation is the intellectual property of the authors/presenter. Please contact Dr Giuseppe Viale at [email protected] for permission to reprint and/or distribute. Poster presented at ASCO Annual Meeting, June 3-7, 2022; Chicago, IL and online by Dr Giuseppe Viale. Corresponding author email address: [email protected] Positive agreement 85.1% Negative agreement 71.4% Historical HER2-low *Only patients with available historical scores were included *Ventana and non-Ventana groups based on the historical score Includes HercepTest, Bond Oracle, or unknown. Positive agreement 78.2% Negative agreement 79.6% Rescored HER2-low Historical HER2 IHC 0 Rescored HER2 IHC 0 Discussion and limitations • These data are from a retrospective study, and findings may be impacted by the inherent limitations associated with this type of data (eg, missing/inaccurate data from health/medical records); as such, these data should be interpreted carefully - Furthermore, this data set may not have been optimal for robust analyses of treatment patterns and outcomes because of the relatively short window of follow-up ⚫ Our data from an unresectable/mBC population have shown a similar HER2-low prevalence (61.2%) in a HER2-negative cohort as that found in a previous study of a HER2-negative BC population (60%)1 ⚫ Treatment findings are in line with the typical standard of care for HR-positive and HR-negative subgroups, with endocrine therapy being the most common for HR-positive mBC and chemotherapy being the most common for HR-negative mBC11 ⚫ Survival outcomes are also consistent with previous reports, with no overall difference in OS observed between HER2-low and HER2 IHC 0 BC,1,12,13 although other studies have shown differing results 14,15 • Future analyses will investigate stratification of HER2-low status by IHC 1+ vs 2+, which may impact outcomes 12 *Data for HR-negative subgroups not reported due to small sample size (le, use of CDK416 Inhibitors not indicated for patients with HR-negative BC). References 1. Schettini F, et al. NPU Breast Cancer. 2021;7(1):1. 2. AstraZeneca. Entertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2-low metastatic breast cancer. Accessed May 4, 2022. https://www.astrazeneca.com/media- centre/press-releases/2022/enhertu-improves-pfs-and-os-in-her2-low-bc.html 3. Modi S, et al. J Clin Oncol. 2020;38(17):1887-1896. 4. Dieras V, et al. Presented at: San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, Texas. Abstract PD8-02. 7. Arteaga CL, et al. Nat Rev Clin Oncol. 2012;9(1):16-32 Pauletti G, et al. Oncogene. 1996;13(1):63-72. Femandez Al, et al. JAMA Oncol. 2012;217239. [online ahead of print] 10. Landis JR and Koch GG. Blometrics. 1977;33(1):159-174. 11. Lolbl 3, et al. Lancet. 2021:397(10286):1750-1769. 12. Omar AMA, Darwish AMA. J Clin Oncol. 2021;39(suppl 15): Abstract e12515. 13. Gampenrieder SP, et al. Breast Cancer Res. 2021:23(1):112 14. Denkert C, et al. Lancet Oncol. 2021:22(8):1151-1161. 5. Modi S, et al. Presented at: San Antonio Breast Cancer Symposium; December 15. Mutal R, et al. Breast. 2021;60:62-69. 10-14, 2019; San Antonio, Texas. Abstract OT1-07-02. 6. Bardia A, et al. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract OT-03-09. Abbreviations COKE , breast cancer, CDK4/6, cyclin-dependent kinase 4/6; CDK4/6 Inhibitor, HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ICH, in situ hybridization; mBC, metastatic BC, NC, not calculable: 00, overall survival; T-DXd, trastuzumab deruxtecan. Acknowledgments We thank Olga Aleynikova (Jewish General Hospital, McGill University) for her contributions to this work. We thank the patients who are participating in this study as well as their familles and caregivers. This study is sponsored by AstraZeneca Pharmaceuticals and Dalichi Sankyo Inc. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruate can (T- DXd; D3-8201). Medical writing support was provided by JoAnna Anderson, PhD, CMPP (Articulate@cience, LLC), and was funded by AstraZeneca. 22 34.4 (25.4-46.4) HR+ HER2 IHC 0 (n=55) 40.6 (30.3-48.9) HR-HER2-low (n=35) 29.8 (20.6-41.6) HR-HER2 IHC 0 (n=36) 11.5 (8.6-20.5) 12 40 60 72 Kaplan-Meier estimate, median (95% CI), months#23DESTINY-Breast03 Trastuzumab Deruxtecan vs Trastuzumab Emtansine in Patients With HER2-Positive Unresectable and/or Metastatic Breast Cancer: Safety Follow-up of the Randomized, Phase 3 Study DESTINY-Breast03 Erika Hamilton, MD, a Vanessa Petry, Winnie Yeo, Sung-Bae Kim, Giampaolo Bianchini, Toshinari Yamashita, Kan Yonemori, Kenichi Inoue, Giuseppe Curigliano, Sara A. Hurvitz, Javier Cortés, Hiroji Iwata, Jillian Cathcart, Yali Liu, Caleb Lee, Emarjola Bako, Rachel Kim, Seock-Ah Im On behalf of the DESTINY-Breast03 investigators aSarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA Daiichi-Sankyo ASCO 2022 #1000 Oral On behalf of the investigators 23#24Background 10 Daiichi-Sankyo DESTINY-Breast03 Progression-Free Survival Probability, % 100 PFS by BICR¹‚ª mPFS (95% CI), mo 12-mo PFS rate (95% CI), % T-DXd NR (18.5-NE) 75.8 (69.8-80.7) HR (95% CI) 80 60 40 2 + Censor T-DXd (n = 261) 0 T-DM1 (n = 263) 0 1 2 3 4 5 6 7 8 Patients Still at Risk: T-DM1 6.8 (5.6-8.2) 34.1 (27.7-40.5) 0.28 (0.22-0.37) P= 7.8 X 10-22 HHHHH 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Time, months T-DXD (261) 261 256 250 244 240 224 214 202 200 183 168 164 150 132 112 105 79 84 53 45 38 29 25 19 T-DM1 (263) 263 252 200 163 155 132 108 98 93 78 65 60 51 43 37 34 29 23 21 16 12 8 8 4 1 1 1 10 8 5 3 2 0 1 1 1 1 1 0 T-DXd, a HER2-targeted ADC, was approved for the treatment of patients with HER2+ unresectable or mBC who have received a prior anti-HER2 therapy in the metastatic or neoadjuvant/adjuvant setting and had recurrence during or within 6 months after therapy² DESTINY-Breast03 (NCT03529110) investigated T-DXd vs T-DM1 in patients with HER2+ unresectable or mBC ■ In the primary analysis (May 21, 2021), T-DXd was superior to T-DM1 for PFS by BICR (primary endpoint)1 ■ Overall health status and QoL was maintained with T-DXd and numerically favored T-DXd over T-DM13 ADC, antibody-drug conjugate; BICR, blinded independent central review; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; mBC, metastatic breast cancer; mPFS, median progression-free survival; PFS, progression-free survival; QoL, quality of life; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. 1. Cortés J et al. N Engl J Med. 2022;386:1143-1154. 2. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use. Daiichi Sankyo, Inc; 2022. 3. Curigliano G et al. Presented at ESMO Breast Cancer meeting; May 3-5, 2022; Berlin, Germany. Presentation 1630. From New England Journal of Medicine, Cortés J et al, Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer, Vol. 386, Pages 1143-1154. Copyright ©2022 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. ASCO 2022 #1000 Oral 24 24#25DESTINY-Breast03 Study Design Patients with HER2+ mBCa treated with trastuzumab and/or taxane R 1:1 Received T-DXd 5.4 mg/kg Q3W n = 257b Received T-DM1 3.6 mg/kg Q3WC n = 261b 10 Daiichi-Sankyo DESTINY-Breast03 Primary data cutoff: May 21, 2021 Median treatment duration1: T-DXd: 14.3 months T-DM1: 6.9 months Safety update: Sept 7, 2021 Median treatment duration: T-DXd: 16.1 months T-DM1: 6.9 months Prespecified analysis of TEAEs Selected TEAES (ILD/pneumonitis, nausea, vomiting, fatigue, alopecia, hematologic events), including EAIRS Objective of the study was to provide updated safety data with additional analyses in patients with HER2+ MBC treated with T-DXd or T-DM1 in DESTINY-Breast03 EAIRS, exposure-adjusted incidence rates; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; mBC, metastatic breast cancer; Q3W, every 3 weeks; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. aCentral testing of archived sample for HER2 status. "Number of treated patients (not the randomized number of patients). Or in accordance with the local label. 1. Cortés J et al. N Engl J Med. 2022;386:1143-1154. ASCO 2022 #1000 Oral 25#26Safety Update Overview (September 7, 2021) T-DXd n = 257 T-DM1 n = 261 n(%) Patients discontinued from study treatment 141 (54.9) 222 (85.1) Any grade TEAE 256 (99.6) 249 (95.4) Grade ≥3 TEAE 137 (53.3) 130 (49.8) Any grade serious TEAE 54 (21.0) 50 (19.2) Grade 3 serious TEAE 39 (15.2) 38 (14.6) TEAE associated with drug discontinuation 38 (14.8) 19 (7.3) TEAE associated with dose reduction 59 (23.0) 36 (13.8) T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral DESTINY-Breast03 Daiichi-Sankyo Rates of TEAEs (any grade and grade ≥3) and serious TEAEs were similar between the T-DXd and T-DM1 arms TEAEs associated with drug discontinuation occurred in 38 patients (14.8%) in the T-DXd arm and 19 patients (7.3%) in the T-DM1 arm 26#27Exposure-Adjusted Incidence Rates (EAIRS) a Daiichi-Sankyo DESTINY-Breast03 Patients remaining on treatment, n (%) 116 (45.1) 39 (14.9) Treatment duration, median (range), months 16.1 (0.7-33.0) 6.9 (0.7-28.5) Exposure, patient-yearsb 327.2 186.3 EAIR, grade ≥3 TEAE 0.42 0.70 EAIR, any grade serious TEAE 0.17 0.27 EAIR, grade ≥3 serious TEAE 0.12 0.20 Exposure-adjusted incidence per total patient-years of exposure T-DXd n = 257 T-DM1 n = 261 EAIRS were measured to account for differences in treatment duration exposure between T-DXd and T-DM1 and provide a more meaningful comparison EAIRS per patient-year were lower in the T-DXd arm than the T-DM1 arm except for TEAEs associated with drug discontinuation, which were primarily associated with ILD/pneumonitis in the T-DXd arm EAIR for grade ≥3 TEAES was 0.42 for T-DXd and 0.70 for T-DM1 • EAIR, TEAE associated with drug 0.12 0.10 discontinuation • EAIR, TEAE associated with dose reduction 0.18 0.19 EAIR for any grade serious TEAES was 0.17 for T-DXd and 0.27 for T-DM1 EAIRS, exposure-adjusted incidence rates; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. aEAIR was the number of patients with at least 1 event incidence divided by the sum of patient-years of exposure over patients in the safety analysis set (total patient-years of exposure). "Patient years of exposure were the treatment duration with year as unit. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 27#28Drug-Related TEAEsa Reported in ≥20% of Patients in Either Treatment Arm T-DXd n = 257 T-DM1 n = 261 n(%) Any Grade Grade ≥3 Any Grade Grade ≥3 Nausea Fatigue 189 (73.5) 17 (6.6) 72 (27.6) 1 (0.4) 118 (45.9) 16 (6.2) 76 (29.1) 2 (0.8) Vomiting 114 (44.4) 4 (1.6) 15 (5.7) 1 (0.4) Neutropenia 111 (43.2) 51 (19.8) 30 (11.5) 8 (3.1) Alopecia 97 (37.7) 1 (0.4) 7 (2.7) 0 Anemia 82 (31.9) 16 (6.2) 37 (14.2) 11 (4.2) Leukopenia 79 (30.7) 17 (6.6) 21 (8.0) 2 (0.8) Decreased appetite 68 (26.5) 3 (1.2) 34 (13.0) 0 Thrombocytopenia 65 (25.3) 19 (7.4) 137 (52.5) 65 (24.9) Diarrhea 61 (23.7) 1 (0.4) 11 (4.2) 2 (0.8) Constipation 60 (23.3) 0 25 (9.6) 0 • Daiichi-Sankyo DESTINY-Breast03 Most of the selected drug-related TEAEs in either treatment arm were hematologic or gastrointestinal T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse events. Selected TEAEs (and preferred terms included): anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased); neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); fatigue (fatigue, asthenia, malaise). aBased on nonclinical data, clinical data, epidemiology data, and reported data from drugs in a similar class (anti-HER2 therapies), selected TEAEs for T-DXd were reviewed for additional characterization. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 28#29Time to First Onset of TEAES T-DXd T-DM1 • Median time to event, days n = 257 n = 261 TEAE associated with treatment 224 147 discontinuation TEAE associated with first dose reduction 96 19 Selected TEAES Anemia Lymphopenia Thrombocytopenia Fatigue Leukopenia Neutropeniaa Nausea Vomiting Alopecia 70.0 42.0 196.0 168.0 132.0 8.0 22.0 24.0 74.5 92.0 64.0 105.0 2.0 3.0 10.0 27.0 6.0 43.0 10 Daiichi-Sankyo DESTINY-Breast03 . TEAEs associated with first drug discontinuation or first dose reduction occurred later with T-DXd treatment than with T-DM1 treatment Median time to any TEAE associated with first dose reduction was longer in the T-DXd arm at 96 days compared with the T-DM1 arm at 19 days T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. Selected TEAEs (and preferred terms included): anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased); lymphopenia (lymphocyte count decreased, lymphopenia); neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); leukopenia (white blood cell count decreased, leukopenia); fatigue (fatigue, asthenia, malaise). a11.7% of patients in the T-DXd group and 2.3% of patients in the T-DM1 group were treated with G-CSF within 28 days after onset of neutropenia, including febrile neutropenia. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 29 20#30Time to First Occurrence of Nausea and Vomiting 10 Daiichi-Sankyo DESTINY-Breast03 Nausea + Censor 1.0 Cumulative Probability 0.9 P<0.0001 0.8 0.7 0.6 0.5 0.4 T-DXd T-DM1 0.3 0.2 Cumulative Probability + 1.0¬ Censor T-DXd Vomiting 0.9- T-DM1 P<0.0001 0.8- 0.7- 0.6- www 0.5 0.4- 0.3- 0.2- படட 0.1 0.1 0.0 0.0 0 90 180 270 360 450 540 630 720 810 900 990 1080 0 90 180 270 360 450 540 630 720 810 900 990 1080 Days Days T-DXd 257 T-DM1 261 71 150 59 100 46 37 27 74 50 39 22 20 9 6 29 15 4 42 1 0 0 T-DXd 257 T-DM1 261 153 133 115 95 202 141 95 66 24 79 55 47 53 29 14 8 3 1 0 34 19 7 3 0 Risk of first event of nausea and vomiting was higher with T-DXd in earlier cycles T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. Time to first occurrence of the TEAE was defined as the date of the first occurrence of the TEAE minus the date of first study drug plus 1. Patients that did not experience the TEAE were censored at min (treatment end date + 47 days, new treatment start date, death date, date last known alive) minus first study drug date plus 1. P value was from the unstratified log rank test and was for descriptive purposes only. ASCO 2022 #1000 Oral 30#31Time to First Occurrence of Fatigue and Alopecia 10 Daiichi-Sankyo DESTINY-Breast03 Cumulative Probability + Censor Fatigue 1.0 - T-DXd 0.9- -T-DM1 P = 0.2376 0.8- 0.7- 0.6- 0.5- 1.0. + Censor Alopecia T-DXd 0.4- 0.3- 0.2- 0.1- பட Cumulative Probability 0.9 T-DM1 0.8. P<0.0001 0.7- 0.6- 0.5- 0.4- 0.3- 0.2- 0.1- LIL 0.0 0.0- 0 g- 90 180 270 360 450 540 630 720 810 900 990 1080 0 90 180 270 360 450 540 630 720 810 900 990 1080 Days Days T-DXd 257 T-DM1 261 201 175 171 148 125 105 74 41 19 9 1 0 117 78 49 37 27 13 1 0 T-DXd 257 T-DM1 261 168 140 123 105 86 59 32 17 8 2 1 0 206 146 100 67 50 38 19 7 3 0 • The cumulative incidence and trend of fatigue over time was similar between T-DXd and T-DM1 Risk of first event of alopecia was higher with T-DXd in earlier cycles T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. Time to first occurrence of the TEAE was defined as the date of the first occurrence of the TEAE minus the date of first study drug plus 1. Patients that did not experience the TEAE were censored at min (treatment end date + 47 days, new treatment start date, death date, date last known alive) minus first study drug date plus 1. P value was from the unstratified log rank test and was for descriptive purposes only. ASCO 2022 #1000 Oral 31#32100 90 90 Prevalence 80 Prevalence of Nausea and Vomiting 70 60 50 40 30 20 10 0 Nausea Cycle DESTINY-Breast03 100 Vomiting 90. 80 70 60 60 50 50 40. 40 30 20 10 123 Cycle Daiichi-Sankyo T-DXd (n=257) T-DM1 (n=261) T-DXD 257 256 254 252 247 242 227 225 215 213 203 197 191 182 175 172 167 160 153 149 138 136 126 117 105 97 85 76 62 50 44 40 31 27 22 19 17 17 10 8 6 5 21 T-DXd 257 256 254 252 247 242 227 225 215 213 203 197 191 182 175 172 167 160 153 149 138 136 126 117 105 97 85 76 62 50 44 40 31 27 22 19 17 17 10 8 6 5 21 T-DM1 261 252 221 209 189 175 161 150 138 133 118 108 93 87 78 73 68 63 59 58 52 51 48 43 41 39 36 30 22 18 16 13 11 6 5 5 4 3 3 2 2 0 0 0 T-DM1 261 252 221 209 189 175 161 150 138 133 118 108 93 87 78 73 68 63 59 58 52 51 48 43 41 39 36 30 22 18 16 13 11 65 5 4 3 3 2 2 000 The prevalence of nausea and vomiting was higher with T-DXd than with T-DM1 and was relatively consistent over time Majority of events with T-DXd were grade 1 and 2 and resolved, and one patient discontinued study drug due to vomiting Antiemetic prophylaxis recommendations were updated during the study based on emerging data supporting the moderately emetogenic potential of T-DXd1,2 T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. Prevalence was defined as the number of patients who had the event starting at a particular cycle or still ongoing at that cycle divided by the number of patients on treatment at that cycle. 1. Hesketh PJ et al. J Clin Oncol. 2020;38(24):2782-2797. 2. Modi S et al. N Engl J Med. 2020;382:610-621. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 32#33Prevalence 30 20 10 0 100 90 90 80 70 60 Prevalence of Fatigue and Alopecia 61 Fatigue Cycle T-DXD 257 258 254 252 247 242 227 225 215 213 203 197 191 182 175 172 167 160 153 149 138 138 126 117 105 97 85 76 62 50 44 40 31 27 22 19 17 17 10 8 8 5 21 T-DM1 261 252 221 209 189 175 181 150 138 133 118 108 93 87 78 73 68 63 59 58 52 51 48 43 41 39 36 30 22 18 16 13 11 6 5 5 4 3 3 2 2 0 00 100 90 90 Alopecia 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 1 8 10 Daiichi-Sankyo DESTINY-Breast03 T-DXD (n = 257) T-DM1 (n=261) Cycle T-DXD 257 256 254 252 247 242 227 225 215 213 203 197 191 182 175 172 167 160 153 149 138 136 126 117 105 97 85 78 82 50 44 40 31 27 22 19 17 17 10 8 8 5 2 1 T-DM1 261 252 221 209 189 175 161 150 138 133 118 108 93 87 78 73 88 83 59 58 52 51 48 43 41 39 38 30 22 18 18 13 11 8 5 5 4 3 3 2 2 0 0 0 The prevalence of fatigue and alopecia was relatively consistent over time T-DM1, trastuzumab emtansine, T-DXd, trastuzumab deruxtecan. Prevalence was defined as the number of patients who had the event starting at a particular cycle or still ongoing at that cycle divided by the number of patients on treatment at that cycle. ASCO 2022 #1000 Oral 33#34Adjudicated Drug-Related ILD/Pneumonitis Any grade, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Time to first onset, median (range), days Outcome of worst event, n (%) Fatal Not recovered/not resolved Ongoing Recovering/resolving Recovered/resolved with sequelae Recovered/resolved 10 Daiichi-Sankyo DESTINY-Breast03 T-DXd n = 257 T-DM1 n = 261 For this safety update: • Majority of adjudicated 28 (10.9) 5 (1.9) 7 (2.7) 4 (1.5) 19 (7.4) 1 (0.4) 2 (0.8) 0 0 0 0 0 • 181 (33-507) 289 (80-499) • 0 8 (28.6) 0 1 (20.0)a 0 0 2 (7.1) 0 2 (7.1) 16 (57.1) 0 4 (80.0) ILD/pneumonitis cases were low grade and no new grade 4 or 5 events occurred in either treatment arm One additional grade 2 adjudicated drug-related ILD/pneumonitis occurred The majority of events resolved with ongoing follow-up ILD, interstitial lung disease; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aPatient had an event of pulmonary embolism that the investigator considered to be grade 5. This was initially reported as respiratory failure but subsequently updated to pulmonary embolism. The ILD adjudication committee adjudicated this event as drug-related grade 1 ILD/pneumonitis. The death was not evaluable for adjudication. The investigator recorded disease progression as the primary cause of death.1 1. Cortés J et al. N Engl J Med. 2022;386:1143-1154 (supplementary appendix). Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 34#3510 Daiichi-Sankyo Conclusions DESTINY-Breast03 No new safety signals were observed for T-DXd in patients with HER2+ mBC in this safety update, 1-3 and in-depth analysis demonstrated that: ■ Most TEAEs were grade 1 or 2, and exposure-adjusted incidence rates of grade ≥3 TEAEs and serious TEAEs were lower with T-DXd than T-DM1 Risk of nausea, vomiting, fatigue, and alopecia was higher for T-DXd in the initial treatment cycles ■ Prevalence of nausea and vomiting was higher for T-DXd in the initial treatment cycles and was consistent over time for alopecia and fatigue o In the T-DXd arm, the increased risk and higher prevalence of these events that persisted throughout treatment duration necessitates ongoing supportive care ■ There were no additional grade 3 adjudicated ILD/pneumonitis events with T-DXd (overall rate = 0.8%), and no grade 4 or 5 events overall These data reinforce the established favorable benefit/risk profile of T-DXd over T-DM1 in HER2+ mBC HER2, human epidermal growth factor receptor-2; ILD, interstitial lung disease; mBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. 1. Modi S et al. J Clin Oncol. 2020;38:1887-1896. 2. Modi S et al. N Engl J Med. 2020;382:610-621. 3. Cortés J et al. N Engl J Med. 2022;386:1143-1154. Safety update: Sept 7, 2021 ASCO 2022 #1000 Oral 35#36PATIENT-REPORTED OUTCOMES FROM DESTINY-Breast03, A RANDOMIZED PHASE 3 STUDY OF TRASTUZUMAB DERUXTECAN (T- DXD) VS TRASTUZUMAB EMTANSINE (T-DM1) IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER GIUSEPPE CURIGLIANO, KYLE DUNTON, MATS ROSENLUND, MARTIN JANEK, JILLIAN CATHCART, YALI LIU, PETER A. FASCHING, HIROJI IWATA Giuseppe Curigliano, MD European Institute of Oncology IRCCS, University of Milan, Milan, Italy Daiichi-Sankyo ESMO BC 2022 #1630 Oral On behalf of the investigators 36#37DESTINY-Breast03 Study Design Patients (N = 524) Unresectable or metastatic HER2- positivea breast cancer that has R 1:1 been previously treated with trastuzumab and a taxaneb Stratification factors • Hormone receptor status Prior treatment with pertuzumab . History of visceral disease PRO endpoint assessment schedulee Cycle 1 Cycle 2 Cycle 3 Every 2 cycles (cycle 5, 7, 9, etc) DESTINY-Breast03 10 Daiichi-Sankyo T-DXd 5.4 mg/kg Q3W (n = 261)c (open-label) T-DM1 3.6 mg/kg Q3W (n = 263)d Primary endpoint PFS (BICR) Key secondary endpoint OS Secondary endpoints ORR (BICR and investigator) DOR (BICR) PFS (investigator) Safety HEOR outcomes (PROs and hospitalization rates) EOT 40-day follow-up visit 3-month follow-up visit BICR, blinded independent central review; DOR, duration of response; EOT, end of treatment; HEOR, health economics outcomes research; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcome; Q3W, every 3 weeks; R, randomization; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aHER2 IHC3+ or IHC2+/ISH+ based on central confirmation. Progression during or <6 months after completing adjuvant therapy involving trastuzumab and a taxane. c4 patients were randomly assigned but not treated. d2 patients were randomly assigned but not treated. º1 cycle = 21 days; T-DXd or T-DM1 administered on day 1 of each cycle; questionnaires completed before treatment on day 1 of cycles indicated. ESMO BC 2022 #1630 Oral 37#38Demographics and Baseline Clinical Characteristics DESTINY-Breast03 Baseline Characteristics Age, median (range), years Region, n (%) Asia North America 149 (57.1) 17 (6.5) 54 (20.7) T-DXd n = 261 54.3 (27.9-83.1) T-DM1 n = 263 54.2 (20.2-83.0) 160 (60.8) 17 (6.5) 50 (19.0) Europe 41 (15.7) 36 (13.7) Rest of World Hormone-receptor status, n (%) 131 (50.2) 134 (51.0) Positive 130 (49.8) 129 (49.0) HER2 status,a n (%) Negative 3+ 2+ with HER2 ISH+ 1+ Visceral disease, n (%) Yes | No Prior treatment for mBC, n (%) 234 (89.7) 232 (88.2) 25 (9.6) 30 (11.4) 0 1 (0.4) 184 (70.5) 77 (29.5) 185 (70.3) 78 (29.7) Pertuzumab Prior lines of therapy for metastatic disease, n (%) 0-1 2+ HER2, human epidermal growth factor receptor 2; ISH, in situ hybridization; mBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aHER2 status was evaluated by immunohistochemical analysis at a central laboratory. HER2 ISH-positive refers to positive results on in situ hybridization. HER2 status could not be evaluated for 1 patient in each treatment group. Excluding hormone therapy. "Patients who had had rapid progression (i.e., progression that had occurred within 6 months after receipt of neoadjuvant or adjuvant therapy or within 12 months after receipt of a neoadjuvant or adjuvant pertuzumab-containing regimen) were considered to have had one line of previous therapy. Lines of previous therapy did not include endocrine therapy. 1. Cortés J et al. N Engl J Med. 2022:386:1143-1154. 240 (92.0) 162 (62.1) 132 (50.6) 129 (49.4) 234 (89.0) 158 (60.1) 126 (47.9) 137 (52.1) ESMO BC 2022 #1630 Oral From New England Journal of Medicine, Cortés J et al, Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer, Vol. 386, Pages 1143-1154. Copyright © 2022 Massachusetts Medical Society. Reprinted with permission [pending] from Massachusetts Medical Society. 38 Daiichi-Sankyo 10#39DESTINY-Breast03: PFS by BICR1-3 100- Progression-Free Survival Probability, % T 40- 60- 80 80- 20- Censor T-DXD (n = 261) DESTINY-Breast03 mPFS, mo (95% CI) 12-mo PFS rate, % (95% CI) HR (95% CI) T-DXd NR (18.5-NE) 75.8 (69.8-80.7) T-DM1 6.8 (5.6-8.2) 34.1 (27.7-40.5) 0.28 (0.22-0.37) P=7.8 × 10-22 T-DM1 (n=263) 2 3 4 Patients Still at Risk: 55 17 -6 Median duration of follow-up: T-DXd, 16.2 months; T-DM1, 15.3 months 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Time, months T-DXd (261) 261 256 250 244 240 224 214 202 200 183 168 164 150 132 112 105 79 64 53 45 36 29 25 19 10 6 5 3 2 0 T-DM1 (263) 263 252 200 163 155 132 108 96 93 78 65 60 51 43 37 34 29 23 21 16 12 8 6 4 1 1 1 1 1 1 1 1 0 BICR, blinded independent central review; HR, hazard ratio; mPFS, median progression-free survival; NE, not estimable; NR, not reached; PFS, progression-free survival; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. 1. Cortès J et al. N Engl J Med. 2022:386:1143-1154. 2. Cortés J et al. N Engl J Med. 2022; 2022;386(supplement). 3. Hurvitz SA et al. Presented at: San Antonio Breast Cancer Symposium 2021; December 7-10, 2021. Presentation GS3-01. ESMO BC 2022 #1630 Oral From New England Journal of Medicine, Cortés J et al, Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer, Vol. 386, Pages 1143-1154. Copyright 2022 Massachusetts Medical Society. Reprinted with permission [pending] from Massachusetts Medical Society. 39 Ο Daiichi-Sankyo#40DESTINY-Breast03: Safety Summary Ο DESTINY-Breast03 Daiichi-Sankyo Median (range) treatment duration²: • ⚫ T-DXd: 14.3 (0.7-29.8) months • ⚫ T-DM1: 6.9 (0.7-25.1) months ⚫ Most common TEAE associated with treatment discontinuation³: T-DXd T-DM1 n (%)¹ (n = 257) (n = 261) Any drug-related TEAE 252 (98.1) 226 (86.6) • Drug-related TEAE grade ≥3 116 (45.1) 104 (39.8) Serious drug-related TEAE 28 (10.9) 16 (6.1) Drug-related TEAE associated with discontinuation 33 (12.8) 13 (5.0) Drug-related TEAE associated 91 (35.4) 34 (13.0) with dose interruption • Drug-related TEAE associated 55 (21.4) 33 (12.6) with dose reduction Drug-related TEAE associated 0 0 with an outcome of death • T-DXd: ILD/pneumonitisa (8.2%) • T-DM1: thrombocytopenia (2.7%) Most common TEAEs associated with dose reduction³: • T-DXd: nausea (6.2%), neutropenia (3.5%) T-DM1: thrombocytopenia (4.2%), • ALT and AST increased (2.7% each) ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; PTs, preferred terms; SMQ, standardized MedDRA query; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. Relationship to study drug was determined by the treating investigator. Interstitial lung disease includes events that were adjudicated as ILD and related to use of T-DXd or T-DM1 (includes cases of potential ILD/pneumonitis, based on MedDRA v23.0 for the narrow ILD SMQ, selected terms from the broad ILD SMQ, and PTS of respiratory failure and acute respiratory failure). This category includes the PTs platelet count decreased and thrombocytopenia. This category includes the PTs neutrophil count decreased and neutropenia. 1. Cortés J et al. N Engl J Med. 2022;386(supplement). 2. Cortés J et al. N Engl J Med. 2022;386:1143-1154. 3. Cortés J et al. Presented at: ESMO Virtual Congress 2021; September 16-21, 2021. Presentation 2525. ESMO BC 2022 #1630 Oral From New England Journal of Medicine, Cortés J et al, Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer, Vol. 386, Pages 1143- 1154(supplement). Copyright © 2022 Massachusetts Medical Society. Reprinted with permission [pending] from Massachusetts Medical Society. 40#41DESTINY-Breast03 PRO & Hospitalization Endpoints & Analyses Endpoint EORTC QLQ-C30 Description Oncology-specific questionnaire . Measures of interest Global health status (GHS)/QoLa Functioning scales: physical, role, emotional, cognitive, and social Symptom scales: pain Symptom scales: arm and breast DESTINY-Breast03 Daiichi-Sankyo Main analyses • Change from baseline • Time to definitive deterioration (TDD)b,c EORTC QLQ-BR45 Breast cancer-specific questionnaire TDDb,c EQ-5D-5L Generic questionnaire • Hospitalization Records assessment Self-rated health status (visual analog scale [VAS]) Date of admission to hospital Status/date of discharge • TDDC • Time to first hospitalization • Length of stay Completion compliance for HRQoL patient questionnaires was high in both treatment groups, with >97% completion at baseline and >82% completion from cycles 3-27 in both arms EORTC, European Organization for Research and Treatment of Cancer; EQ-5D-5L, EuroQol 5-dimension, 5-level questionnaire; GHS, global health status; HRQoL, health-related quality of life; PRO, patient-reported outcome; QLQ-BR45, Quality of Life Breast cancer questionnaire; QLQ-C30, Quality of Life Core 30 questionnaire; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aPrimary PRO variable of interest. Clinically meaningful deterioration defined as a change of 10 points or more in the GHS and subscale scores. Not all variables measured were assessed for TDD. ESMO BC 2022 #1630 Oral 41#42Overall Health Status and QOL on Treatment Worse 70 DESTINY-Breast03 Daiichi-Sankyo Ο GHS 60 -40 -50 Better GHS Mean (SE) Change From Baseline in EORTC QLQ-C30 GHS T-DXd 50 40 30 20 10 considered clinically meaningful A 10-point change is Mean (SD) change from baseline at EOT Min, Max T-DM1 1.98 (21.340) 4.07 (22.048) -50.0, 66.7 -75.0, 58.3 • As of May 21, 2021, patients still receiving study drug included:1 • ⚫ T-DXd: 132 (51.4%) 0 HOH -30 Treatment T-DXd (baseline, n = 252) T-DM1 (baseline, n = 259) C17D1 C9D1 C11D1 C13D1 C15D1 C7D1 C5D1 C3D1 C2D1 C31D1 C29D1 C27D1. C25D1 C23D1 C21D1 C19D1 Nominal Time Point (visits) C, cycle; D, day; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of treatment; GHS, global health scale; QLQ-C30, Quality of Life Core 30 questionnaire; QoL, quality of life; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. ESMO BC 2022 #1630 Oral Scores range from 0 to 100; a linear transformation was applied to the raw GHS score, thus a higher score represents lower ("worse") GHS/overall QoL 1. Cortés J et al. Presented at: ESMO Virtual Congress 2021; September 16-21, 2021. Presentation 2525. 2. Cortés J et al. N Engl J Med. 2022;386:1143-1154. C33D1 C35D1 C41D1 C39D1 C37D1 T-DM1 n < 20 T-DXd n < 20 • • • T-DXd: 14.3 (0.7-29.8) months T-DM1: 6.9 (0.7-25.1) months Global health was maintained in patients treated with T-DXd while on treatment (until n < 20 when results are no longer informative) • T-DM1: 47 (18.0%) • Median (range) treatment duration:² 42#43Time to Definitive Deterioration (TDD) of QLQ-C30 GHS Time to definitive deterioration, % 100 80 60 T 60 60 T 40 20 20 T 0 1 2 3 4 5 T T CO 6 7 8 00 + Censor T-DXd (n = 261) T-DM1 (n = 263) Ο DESTINY-Breast03 Daiichi-Sankyo Median (95% CI) TDD, months 9.7 (7.3-12.5) HR (95% CI): 0.88 (0.70-1.11) 8.3 (7.0-10.3) P value: 0.2829 HH + 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Patients at risk: Time, months 79 66 55 50 34 23 16 15 11 10 10 8 37 32 26 23 21 16 12 9 7 4 3 3 1 7 4 3 20 0 T-DXD 261 232 198 179 175 158 146 136 125 116 101 92 T-DM1 263 237 191 171 162 146 121 102 86 70 64 56 EORTC, European Organization for Research and Treatment of Cancer; GHS, global health status; HR, hazard ratio; QLQ-C30, Quality of Life Core 30 questionnaire; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. P values are not adjusted for multiple testing. TDD is defined as a >10-point change from baseline. ESMO BC 2022 #1630 Oral 43#44TDD in PRO Measures of Interest Median (95% CI) TDD, months DESTINY-Breast03 Daiichi-Sankyo T-DXd (n = 261) EORTC QLQ-C30 Global health status/QoLa Pain symptomsb 9.7 (7.3-12.5) 10.8 (8.3-14.0) T-DM1 (n = 263) 8.3 (7.0-10.3) HR (95% CI) Nominal P value 0.88 (0.70-1.11) 0.2829 Physical functioningb 16.7 (14.5-NE) 8.3 (6.6-9.8) 10.3 (8.3-21.0) 0.75 (0.59-0.95) 0.0146 0.77 (0.59-1.01) 0.0529 Emotional functioningb 16.4 (14.1-19.9) 10.5 (9.0-13.8) 0.69 (0.53-0.89) 0.0049 Social functioningb 11.1 (7.3-13.4) 9.0 (7.1-11.3) 0.90 (0.71-1.14) 0.3577 Arm symptomsb 11.1 (8.5-14.8) EORTC QLQ-BR45 Breast symptomsb EQ-5D-5L VASb 26.4 (26.4-NE) 13.2 (10.1-15.3) 7.0 (5.6-9.3) NE (NE-NE) 8.5 (7.3-10.4) 0.70 (0.55-0.89) 0.0033 0.76 (0.53-1.09) 0.1329 0.77 (0.61-0.98) 0.0354 0.5 1.0 1.5 2.0 Favors T-DXd (log10) Favors T-DM1 EORTC, European Organization for Research and Treatment of Cancer; EQ-5D-5L, EuroQol 5-dimension, 5-level questionnaire; GHS, global health status; HR, hazard ratio; PRO, patient-reported outcome; QLQ-BR45, Quality of Life Breast cancer questionnaire; QLQ-C30, Quality of Life Core 30 questionnaire; QoL, quality of life; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; VAS, visual analog scale. P values are not adjusted for multiple testing. TDD is defined as a >10-point change from baseline. aPrimary PRO variable of interest. Secondary PRO variable of interest. ESMO BC 2022 #1630 Oral 44#45TDD of QLQ-C30 Pain Symptoms 100 80 80 60 60 Time to definitive deterioration, % T 40 40 20 20 60 LO T T 01 2 3 4 5 T 7 8 00 + Censor T-DXD (n = 261) T-DM1 (n = 263) 나가 화가 жи DESTINY-Breast03 10 Daiichi-Sankyo Median (95% CI) TDD, months 10.8 (8.3-14.0) HR (95% CI): 0.75 (0.59-0.95) 8.3 (6.6-9.8) P value: 0.0146 T T T 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Time, months Patients at risk: T-DXD 261 240 210 193 182 168 152 141 129 120 111 100 89 80 68 58 44 31 26 17 14 11 11 6 6 3 1 1 0 T-DM1 263 237 185 169 161 141 118 100 87 67 59 49 34 28 24 20 18 13 11 7 7 4 3 3 0 EORTC, European Organization for Research and Treatment of Cancer; HR, hazard ratio; QLQ-C30, Quality of Life Core 30 questionnaire; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. P values are not adjusted for multiple testing. TDD is defined as a >10-point change from baseline. ESMO BC 2022 #1630 Oral 45#46TDD of QLQ-C30 Emotional Functioning 100 80 60 60 60 Time to definitive deterioration, % 40 40 T 20 20 + Censor T-DXd (n = 261) T-DM1 (n=263) Ο DESTINY-Breast03 Daiichi-Sankyo Median (95% CI) TDD, months 16.4 (14.1-19.9) HR (95% CI): 0.69 (0.53-0.89) 10.5 (9.0-13.8) P value: 0.0049 0 1 2 3 4 5 Patients at risk: CO 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Time, months 20 19 17 12 10 7 3 10 T-DXD 261 241 220212 209 195 189 178 166 155 144 132 116 100 89 74 57 39 32 25 T-DM1 263 243 208 187 177 155 130 117 102 80 71 59 43 32 26 22 18 15 10 7 7 6 4 4 1 1 0 EORTC, European Organization for Research and Treatment of Cancer; HR, hazard ratio; QLQ-C30, Quality of Life Core 30 questionnaire; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. P values are not adjusted for multiple testing. TDD is defined as a >10-point change from baseline. ESMO BC 2022 #1630 Oral 46 40#47TDD of EQ-5D-5L VASa 100 80 80 Time to definitive deterioration, % 60 60 40 40 20 20 + Censor T-DXd (n = 261) T-DM1 (n = 263) + DESTINY-Breast03 10 Daiichi-Sankyo Median (95% CI) TDD, months 13.2 (10.1-15.3) HR (95% CI): 0.77 (0.61-0.98) 8.5 (7.3-10.4) P value: 0.0354 ++ T T 01 2 3 4 15 T 5 Patients at risk: CO 6 F7 7 T 80 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Time, months 7 6 2 1 10 T-DXD 261 237 204 186 184 169 156 151 141 135 122 112 97 85 74 62 44 30 23 19 12 9 9 T-DM1 263 244 199 176 169 147 124 108 98 77 68 58 40 29 24 18 16 10 8 5 5 2 2 1 0 EQ-5D-5L, EuroQol 5-dimension, 5-level questionnaire; HR, hazard ratio; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; VAS, visual analog scale. P values are not adjusted for multiple testing. TDD is defined as a >10-point change from baseline. aVAS of self-rated overall health and quality of life, measured on a scale from 0 to 100. ESMO BC 2022 #1630 Oral 47#48Hospitalization-Related Endpoints Parameter DESTINY-Breast03 T-DXd (n = 261) T-DM1 (n = 263) Subjects with hospitalization, n (%) 18 (6.9) 19 (7.2) Median (range) time to first hospitalization, a days 219.5 (0-723) 60.0 (0-399) Median (range) length of hospital stay, days 10.5 (1-181) 9.0 (2-25) 2 (0.8) 1 (0.4) Died, n (%) Discharged home, n (%) 15 (5.7) 16 (6.1) Discharged to home health care, n (%) 1 (0.4) 1 (0.4) T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aTime to first hospitalization is defined as the time from the date of randomization to the date of the first hospitalization during the study treatment (from date of first dose to 47 days after last dose). Time for subjects whose first hospitalization date was prior to treatment start date was calculated as 0. ESMO BC 2022 #1630 Oral 48 48 Ο Daiichi-Sankyo#49Conclusions Overall health status and QoL was maintained with T-DXd, based on mean change from baseline of EORTC QLQ-C30 GHS scale (primary PRO variable of interest) and other specified subscales of interest Median (range) treatment duration was longer in the T-DXd arm (14.3 [0.7-29.8] months) than in the T-DM1 arm (6.9 [0.7-25.1] months)1 For all prespecified PRO variables of interest, the HR for TDD numerically favored T-DXd over T-DM1 (HR range, 0.69-0.90), indicating T-DXd treatment delays the deterioration of QoL in patients with mBC • Delayed TDD of pain symptoms with T-DXd (HR, 0.75) is particularly salient, given its profound impact on QoL 2,3 Time to first hospitalization was delayed with T-DXd versus T-DM1: median 219.5 days versus 60.0 days, respectively (interpretation limited by low rates of hospitalization in both arms) This evidence of maintained QoL while on treatment with T-DXd and delayed definitive deterioration across prespecified scales versus T-DM1 further supports the improved efficacy (including superior PFS) and manageable safety profile of T-DXd versus T-DM1,1 thus supporting T-DXd as a standard of care for patients with HER2+ mBC EORTC, European Organization for Research and Treatment of Cancer; GHS, global health status; HR, hazard ratio; mBC, metastatic breast cancer; QLQ-C30, Quality of Life Core 30 questionnaire; QoL, quality of life; TDD, time to definitive deterioration; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. Daiichi-Sankyo 1. Cortés J et al. N Engl J Med. 2022;386:1143-1154. 2. Dueñas M, et al. J Pain Res. 2016;9:457–467. 3. Dams L et al. Supportive Care Cancer. 2022; doi: 10.1007/s00520-022-06805-0. ESMO BC 2022 #1630 Oral 49#50Daiichi-Sankyo Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: Primary outcome analysis from the TUXEDO-1 trial Rupert Bartsch¹, Anna Sophie Berghoff 1, Julia Furtner 2, Maximilian Marhold 1, Elisabeth Sophie Bergen 1, Sophie Roider-Schur ³, Angelika Martina Starzer 1, Heidrun Forstner 1, Beate Rottenmanner 1, Karin Dieckmann 4, Zsuzsanna Bago-Horvath 5, Georg Widhalm 6, Aysegül Ilhan-Mutlu 1, Christoph Minichsdorfer 1, Thorsten Fuereder 1, Christian Singer 7, Ansgar Weltermann 8, Rainer Puhr 1, Matthias Preusser 1 3 1 Department of Medicine 1, Division of Oncology, Medical University of Vienna; 2 Department of Radiology, Medical University of Vienna, Vienna, Austria; ³ Department Oncology, St. Joseph's Hospital, Vienna, Austria; 4 Department of Radio-Oncology, Medical University of Vienna, Vienna, Austria; 5 Department of Pathology, Medical University of Vienna, Vienna, Austria; 6 Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; 7 Department of Gynaecology, Medical University of Vienna, Vienna, Austria; 8 Department of Medicine 1, Elisabethinen Hospital Linz, Ordensklinkum Linz, Linz, Austria Investigator-Initiated Study ESMO BC 2022 #165 Mini Oral On behalf of the investigators 50 50#51Background Breast cancer is the second most common cause of brain metastases among solid cancers¹ Growing interest in systemic treatment to improve disease control HER2 tyrosine-kinase inhibitors in combination with capecitabine yielded clinically relevant activity in BM progressing. after prior local therapy2,3 Upfront therapy with lapatinib and capecitabine delayed WBRT4 HER2Climb5 ☐ Tucatinib + trastuzumab +capecitabine vs. placebo + trastuzumab + capecitabine ☐ Largest population of patients with active BM in a randomized study Intracranial response rate (active BM): 47.3% PFS in patients with active BM 9.5 months (95% CI 7.5-11.1) ESMO guidelines: standard-of-care for active BM if no immediate local therapy is required Role of antibody drug-conjugates is less well established 6,7 ■ DEBBRAH: RR (T-DXd) in progressive BM 44.4% (4/9 pts.)8 1 Weil RJ et al. Am J Pathol 2005;167:913-920.; 2 Lin NU et al. Clin Cancer Res 2009;15:1452-1459.; 3 Freedman RA et al. J Clin Oncol 2019;37:1081-1089.; 4 Bachelot T et al. Lancet Oncol 2013;14:64-71.; 5 Lin NU et al. J Clin Oncol 2020;38:2610-2619.; 6 Montemurro F et al. Ann Oncol 2020;31:1350-1358.; 7 Hurvitz S et al. GS3-01; SABCS 2021.; 8 Vaz Batista M et al. PF4-06; SABCS 2021. ESMO BC 2022 #165 Mini Oral Daiichi-Sankyo 51#52Study Design TUXEDO-1 (NCT04752059) Primary Endpoint: ORR (CNS) by RANO-BM criteria Secondary Endpoints: ☐ Clinical Benefit Rate (CR+PR+SD ≥6 months) ■ Extracranial Response rate ■ PFS ■ OS Safety ☐ Ouality of Life Inclusion/exclusion criteria Histologically confirmed HER2+ breast cancer Radiologically documented metastatic disease Newly diagnosed brain metastases or brain metastases progressing after prior local therapy Measurable disease (RANO-BM criteria) No indication for immediate local treatment No indication of leptomeningeal disease KPS >70%, ECOG <2 Indication for systemic anti-HER2 treatment Prior exposure to trastuzumab and pertuzumab Prior exposure to T-DM1 allowed Life expectancy of at least 3 months Age >18 years LVEF ≥50% Trastuzumab deruxtecan (5.4 mg/kg IV q3w Follow up Treatment until progression, unacceptable toxicity or withdrawal for any reason Further treatment according to local standard Safety FU four weeks after EOT Survival FU at 3, 9, 18 and 30 months BM, brain metastasis; BW, body weight; CNS, central nervous system; D1, day 1; EOT, end of treatment; FU, follow up; IV, intravenous; KPS, Karnofsky performance; LVEF, left ventricular ejection fraction; q3w, once every 3 weeks; RANO, response assessment in neuro-oncology; T-DXd, trastuzumab deruxtecan. EudraCT: 2020-000981-41. Simon Two Stage Design ■ RR (CNS) >60% suggests clinically relevant activity ■ RR (CNS) <26% suggests no benefit compared to previous systemic treatment options ☐ ■ Stage 1:6 pts. (at least three responses); Stage 2: 9 pts; overall 15 pts. (at least 7 responses) Type 1 error rate 5%; power 80% ESMO BC 2022 #165 Mini Oral Daiichi-Sankyo 52 62#53Patient Populations and Disposition ESMO BC 2022 #165 Mini Oral Enrollment Assessed for eligibility (n=17) Accrued (n=15) Excluded (n=2) + Not meeting inclusion criteria (n=2) Treatment Received trastuzumab-deruxctecan (n=15) Follow-Up Discontinued trastuzumab-deruxtecan (n=9) • Discontinuation due to progression (n=3) + Discontinuation for reasons other than progression (n=6) Analysis Intention-to-treat population (n=15) Evaluable for analysis of BM response (n=14) * Excluded from analysis due to absence of BM (n=1) Safety population (n=15) Daiichi-Sankyo 53#54Patient Characteristics Patient Characteristcs Sex; n (%) Female Male |Age; median (range) Age at Baseline ECOG Performance Status; n (%) ECOG O N=15 14 (93.3%) 1 (6.7%) 69 (30-76) 9 (60%) ECOG 1 6 (40%) Presence of Neurologic Symptoms at Baseline; n (%) Yes 6 (40%) No 9 (60%) Disease Subtype; n (%) HER2-positive/Luminal B 12(80%) HER2-positive/non-luminal 3 (20%) Brain Metastases Free Survival (BMFS); median (range) BMFS from Diagnosis of Metastatic Disease (months) 17 (0-48) Visceral Metastases; n (%) Yes 12 (80%) No 3 (20%) Prior HER2-directed Therapy; n (%) Trastuzumab+Pertuzumab T-DM1 15 (100%) 9 (60%) Lapatinib Other Status of Brain Metastases; n (%) Untreated ESMO BC 2022 #165 Mini Oral Progressive BM after prior Local Therapy Prior Lines of Treatment for mBC; median (range) Prior Lines of Treatment before T-DXd 4 (26.7%) 1 (6.7%) 6 (40%) Daiichi-Sankyo 9 (60%) 2 (1-5) 54#55Primary Endpoint 25 25 Objective Response Rate (RANO-BM criteria) ORR (intention-to-treat population; n=15): 73.3% (95% CI 48.1-89.1) Maximum change in tumor size from baseline (%) -75 50 25 0 -100 ESMO BC 2022 #165 Mini Oral One patient with dural metastases RR (per-protocol-population; n=14): 78.6% 55 Daiichi-Sankyo#56Secondary Endpoints 0.75 0.5 0.25 0 T 5 10 15 Time Numbers at risk 14 11 0 ■ 5 7 1 10 15 PFS: 14 months (95% CI 11.0-n.r.) - Median follow-up 11 months (range 3 – 17 months) ESMO BC 2022 #165 Mini Oral Daiichi-Sankyo ◉ ☐ Clinical Benefit Rate (CR+PR+SD ≥6 months): 13/15 (86.7%) in the ITT population and 13/14 (92.9%) in the PP population Median OS not reached Extracranial Response Rate: Pts. with extracranial metastases at baseline (n=13): PR 5/13 (27.8%) Pts with measurable extracranial disease at baseline (n=8): PR 5/8 (62.5%) 56#57Safety Safety population n=15 Any adverse event 15 pts. (100%) Haematological adverse events Grade 1/2 Grade 3 Grade 4 Anaemia Neutropenia 46.6% 6.7% 46.6% Non-haematologic adverse events >2 patients Grade 3 15.3% Grade 4 Grade 1/2 Fatigue 66.7% Nausea 46.7% Constipation 40% Hypokalaemia 40% Diarrhoea 33.4% 6.7% Bone pain 26.6% Dyspnoea 26.6% 6.7% Fall 20% Urinary tract infection 20% 6.7% Vomiting 20% ESMO BC 2022 #165 Mini Oral AEs of special interest: ☐ Ejection fraction decrease grade 3: 1 pt., ILD grade 2 1 pt. 6 SAEs in a total of 4 patients 1 Pt. grade 5 urosepsis (not related to IMP) Daiichi-Sankyo 57#58Quality-of-Life 100 80 60 40 40 20 Global health status 100 80 60 60 40 20 20 Physical functioning 0 0 C1D1 C3D1 C5D1 C8D1 C11D1 C14D1 C17D1 EOT C1D1 C3D1 C5D1 C8D1 C11D1 C14D1 C17D1 EOT Responders Non-Responders (9/10) (8/10) (10/10) (7/7) (7/7) (6/6) (5/5) (4/5) Responders (9/10) (8/10) (10/10) (7/7) (7/7) (6/6) (5/5) (5/5) (2/3) (3/3) (2/2) (1/1) (1/1) (0/1) (0/0) (1/1) Non-Responders (3/3) (3/3) (2/2) (1/1) (1/1) (1/1) (0/0) (1/1) 100 80 60 40 20 Overall Responders Non-responders Emotional functioning 0 C1D1 C3D1 C5D1 C8D1 C11D1 C14D1 C17D1 EOT Responders (9/10) (8/10) (10/10) Non-Responders (2/3) (3/3) (2/2) (7/7) (1/1) (7/7) (6/6) (5/5) (1/1) (0/1) (0/0) (4/5) (1/1) Overall -- Responders Non-responders 100 80 60 40 20 Overall -- Responders A Non-responders Cognitive functioning 0 C1D1 C3D1 C5D1 C8D1 C11D1 C14D1 C17D1 EOT Responders. Non-Responders (9/10) (8/10) (10/10) (7/7) (7/7) (6/6) (5/5) (4/5) (2/3) (3/3) (2/2) (1/1) (1/1) (0/1) (0/0) (1/1) Overall Responders Non-responders ESMO BC 2022 #165 Mini Oral QoL was maintained over the treatment period Daiichi-Sankyo 58#59Conclusions Trastuzumab-deruxtecan was active in patients with HER2-positive breast cancer brain metastases ◉ TUXEDO-1 met its primary endpoint Response rate (intention-to-treat population) 73.3% Comparable extra- and intracranial response rates Prolonged disease control ■ No new safety signals were observed ■ Quality-of-life was maintained over the treatment period ■ Adds to the growing body of evidence that systemic therapy is feasible in HER2-positive breast cancer with CNS metastasis Supports further investigation of ADCs in the context of secondary CNS malignancies ESMO BC 2022 #165 Mini Oral Daiichi-Sankyo 59#60Primary Analysis from DS8201-A-U105: A 2-part, Open-label, Phase 1b Trial Assessing Trastuzumab Deruxtecan (T-DXd) with Nivolumab in Patients with HER2-expressing Advanced Breast Cancer Erika Hamilton, Charles L. Shapiro, Valentina Boni, Miguel Martin, Gianluca Del Conte, Javier Cortes, Laila Agrawal, Hendrik-Tobias Arkenau, Antoinette R. Tan, Philip Debruyne, Anna Minchom, Annemie Rutten, Frances Valdes-Albini, Evan Y. Yu, Fumitaka Suto, Fu-Chih Cheng, Bincy Augustine, Ben Cheng, Daniel Barrios, Sara A. Hurvitz Erika Hamilton, MD Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA ESMO BC 2022 #1620 Oral Daiichi-Sankyo 60 00#61DS8201-A-U105 Study Design Part 1: Dose Escalation Key Eligibility Criteria ⚫ HER2-expressing locally advanced unresectable/ metastatic BC or UC (centrally confirmed)a • ECOG PS 0 or 1 . ≥1 measurable lesion per RECIST v1.1 No prior T-DXd or 1-0 To be eligible for part 1, patients must meet additional cohort-specific criteria of part 2b T-DXd 3.2 mg/kg Nivolumab 360 mg Q3WC n = 4 Nivolumab 360 mg Q3WC n = 3 RDEd T-DXd 5.4 mg/kg Part 2: Dose Expansion Cohort 1: HER2-positive (IHC 3+ or IHC 2+/ISH+) BC after T-DM1 n = 29€ Cohort 2: HER2-low (IHC 1+ or IHC 2+/ISH-) BC after standard treatment n = 16 Cohort 3: HER2-high (IHC 3+/2+) UC after chemotherapy n = 30 Cohort 4: HER2-low (IHC 1+) UC after chemotherapy n = 4 Primary endpoint Part 1: MTD or RDE ⚫ Part 2: ORR! by ICR Secondary endpoints ⚫ DOR, DCR, PFS, and TTR by ICR; investigator-assessed ORR and OS ⚫ PK/PD Safety and tolerability Exploratory endpoint ⚫ Biomarkers of resistance/response DCO: July 22, 2021 Daiichi-Sankyo BC, breast cancer; DCO, data cutoff; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; 1-0, immuno-oncology; ICR, independent central review; IHC, immunohistochemistry; ISH, in situ hybridization; MTD, maximum tolerated dose; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PK/PD, pharmacokinetics/pharmacodynamics; Q3W, every 3 weeks; RECIST v1.1, Response Evaluation Criteria in Solid Tumours, version 1.1; RDE, recommended dose for expansion; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TTR, time to response; UC, urothelial carcinoma. aBy IHC (BC and UC) and ISH (BC) before enrollment. Includes all inclusion criteria listed and cohort descriptions in Part 2. Other inclusion criteria were: cohort 1 patients had prior T-DM1 therapy with documented progression; cohort 2 patients should have exhausted treatments that could confer any clinically meaningful benefit; cohorts 3 and 4 patients had prior platinum-based combination chemotherapy with documented progression. Nivolumab 360 mg Q3W is an approved dose in the United States for certain indications in combination with ipilimumab or fluoropyrimidine- and platinum-containing chemotherapy (Opdivo [nivolumab] prescribing information) and is currently under investigation in monotherapy oncology studies. The RDE for T-DXd was 5.4 mg/kg. Data from 3 patients treated with the RDE of 5.4 kg/mg in part 1 were pooled with data from cohort 1 for part 2. fORR was based on RECIST v1.1. 9Biomarker data (PD-L1 expression by IHC) were assessed from baseline archival or new tumor tissue biopsies. ESMO BC 2022 #1620 Oral 61#62Baseline Demographics and Clinical Characteristics in BC Cohorts Baseline Characteristics Median ageb, years (range) Female, n (%) Region, n (%) Cohort 1 HER2+ n = 32a 55.5 (36.3-76.2) Cohort 2 HER2-low n = 16 47.3 (34.4-64.7) Overall N = 48 Treatment History Cohort 1 HER2+ n = 32a Cohort 2 HER2-low n = 16 Overall N = 48 53.6 (34.4-76.2) 32 (100) 16 (100) 48 (100) Number of lines of unique regimens for metastatic/locally advanced unresectable setting, n (%) 0 Europe 12 (37.5) 9 (56.3) 21 (43.8) 1 1 (3.1) 0 2 (12.5) 1 (6.3) 3 (6.3) 1 (2.1) United States 20 (62.5) 7 (43.8) 27 (56.3) 2 3 (9.4) 1 (6.3) 4 (8.3) 3 5 (15.6) 1 (6.3) 6 (12.5) ECOG PSC, n (%) 0 20 (62.5) 8 (50.0) 28 (58.3) ≥4 23 (71.9) 11 (68.8) 34 (70.8) 1 12 (37.5) 8 (50.0) 20 (41.7) Lines of unique regimens for HER2 expressiond, n (%) IHC 1+ 0 6 (37.5) 6 (12.5) metastatic/locally advanced unresectable setting, 5 (0-14.0) 4 (0-10.0) 4.5 (0-14.0) IHC 2+ 5 (15.6) 10 (62.5) 15 (31.3) median (range) ISH+ 5 (100) 0 5 (33.3) History of brain metastasis, n (%) 7 (21.9) 3 (18.8) 10 (20.8) ISH equivocal 0 1 (10.0) 1 (6.7) ISH- 0 9 (90.0) 9 (60.0) IHC 3+ 27 (84.4) 0 27 (56.3) HR status, n (%) Positive Negative 20 (62.5) 13 (81.3) 12 (37.5) 3 (18.8) 33 (68.8) 15 (31.3) ESMO BC 2022 #1620 Oral ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; RDE, recommended dose for expansion. aIncludes 3 patients treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg during part 1. Median age at informed consent. Performance status on the ECOG scale ranges from 0 to 5, with higher scores indicating greater disability. HER2 expression was centrally confirmed prospectively by analysis of archival tissue (most recent tumor tissue preferred) according to the guidelines from the American Society of Clinical Oncology/College of American Pathologists. According to these guidelines, HER2 positivity was defined as HER2 IHC 3+ or IHC 2+/ISH+. 62 10 Daiichi-Sankyo#63Patient Disposition T-DXd treatment status, n (%) Ongoing 7 (21.9) 1 (6.3) Discontinued 25 (78.1) 15 (93.8) Primary reason for discontinuing T-DXd, n (%) Progressive disease 9 (28.1) 11 (68.8) Clinical progression 3 (9.4) 2 (12.5) Adverse event 10 (31.3)b Patient withdrawal 1 (3.1) Cohort 1 HER2+ n = = 32a Cohort 2 HER2-low n = 16 Overall N = 48 8 (16.7) 40 (83.3) 20 (41.7) 5 (10.4) 11 (22.9) 2 (4.2) 1 (6.3)c 1 (6.3) Physician decision 1 (3.1) 0 1 (2.1) Otherd 1 (3.1) 0 1 (2.1) Nivolumab treatment status, n (%) Ongoing 6 (18.8) 0 6 (12.5) Discontinued 26 (81.3) 16 (100) 42 (87.5) Primary reason for discontinuing nivolumab, n (%) Progressive disease 8 (25.0) 11 (68.8) 19 (39.6) Clinical progression 2 (6.3) 2 (12.5) 4 (8.3) Adverse event 13 (40.6)e 2 (12.5) 15 (31.3) Patient withdrawal 1 (3.1) Physician decision 1 (6.3) 0 2 (4.2) Duration of follow-up, median (range), months Daiichi-Sankyo 2 (6.3) 18.7 (1.7-26.9) 12.7 (1.7-21.4) 2 (4.2) 18.2 (1.7-26.9) HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; RDE, recommended dose for expansion; T-DXd, trastuzumab deruxtecan. aIncludes 3 patients treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg during part 1. b1 troponin T increase (grade 3); 2 ILD (1 grade 1 and 1 grade 2); 4 pneumonitis (1 grade 1, 2 grade 2, and 1 grade 5); 1 amylase increase (grade 3); 1 femur fracture (grade 3); and 1 anemia (grade 3). c1 pneumonitis (grade 1). Patient decision. e1 anemia (grade 3); 1 aspartate aminotransferase increase (grade 2); 1 vision blurred (grade 3); 1 troponin T increase (grade 3); 2 ILD (1 grade 1 and 1 grade 2); 1 femur fracture (grade 3); 1 lymphocyte count decreased (grade 3); 4 pneumonitis (1 grade 1, 2 grade 2, and 1 grade 5); 1 amylase increase (grade 3). f1 neutropenia (grade 3); 1 aspartate aminotransferase increase (grade 3). ESMO BC 2022 #1620 Oral 63#64Summary of Efficacy Results in BC Cohorts Confirmed ORR by ICR (ORR, CR + PR) n (%) 95% CI Best overall response, n (%) Cohort 1 HER2+ n = 32a 21 (65.6) 46.8-81.4 Cohort 2 HER2-low n = 16 8 (50.0) 24.7-75.3 3 (9.4) 0 CR PR SD PD NE 18 (56.3) 8 (50.0) 9 (28.1) 4 (25.0) 2 (6.3) 2 (12.5) 0 Median DORb, months (95% CI) Median PFS, months (95% CI) NE (7.9-NE) 11.6 (6.9-NE) 2 (12.5) 5.5 (2.8-8.0) 7.0 (2.3-10.8) Median TTR, months (range) 1.6 (1.2-5.5) Median OS, months (95% CI) NE (20.8-NE) 3.7 (2.6-9.8) 19.5 (2.7-NE) Median treatment duration, months (range) T-DXd Nivolumab 8.9 (1-23)c 5.5 (1-23) 6.9 (1-21) 5.9 (1-14) Daiichi-Sankyo CR, complete response; DOR, duration of response; HER2, human epidermal growth factor receptor 2; ICR, independent central review; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T-DXd, trastuzumab deruxtecan; RDE, recommended dose for expansion. aIncludes 3 patients treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg during part 1. bAmong patients with confirmed CR or PR. COnly includes the 29 patients treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg during part 2. ESMO BC 2022 #1620 Oral 64#65Best Percentage Change in Tumor Size by ICR in BC Cohorts Best Percentage Change in Sum of Diameters From Baseline 20 0 -20 -40 40 00 100 80 ggg -80 -100 HER2-positive Cohort 1 HER2-positive BC (n = 32) Parts 1/2: T-DXd 5.4 mg/kg and Nivolumab 360 mg Best (minimum) Percentage Change n 31 Mean -53.0 SD 33.82 Median -57.0 CR PR Non-CR/PR Treated with T-DXd 5.4 mg/kg in part 1 Min -100 Max 13 Best Percentage Change in Sum of Diameters From Baseline 100- 880 60 40 20 20 0 -20 -40 -60 -80- -100- HER2-low PR Non-CR/PR • Hormone receptor negative Cohort 2 HER2-low BC (n = 16) Part 2: T-DXd 5.4 mg/kg and Nivolumab 360 mg Best (minimum) Percentage Change SD 28.56 n Mean 15 -29.2 Median -35.0 Min -68 Max 54 BC, breast cancer; CR, complete response; HER2, human epidermal growth factor receptor 2; ICR, independent central review; PR, partial response; RDE, recommended dose for expansion; SD, standard deviation; T-DXd, trastuzumab deruxtecan. 2 of 3 patients with HER2-positive BC treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg in part 1 are shown. In cohort 2, 1 of 3 patients who were hormone receptor negative had a confirmed PR. The line at 20% indicates progressive disease, and the line at -30% indicates a PR. ESMO BC 2022 #1620 Oral 65 Daiichi-Sankyo#66Change in Tumor Size over Time in BC Cohorts Change in Sum of Diameters From Baseline, % 100 80 60 60 HER2-positive Treated with T-DXd 5.4 mg/kg in part 1 100- 80 60- HER2-low Hormone receptor negative 40 40 20 20 0 -20 -40 -60 T ד T Change in Sum of Diameters From Baseline, % 40- 20- 0 -20- -40 -60 -80 -80 -100 -100- T T Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Baseline 1 2 3 4 56 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Time From First Dose of Study Drug, months Cohort 1 HER2 positive (n = 32) (part 1/2: T-DXd 5.4 mg/kg and nivolumab 360 mg) Time From First Dose of Study Drug, months Cohort 2 HER2-low (n = 16) (part 2: T-DXd 5.4 mg/kg and nivolumab 360 mg) BC, breast cancer; HER2, human epidermal growth factor receptor 2; T-DXd, trastuzumab deruxtecan. 2 out of 3 patients with HER2-positive BC treated with T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg in Part 1 are shown. 2 out of 3 patients with HER2-low hormone receptor negative BC shown. ESMO BC 2022 #1620 Oral Daiichi-Sankyo 66#67Overall Safety Summary n (%) TEAEs Related to T-DXd Related to nivolumab Grade 23 TEAES Related to T-DXd Related to nivolumab Serious TEAES Related to T-DXd Related to nivolumab TEAEs leading to any study drug discontinuation Related to T-DXd Related to nivolumab TEAEs leading to T-DXd discontinuation Cohort 1 HER2+ n = 29 Cohort 2 HER2-low Overall N = 48a 29 (100) n = 16 16 (100) 48 (100) 26 (89.7) 13 (81.3) 42 (87.5) 24 (82.8) 13 (81.3) 40 (83.3) 15 (51.7) 7 (43.8) 24 (50.0) 10 (34.5) 1 (6.3) 11 (22.9) 8 (27.6) 3 (18.8) 11 (22.9) 12 (41.4) 4 (25.0) 1 (3.4) 0 18 (37.5) 1 (2.1) 2 (6.9) 1 (6.3) 3 (6.3) 14 (48.3) 3 (18.8) 18 (37.5) 9 (31.0) 2 (12.5) 12 (25.0) 7 (24.1) 3 (18.8) 10 (20.8) 12 (41.4) 1 (6.3) 13 (27.1) Related to and leading to T-DXd discontinuation 9 (31.0)d 1 (6.3) 10 (20.8) TEAEs leading to nivolumab discontinuationb 14 (48.3) 2 (12.5) 17 (35.4) Related to and leading to nivolumab discontinuation 7 (24.1)9 2 (12.5)h 9 (18.8) TEAEs leading to T-DXd dose reduction and related to T-DXd TEAEs leading to any study drug interruption 3 (10.3) 0 4 (8.3) 14 (48.3) 8 (50.0) 23 (47.9) 8 (27.6) 3 (18.8) 12 (25.0) Related to T-DXd Related to nivolumab 5 (17.2) 7 (43.8) 13 (27.1) 2 (6.9) 2 (12.5) 5 (10.4) TEAEs associated with death Drug-related 1 (3.4) 0 1 (2.1) Daiichi-Sankyo HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. aIncludes 3 patients treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg during part 1. "Investigator assessed. Unrelated to T-DXd: 1 troponin T increase (grade 3); 1 blood bilirubin increase (grade 3); 1 femur fracture (grade 3). d1 amylase increase (grade 3); 1 anemia (grade 3); 2 ILD (1 grade 1, 1 grade 2); 4 pneumonitis (1 grade 1, 2 grade 2, and 1 grade 5); 1 lichenoid keratosis (grade 3). e1 pneumonitis (grade 1). Unrelated to nivolumab: 1 blood bilirubin increase (grade 3); 1 ILD (grade 1); 1 pneumonitis (grade 2); 1 amylase increased (grade 3); 1 femur fracture (grade 3); 1 anemia (grade 3); 1 aspartate aminotransferase increased (grade 2). 91 troponin T increase (grade 3); 1 lymphocyte count decrease (grade 3); 1 vision blurred (grade 3); 2 pneumonitis (1 grade 1, 1 grade 5); 1 ILD (grade 2); 1 lichenoid keratosis (grade 3). h1 neutropenia (grade 3), 1 aspartate aminotransferase increased (grade 3). 'Drug-related grade 5 ILD/pneumonitis. 13 disease progression; 1 malignant neoplasm progression; 1 ILD/pneumonitis. ESMO BC 2022 #1620 Oral 67#68Adverse Events of Special Interest: ILD/Pneumonitis and LV Dysfunction Overall N = 48c n (%) Adjudicated as Drug-related ILD/Pneumonitisa,b Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade/Total 0 6 (12.5)d 0 0 1 (2.1) 7 (14.6) • Median time to adjudicated onset was 168 days (range, 40-250 days) A grade 3 adjudicated drug-related ILD/pneumonitis event also occurred in 1 patient (25.0%) with BC who received 3.2 mg/kg T-DXd in combination with nivolumab in part 1 LV Dysfunction • In cohort 1, 2 patients (6.9%) experienced an LV dysfunction evente,f • No patients in cohort 2 experienced LV dysfunction BC, breast cancer; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; LV, left ventricular; RDE, recommended dose for expansion; T-DXd, trastuzumab deruxtecan. aCases of potential ILD or pneumonitis were evaluated by an independent adjudication committee that was separate from the response assessment committee. Data shown here are for cases that were deemed drug-related by the adjudication committee. The adjudication committee did not discriminate between T-DXd and nivolumab-related ILD/pneumonitis. Includes all patients with BC who received T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg in parts 1 and 2. d2 grade 1 ILD events by the principal investigator were adjudicated as grade 2. ePer Standardized Medical Dictionary of Regulatory Activities Query of Cardiac Failure and of Myocardial Infarction. f1 asymptomatic ejection fraction decreased (grade 2) and 1 troponin T increased (grade 3). Neither events recovered and 1 patient discontinued treatment. ESMO BC 2022 #1620 Oral Daiichi-Sankyo 68#69Exploratory Biomarker Analysis in BC Cohorts Cohort 1 HER2+ Cohort 2 HER2-low Biomarkera N ORR, % (n, 95% CI) N ORR, % (n, 95% CI) 64.3% PD-L1 TC ≥ 1% Low: 28 Low: 13 (18, 44.1-81.4) 46.2% (6, 19.2-74.9) 100% 50.0% High: 3 High: 2 (3, 29.2-100) PD-L1 IC+ ≥ 5% Low: 17 64.7 % (11, 38.3-85.8) Low: 9 (1, 1.3-98.7) 44.4 % (4, 13.7-78.8) High: 14 71.4 % (10, 41.9-91.6) High: 6 50.0 % (3, 11.8-88.2) 66.7 % PD-L1 IC+ ≥ 1% Low: 12 (8, 34.9-90.1) Low: 6 33.3 % (2, 4.3-77.7) High: 19 68.4 % (13, 43.4-87.4) 55.6 % High: 9 (5, 21.1-86.3) • • Biomarker analyses for cohorts 1 and 2 were performed on baseline new or archival tumor biopsy tissue Antitumor activity with T-DXd plus nivolumab was observed regardless of PD-L1 IHC status BC, breast cancer; HER2, human epidermal growth factor receptor 2; IC, immune cell; IHC, immunohistochemistry; ORR, objective response rate; PD-L1, programmed death ligand 1; TC, tumor cell; T-DXd, trastuzumab deruxtecan. aVENTANA PD-L1 (SP263) assay. ESMO BC 2022 #1620 Oral Daiichi-Sankyo 69#70Daiichi-Sankyo Conclusions • T-DXd 5.4 mg/kg IV Q3W in combination with nivolumab 360 mg Q3W showed antitumor activity consistent with previously reported data for T-DXd monotherapy in patients with HER2-positive BC • • The addition of nivolumab to T-DXd in the late-line setting, however, showed no discernible benefit The data from the small HER2-low BC cohort are insufficient to determine the effects of anti- PD-1/PD-L1 therapy combined with T-DXd in the late-line setting The overall safety profile was generally consistent with previous studies for T-DXd monotherapy in patients with BC, and the addition of nivolumab did not appear to cause any overall increased toxicity • • The incidence of adjudicated ILD/pneumonitis across both cohorts was 14.6% All but 1 ILD/pneumonitis events were low grade (grade 2) An exploratory biomarker analysis showed that patients with HER2-positive and HER2- low BC responded to treatment with T-DXd plus nivolumab regardless of PD-L1 IHC status However, results should be interpreted with caution given the small sample size BC, breast cancer; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ILD, interstitial lung disease; IV, intravenous; ORR, objective response rate; PD-1, PD-L1, programmed death 1; PD-L1, programmed death ligand 1; Q3W, every 3 weeks; TC, tumor cell; T-DXd, trastuzumab deruxtecan. ESMO BC 2022 #1620 Oral • 70 10#71Poster 17 Dose-finding and expansion studies of trastuzumab deruxtecan in combination with other anticancer agents in patients with advanced/metastatic HER2+ (DESTINY-Breast07) and HER2-low (DESTINY-Breast08) breast cancer Fabrice André, MD, PhD; Erika P. Hamilton, MD²; Sherene Loi, MD, PhD³; Seock-Ah Im, MD, PhD; Joohyuk Sohn, MD, PhD5; Ling-Ming Tseng, MD, Carey K. Anders, MD; Peter Schmid, MD, PhD, FRCP; Sarice Boston, PhD; Annie Darilay, PhD; Pia Herbolsheimer, MD, PhD; Adam Konpa, MBA, MPH, MBBS10; Gargi Patel, MD, PhD, BChir, FRCP11; Magdalena Wrona, PharmDev 10 Shoubhik Mondal, PhD; Komal L. Jhaveri, MD, FACP12 1Gustave Roussy, Université Paris-Sud, Villejur, France; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN "Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; *Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; "Yonse Cancer Center, Seoul, Republic of Korea; *Talpel Veterans General Hospital. Talpel, Talwan: "Duke Cancer Institute, Durham, NC; "Barts Cancer Institute, Centre for Experimental Cancer Medicine, London, UK; "AstraZeneca Pharmaceuticals LP, Gaithersburg, MD, 10AstraZeneca, Warsaw, Mazowieckie, Poland; "AstraZeneca Pharmaceuticals LP, Cambridge, UK; Memorial Sloan Kettering Cancer Center, New York, NY Introduction ⚫ T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload1.2 ⚫ T-DXd is approved in the US for patients with unresectable or metastatic HER2+ breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy³ o T-DXd is also approved in multiple countries for patients with unresectable or metastatic HER2+ breast cancer with 22 prior anti-HER2-based therapies+ . In the phase 3 DESTINY-Breast03 trial, T-DXd has shown lower risk of disease progression or death vs T-DM1 in patients with HER2+ metastatic breast cancer previously treated with trastuzumab and a taxane T-DXd demonstrated preliminary antitumor activity in patients with HER2-low advanced/metastatic breast cancer in a phase 1 trial and improved PFS and OS vs physician's choice of chemotherapy in patients with HER2-low unresectable and/or metastatic breast cancer in the phase 3 DESTINY-Breast04 trial? • Combinations of T-DXd with anticancer therapies are being assessed in 2 ongoing, open-label, multicenter, modular clinical trials in patients with advanced/metastatic HER2+ breast cancer (DB-07) or HER2-low-expressing breast cancer (DB-08) Each trial has a dose-finding phase (part 1) and a dose-expansion phase (part 2) © Here we report preliminary results from the dose-finding phase of DB-07 (module 2: T-DXd+pertuzumab) and DB-08 (module 4: T-DXd + anastrozole; module 5: T-DXd + fulvestrant), including safety and RP2D (DB-07)/ recommended doses for expansion (DB-08) Methods Data are reported for the following part 1 modules of DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773; Figures 1 and 2) © DB-07 module 2: T-DXd 5.4 mg/kg Q3W+pertuzumab 420 mg Q3W (pertuzumab loading dose: 840 mg) ⚫ DB-08 module 4: T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily • DB-08 module 5: T-DXd 5.4 mg/kg Q3W + fulvestrant 500 mg Q4W (fulvestrant loading dose: 500 mg on C1D15) The part 1 primary objective was to assess safety and tolerability and determine the RP2D/recommended doses for expansion according to the modified toxicity probability interval-2 algorithm • Study design details (parts 1 and 2) can be found in the supplemental materials using the QR code Figure 1. DB-07 study design (part 1) Part 1: Dose findinga Population ⚫ HER2+ (IHC 3+ or IHC 2+/ISH+) advanced/unresectable or metastatic breast cancer • ≥1 prior treatment line in the metastatic setting Patents in *The doses administered in the part-2 expansion phase will be based on the RP20s determined in part 1. Patents were followed up beyond the 21-day in a pesarate study (BEGONIA; NCT03742102) es in modue 2 ved the 2 received spuma loading dose of an Figure 2. DB-08 study design (part 1) Part 1: Dose finding Population • HER2-low (IHC 1+ or IHC 2+/ISH-) advanced/metastatic breast cancer Modules 1 to 3: HR+ or HR- • Modules 4 and 5: HR+ ⚫HR+ patients: 21 prior line of endocrine therapy® and 21 prior line of chemotherapy for metastatic disease • HR- patients: ≥1 prior line of chemotherapy for metastatic disease *The doses administered in the part-2 expansion phase will be based on the recommended dose for expansion determined in part 1. Patients were folowed up beyond the 21-day DLT period (28 days for T-xd+vestrant) for safety events. With or without a targeted therapy (such as CDK4/6, mTOR, or PBK inhibitors) Patients in module 5 received a fulvestrant leading dose of 500 m on CID15 Module 1: T-DXd + durvalumab Module 2: T-DXd 5.4 mg/kg Q3W+pertuzumab 420 mg Q3W (data cutoff: October 15, 2021) Module 3: T-DXd + paclitaxel Module 4: T-DXd + durvalumab + paclitaxel Module 5: T-DXd + tucatinib O Module 1: T-DXd+capecitabine Module 2: T-DXd + durvalumab + paclitaxel Module 3: T-DXd+capivasertib Module 4: T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily (data cutoff: January 20, 2022) Module 5: T-DXd 5.4 mg/kg Q3W + fulvestrant 500 mg Q4Wc (data cutoff: January 20, 2022) Primary objectives and endpoints for part 1 -Safety, tolerability, and RP2D assessed by AES, serious AEs, DLTs, and laboratory findings Primary objective and endpoints for part 1 • Safety, tolerability, and recommended dose for expansion assessed by AES, serious AEs, DLTs. and laboratory findings aiichi-Sankyo Objective •The primary objective of part 1 of the ongoing DESTINY-Breast07 (DB-07) and DESTINY-Breast08 (DB-08) clinical trials is to investigate the safety and tolerability and determine the recommended phase 2 dose (RP2D; DB-07) and recommended doses for expansion (DB-08) of combinations of T-DXd with anticancer therapies in patients with HER2+ breast cancer (DB-07) or HER2-low-expressing breast cancer (DB-08) Conclusions •For the following T-DXd combination therapies, the RP2D (DB-07) and recommended doses for expansion (DB-08) were the standard doses for breast cancer for each individual drug: ⚫ DB-07: T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W (pertuzumab loading dose: 840 mg) • DB-08: T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily DB-08: T-DXd 5.4 mg/kg Q3W + fulvestrant 500 mg Q4W (fulvestrant loading dose: 500 mg on C1D15) •These doses of these T-DXd combination regimens were well tolerated and will serve as the doses for further evaluation in part 2 ⚫DB-07 (NCT04538742) and DB-08 (NCT04556773) are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway Plain language summary 600 Why did we perform this research? Some breast cancers have high levels of the HER2 protein (HER2+) and some have lower levels (HER2 low). T- DXd is an anticancer drug designed to target and kill cancer cells that express HER2.1. It is being studied for the treatment of HER2+ breast cancer³ and HER2-low-expressing breast cancer. 4.5 We wanted to find out if T-DXd can be used to treat HER2+ and HER2-low-expressing breast cancer in combination with other drugs that are already used to treat breast cancer and experimental drugs that could potentially be used to treat breast cancer. How did we perform this research? In the ongoing DESTINY-Breast07 and DESTINY-Breast08 trials, we are assessing T-DXd by itself and in combination with other anticancer drugs in patients with HER2+ (IHC 3+ or IHC 2+/ISH+) and HER2-low- expressing (IHC 1+ or IHC 2+/ISH-) breast cancer, respectively. In part 1 of both trials, we are assessing the safety of different doses of each combination treatment; results will be used to decide what dose to use for each combination in part 2. In part 2, we will further assess how safe and effective these drug combinations are for treating patients with HER2+ or HER2-low-expressing breast cancer. What were the findings of this research and what are the implications? In part 1 of DESTINY-Breast07, 7 patients were treated with T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W (pertuzumab loading dose: 840 mg). In part 1 of DESTINY-Breast08, 6 patients each were treated with T-DXd 5.4 mg/kg Q3W combined with either anastrozole 1 mg daily or fulvestrant 500 mg Q4W (fulvestrant loading dose: 500 mg on day 15 of cycle 1). These preliminary results show that T-DXd can be combined with pertuzumab, anastrozole, or fulvestrant. These doses were determined to be the recommended doses to use in part 2 of these trials, where their safety and efficacy (antitumor activity) will be evaluated further. T-DXd combined with other anticancer drugs is also being assessed in both trials. Where can I access more information? DESTINY-Breast07: ClinicalTrials.gov. A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (DB-07). https://clinicaltrials.gov/ct2/show/NCT04538742 DESTINY-Breast08: ClinicalTrials.gov. A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer (DB-08). https://clinicaltrials.gov/ct2/show/NCT04556773 These studies were funded b AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization colaboration agreement with Dalichi Sankyo for T-DXd (DS-8201). References: 1. Nakada T, et al. Chem Pharm BUN (Tokyo). 2019;67(3):173-185.2.0 2. ograni Y, et al. Cin cancer Res. 2016,22,20:5097-5108. 3. Cortes J, et al. N Engl J Med. 2022 386(12):1143-1154. 4. Modi S, et al. J Can Oncol. 2020;38(17):1887-1896. 5. AstraZeneca. News release. Accessed March 31, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-improves-prs-and- -in-her-low-ohmitt-text-Positive20high%20level%20re20from Poster Plain language summary Supplementary material (Study design details, parts 1 and 2) Please scan this quick response (QR) code with your smartphone camera or app to obtain a copy of these materiale. Alternatively, please click on the link below. https://bit.ly/3uF7Wej Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster. This presentation is the intellectual property of the authors/presenter. Please contact Dr Fabrice André at [email protected] for permission to reprint and/or distribute. Poster presented at ASCO Annual Meeting, June 3-7, 2022; Chicago, IL, and virtual. Corresponding author email address: FABRICE [email protected] . Results and interpretation DB-07 part 1: T-DXd + pertuzumab Patients As of the data cutoff, 7 patients were assigned to the T-DXd + pertuzumab module and received the initial dose level (Table 1) о Treatment ongoing: n=5 (71.4%) о Treatment discontinued: n=2 (28.6%; discontinued both T-DXd and pertuzumab) Withdrawal by patient: n=1 (14.3%) AE: n=1 (14.3%; ejection fraction decreased) Treatment duration is reported in Figure 3 Table 1. Patient demographics and disease characteristics Age, mean (range), years Female, n (%) Race, n (%) Asian HER2 status, n (%) IHC 3+ IHC 2+/ISH+ N=7 . 54.3 (38-66) 7 (100.0) Dose modifications: T-DXd+pertuzumab DB-08 part 1: T-DXd + anastrozole and T-DXd + fulvestrant Patients T-DXd+anastrozole • As of the data cutoff, 6 patients were assigned to the T-DXD + anastrozole module and received the initial dose level (Table 3) Treatment ongoing: n-3 (50.0%) Dose modifications: T-DXd + fulvestrant Patients with: Patients with: ≥1 dose delaya 21 dose reduction ≥1 dose delay ≥1 dose reduction ≥1 dose interruption Treatment discontinued: n=3 (50.0%; discontinued both T-DXd and anastrozole) T-DXd 2 (33.3) Reason: AE (n=1) other (n=2) 3 (50.0%) 1 (14.3%) 1 (14.3%) T-DXd 0 Reason: other' Reason: AE Fulvestrant 0 0 Dose modifications not allowed per protocol 0 Pertuzumab *Evaluation for potential pneumonits * Grade 3 platelet count decreased. Safety ° objective disease 21 dose interruption 0 Six patients were evaluable for DLTS (1 was not evaluable for DLTS due to using G-CSF for grade 3 neutropenia); no DLTs were reported - Objective disease progression: n=2 (33.3%) Clinical disease progression: n=1 (16.7%) T-DXd+fulvestrant As of the data cutoff, 6 patients were assigned to the T-DXd+ fulvestrant module and received the initial dose level o Treatment ongoing: n=5 (83.3%) Treatment discontinued: n=1 (16.7%; discontinued T-DXd due to AE [pneumonitis] and fulvestrant due progression) Treatment duration is reported in Figure 4 Table 3. Patient demographics and disease characteristics Reason: AE (n=3)d Dose modifications not allowed per protocol 1 (16.7%) Reason: other *Reasons for dose delays were not mutually exclusive; patients with multiple dose delays were counted only once per category. Nausea (vas updated from a dose interruption after the data cutor). Public holiday (n-1) and assessment of possible disease progression (n=1; was updated from a dose interruption after the data cutof). "Nausea (n-2) and platelet count decreased (n-1). Assessment of possible disease progression Safety . All patients were evaluable for DLTS; no DLTs were reported in either module Both combination treatments were generally well tolerated (Table 4) T-DXd+ anastrozole One patient (16.7%) died 226 days after the first dose due to disease progression; no patients had ILD/pneumonitis T-DXd+fulvestrant No patients died; 1 patient (16.7%) experienced drug-related ILD/pneumonitis outside the 28-day DLT cycle . . The combination treatment was generally well tolerated (Table 2) There were no deaths; no patients experienced ILD/pneumonitis 6 (85.7) T-DXd+ anastrozole N=6 T-DXd+ fulvestrant N=6 . White 1 (14.3) Table 2. Safety with RP2D Age, mean (range), years 57.7 (47-71) Patients, n (%) N=7 Primary tumor location at diagnosis, n (%) Breast Female, n (%) 6 (100.0) 59.0 (46-74) 6 (100.0) Any AE 7 (100.0) 7 (100.0) Race, n (%) Any grade 23 AE 3 (42.9) Asian 6 (100.0) 4 (66.7) Hematologic White 0 2 (33.3) 5 (71.4) Neutrophil count decreased 2 (28.6) Primary tumor location, n (%) Patients, n (%) Table 4. Safety with recommended doses for expansion T-DXd+ anastrozole T-DXC + fulvestrant 1 (14.3) White blood cell count decreased 2 (28.6) N=6 N=6 Breast 6 (100.0) 6 (100.0) Anemia 1 (14.3) Any AE 6 (100.0) 6 (100.0) Missing 1 (14.3)a HER2 status, n (%) Febrile neutropenia 1 (14.3) ECOG performance status, n (%) IHC 2+/ISH- 3 (50.0) 4 (66.7) Any grade ≥3 AE 2 (33.3) 3 (50.0) Platelet count decreased 1 (14.3) IHC 1+ 3 (50.0) 2 (33.3) Hematologic 0 4 (57.1) Non-hematologic ECOG performance status, n (%) Anemia 2 (33.3) 1 (16.7) 1 3 (42.9) Ejection fraction decreased. 1 (14.3) 0 5 (83.3) 4 (66.7) Hypokalemia 1 (14.3) 1 1 (16.7) 2 (33.3) Platelet count decreased Non-hematologic 0 1 (16.7) Serious AEs 1 (14.3) AEs leading to treatment discontinuation Femoral neck fracture 1 (14.3) 1 (16.7) 0 Hypokalemia 1 (16.7) 1 (16.7) 7.5 (range, 3-11) months Nausea 0 1 (16.7) 7.0 (range, 2-11) months Serious AEs 2 (33.3) 1 (16.7) 7.5 (range, 7-10) months AEs leading treatment discontinuation 0 1 (16.7) AEs of special interest 8.0 (range, 7-10) months ILD/pneumonitis Deaths 0 1 (16.7) 1 (16.7)e 0 ore patient (16.7%) "The HER2 status for this patient was missing at the time of the data cutoff and was later confirmed to be HC 3- Figure 3. Median actual treatment duration" T-DXd+ pertuzumab (N=7) T-DXd Pertuzumab *Dose delays were excluded in the analysis of actual treatment duration. Acknowledgments AES of special interest ILD/pneumonitis 7.6 (range, 2.8-7.7) months Left ventricular ejection fraction decreased Deaths 7.3 (range, 2.8-7.7) months We thank the patents who are participating in these studies as well as their families and caregivers These studies are sponsored by AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daichi Sankyo for trastuzumab derurtecan (T-DXd; DS-8201) The authors thank Tinghul Yu, PhD (formerly an employee of AstraZeneca) and Caron Lloyd AstraZenecal for their contributions to this work. Medical wrting support was provided by Christopher Edwards, PhD, CMPP (Articulate Science, LLC), and was unded by Aazeneca References 1. Natada T, et al. Chem Pram Bull (Tokyo). 2010;67(2):172- Cortes et al. N Engl J Med. 2022,206(12):1142-1154 2 Ogitani Y, et al. Clin Cancer Res. 2016;22(205097-5108 3. Ennertu (tan-trastuzumat deruxtecan-Prescribing Information Dalich Sankyo, Inc: 2022 4 Enhertu (trastuzumab denate car) Summary of product characteristics. Daichi Sankyo Europe GmbH; 2021. 6. Nodi S, et al. J Clin Oncol. 2020;38(17):1887-1896 7. AstraZeneca. News release. Accessed March 31, 2022 hps://www.asazeneca.commedia centrepress releases/2022 entertu-improves-pfs-and-os-in-her-low- bc.mtext-Positive%20high%20level%209620from 8. Guo W, et al. Contemp Clin Titals. 2017;58:23-33 Figure 4. Median actual treatment duration² 0 T-DXd 1 (14.3) T-DXd+ anastrozole (N=6) Anastrozole 0 T-DXd Fulvestrant *Febrile neutropenia. One patient (14.3%) experienced a nonserous AB AE of rade 3 election fraction decreasect it was considered related to T-DX but not to pertuzumab, led to discontinuation of T-Dxd and pertuzumab, and was not resolved by the data cutof RP2D was TDXd+ fulvestrant (5=N T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W (pertuzumab loading dose: 840 mg) Abbreviations AE, adverse event, C. cycle; COK, cyclin-dependent kinase; D, day; DB-17, DESTINY-Breast 7; DB-08, DESTINY-Breast08; DLT, dose-limiting toxicity: ECOG. Fastem Cooperative Oncology Group: G-CSF. granulocyte-colony stimulating factor: HER2, human epderma growth factor receptor 2; HR, hormone receptor, IHC, Immunohistochemistry; ILD, interstal lung disease; ISH, In situ hybridization: mTOR, mechanistic target of momych kinase Os overal survival: PFS progression three survival: P phosphoinositide 3-kinase; Q3W, every 3 weeks; Q+W, every weeks, RF2D, recommended phase 2 dose, T-DX, deurtean; T-DM1, trastuzumab emtansine *Dose delays and interruptions were excuded is the analysis of actual treatment duration Dose modifications: T-DXd + anastrozole Patients with: Disclosures Fabrice André reports travel, accommodations, and/or expenses from Novartis, Roche, GSK, and AstraZeneca; stock and other ownership interests in regacy and research funding from Novaras, Roche, Arazeneca, Pitzer,uty, and palchi sankyo 0 21 dose delaya ≥1 dose reduction ≥1 dose interruption T-DXd 4 (66.7%) Reasons: AE (n=3);" other (n=1) 0 Dose modifications 2 (33.3%) Reason: AE (n=2) not allowed per protocol 1 (16.7%) Reason: AE Anastrozole *Reasons for dose delays were not mutually exclusive in patients who had mutiple dose delays; patients were counted only pricamont (n-1) Medication error (1) once per category. Anemia (1), femoral nech fracture (1), and vomiting and prica Vomiting and pneumonies (n-1) and nasopharyngitis (n-1). "Nasopharyngitis entenced a serious AES, vomiting and anemia; neither were considered related to study arug patient delayed TOXd and anastrozole treatment due to the vomitsa: the patient had eered related to stay aras, the anemia had not resolved by the data cutoff. One (16.7%) patient experienced a serious AE of femoral neck fracture that was not considered related to study drugs: the patentdel ntdelayed T-DX treatment and the event was not resolved by the data cutoff. One patient (16.7%) experienced a serious AE of seizure that was not considered related to study drugs; the seizure hadresolved by the data cutoff. Pneumonits. Occurred outside 20-day DLT period. Due to disease progression, 226 days after frat doss Recommended doses for expansion were T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily and T-DXd 5.4 mg/kg Q3W+ fulvestrant 500 mg Q4W (fulvestrant loading dose: 500 mg on C1D15) 71#72Datopotamab deruxtecan + durvalumab as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer Initial results from BEGONIA, a phase 1b/2 study Peter Schmid, FRCP, MD, PhD Barts Cancer Institute, Queen Mary University of London, London, UK K. H. Jung, P. J. Wysocki, 2 J. Jassem, ³ C. X. Ma, 4 R. Fernandes, 5 R. Huisden, 6 R. Stewart, 6 P. Vukovic, 6 A. Tablante Nunes, 7 Z. Nowecki8 1Asan Medical Center - University of Ulsan, College of Medicine, Seoul, Korea; 2Jagiellonian University - Medical College, Krakow, Poland; 3 Medical University of Gdańsk, Gdańsk, Poland; 4Washington University School of Medicine, St. Louis, MO, USA; 5Schulich School of Medicine & Dentistry, Western University, London Health Sciences Centre, London, Canada; 6AstraZeneca, Cambridge, UK; AstraZeneca, Gaithersburg, MD, USA; ³Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland ESMO BC 2022 #166 Mini Oral On behalf of the investigators Daiichi-Sankyo 22 72#73Background Combining immune checkpoint inhibitors with 1st-line chemotherapy improves outcomes in patients with advanced/metastatic triple-negative breast cancer (a/mTNBC), but only in PD-L1-positive disease 1.2 ◆ Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC) with topoisomerase | inhibitor payload, demonstrated promising antitumor activity as monotherapy in heavily pretreated patients with recurrent a/mTNBC³ BEGONIA is an ongoing 2-part, open-label platform study evaluating durvalumab, an anti-PD-L1 antibody, combined with other therapies, including ADCs, as 1st-line treatment of a/mTNBC in a biomarker unselected population - - In the paclitaxel + durvalumab arm, a confirmed ORR of 58.3% was demonstrated and responses were durable (median PFS: 7.3 mos., 95% CI 5.4-13.8)4, consistent with reported response rates for immune checkpoint inhibitors in first-line mTNBC and independent of PD-L1 status. In the trastuzumab deruxtecan + durvalumab arm, a confirmed ORR of 66.7% was demonstrated, with 87.5% of patients remaining in response at time of data cutoff We report preliminary results with Dato-DXd + durvalumab in BEGONIA, the first data with this novel combination in patients with newly diagnosed a/mTNBC 1. Cortes J, et al. Lancet. 2020,396(10265): 1817-1828. 2. Emens LA, et al. J Natl Cancer Inst. 2021;113(8):1005-1016. 3. Krop I, et al. Cancer Res. 2022;82(Suppl 4):GS1-05. ESMO BC 2022 #166 Mini Oral PD-L1, programmed cell death ligand-1; TROP2, trophoblast cell-surface antigen 2. Daiichi-Sankyo 4. Schmid P, et al. Presented at 2021 SABCS Annual Meeting, Poster PD 10-03. 5. Schmid P, et al. Presented at 2021 ASCO Annual Meeting, Poster 1023. 73#74BEGONIA (NCT03742102) Study Design Females aged ≥18 years Unresectable a/mTNBC No prior treatment for Stage IV TNBC ≥12 months since prior taxane therapy ECOG PS 0-1 Adequate organ function Measurable disease per RECIST v1.1 No prior treatment with checkpoint inhibitor or TOPO I-based ADCa First 20 patients Part 1 (this presentation includes results from part 1) Paclitaxel Durvalumab (P + D) (N=20) Dato-DXd+Dc (N=30) Q3W until PD Capivasertib +P+D (N=30) All others randomized to an open cohort Oleclumab +P+D (N=30) T-DXd+D (N=30) Randomized Each novel combination cohort Primary endpoint: Safety and tolerability Secondary endpoints: ORR, PFS, DOR, OS Part 2 expansion (currently active/ongoing) Dato-DXd + Db Q3W until PD if multiple cohorts open T-DXd + D Daiichi-Sankyo Simon 2-stage futility analysis for Part 2 expansion Enroll additional 27 patients in each arm Primary endpoint: ORR Secondary endpoints: PFS, DOR, PFS6, OS Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral *ADC-cohort-specific criteria. Dato-DXd 6 mg/kg + D 1120 mg. "Novel treatment combinations may enter Part 2 expansion if confirmed ORR is at least 57%. ADC, antibody-drug conjugate; a/mTNBC, locally advanced/metastatic triple negative breast cancer; DLT, dose-limiting toxicity; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance scale; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PD, progressive disease; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; T-DXd, trastusumab deruxtecan; TOPO I, topoisomerase I. 74#75Disposition and Baseline Characteristics Dato-DXd + D 29 patients treated 5 (17%) discontinued all treatmenta 2 (7%) disease progression 2 (7%) had an adverse event 2 (7%) other 24 (83%) treatment ongoing Median follow-up: 3.9 (range, 2-6) months Characteristic Age, median (range), years No prior treatment, n (%) Prior treatments for early-stage disease, n (%) Radiotherapy Cytotoxic chemotherapy Taxane Anthracycline Platinum compound Hormonal therapy Targeted therapy Visceral metastases, b n (%) Lymph node metastasis, n (%) PD-L1 expression©, n (%) High (≥5%) Low (<5%) Unknown Missing N=29 51 (33-72) 9 (31) 17 (59) 19 (66) 14 (48) 16 (55) 5 (17) 6 (21) 2 (7) 20 (69) 22 (76) 5 (17.2%) 21 (72.4%) 3 (10.3%) Daiichi-Sankyo Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral aPatients may have discontinued for more than 1 reason. "Defined as liver/hepatic and/or respiratory metastases. <PD-L1 expression was assessed by immunohistochemistry using the VENTANA PD-L1 (SP263) Assay. PD-L1 expression was defined as "high" if 25% of the tumor area was populated by PD-L1 expressing tumor or immune cells, otherwise it was defined as "low". a/mTNBC, locally advanced/metastatic triple negative breast cancer, PD-L1, programmed cell death ligand-1; TROP2, trophoblast cell-surface antigen 2. 75#76Antitumor Responses Best change from baseline in target lesion size (%) 100. N=29 50- 0. -50- -100- I Patients evaluable for confirmed response" 27 Confirmed ORR, n (%) 20 (74) 95% CI CR, n (%) PR, n (%) 54-89 2 (7) 18 (67) † Daiichi-Sankyo ◆ Confirmed ORR was observed in 20/27 (74%) patients Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral "Had the opportunity to have 2 postbaseline scans. Dotted lines indicate thresholds for partial response (-30%) and progressive disease (20%). *If the best percentage change from baseline of target lesions cannot be calculated due to progression, withdrawal, or death, the value is imputed at +20%. ".*" Patients with PD as best overall response. †CR with lymph node disease (CR per RECIST in lymph nodes, is <10mm) | Unconfirmed response. CR, complete response; ORR, objective response rate; PR, partial response. 76#77Antitumor Responses Responses observed regardless of PD-L1 expression Best change from baseline in target lesion size (%) 100- N=29 50- 0 -50- -100- Patients evaluable for confirmed response" Confirmed ORR, n (%) 27 20 (74) 95% CI 54-89 CR, n (%) 2 (7) PR, n (%) 18 (67) + t Daiichi-Sankyo ◆ Confirmed ORR was observed in 20/27 (74%) patients PD-L1 expression (TAP 5% cutoff): Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral High ILow aHad the opportunity to have 2 postbaseline scans. Unknown/Missing Dotted lines indicate thresholds for partial response (-30%) and progressive disease (20%). *If the best percentage change from baseline of target lesions cannot be calculated due to progression, withdrawal, or death, the value is imputed at +20%. "." Patients with PD as best overall response. †CR with lymph node disease (CR per RECIST in lymph nodes, is <10mm). ‡ Unconfirmed response. CR, complete response; ORR, objective response rate; PR, partial response. 77#78Antitumor Responses 100 Change in target lesion from baseline (%) -50 0 50 50 -100 0 6 12 Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral 18 Time (weeks) Daiichi-Sankyo Complete response Partial response Stable disease RECIST Progression New lesion Median follow-up: 3.9 months ◆ Median time to response was 1.4 mos. (95% CI, 1.35-1.58) ◆ All patients with a response had an ongoing response at data cutoff ◆ Median duration of response was not reached 24 30 50 36 36 Dotted lines indicate thresholds for partial response (-30%) and progressive disease (20%). 78#79Safety Summary No dose limiting toxicities Patients, n (%) Any grade AEs Grade 3/4 Any grade treatment-related AEs Grade 3/4 Dose adjustments Dato-DXd dose reduction a Dato-DXd dose delay Durvalumab dose delay Serious AEs AEs leading to death AEs leading to discontinuation of all treatments Data cutoff: November 15, 2021 ESMO BC 2022 #166 Mini Oral Dato-DXd + D N=29 29 (100) 8 (28) 27 (93) 8 (28) 4 (14) 1 (3) 4 (14) 5 (17) 1 (3)b 2 (7) Daiichi-Sankyo a All 4 Dato-DXd dose reductions were due to stomatitis. b One patient died due to hypotension unrelated to treatment. c Includes 1 case of anaphylactic reaction and 1 case of troponin increase. 12 79#80Most Reported Adverse Events (≥15% all grades) Preferred term, n (%) AEs all causes Dato-DXd + D N=29 All Grades, Grade Grade Grade ≥15% of patients 1 2 3 Stomatitis 20 (69) 8 (28) 8 (28) 4 (14) 13 Alopecia 19 (66) 6 (21) 0 (45) 13 Nausea 19 (66) 6 (21) (45) Constipation 11 (38) 8 (28) 3 (10) Fatigue 11 (38) 9 (31) 2 (6.9) Rash 9 (31) 8 (28) 1 (3) 0 Vomiting 5 (17) 3 (10) 2 (6.9) 0 Data cutoff: November 15, 2021 0 O O O 0 0 ◆ Low rates of diarrhea reported (4 [14%]; all Grade 1) Daiichi-Sankyo ◆ No cases of ILD/pneumonitis or neutropenic events were reported ◆ 13.7% of patients required dose reduction due to stomatitis ◆ Updated TMGs and prophylaxis for stomatitis are being implemented ILD, interstitial lung disease; TMG, trial management guide. ESMO BC 2022 #166 Mini Oral 80 60#81Conclusions Daiichi-Sankyo Preliminary results of BEGONIA show that Dato-DXd + durvalumab demonstrated a robust response rate in first line a/mTNBC in a biomarker-unselected population - - Confirmed ORR was 74%, with all patients ongoing response at the time of data cut-off Responses were observed regardless of PD-L1 expression The combination of Dato-DXd + durvalumab had a manageable safety profile consistent with the known profile of the individual agents, with no new safety signals - No dose-limiting toxicities - Stomatitis and low-grade nausea and alopecia were the most frequent AEs - · Low rates of diarrhea, and no cases of ILD/pneumonitis or neutropenic events, were reported Enrollment to Part 2 Dato-DXd + durvalumab arm is currently ongoing; follow-up continues in order to determine duration of response and PFS/OS ESMO BC 2022 #166 Mini Oral a/mTNBC, locally advanced/metastatic triple negative breast cancer; Dato-DXd, datopotamab deruxtecan; ORR, objective response rate. 81#82Results From the Phase 1/2 Study of Patritumab Deruxtecan, a HER3-Directed Antibody-Drug Conjugate (ADC), in Patients With HER3-Expressing Metastatic Breast Cancer lan E. Krop, 1 Norikazu Masuda,2 Toru Mukohara,3 Shunji Takahashi,4 Takahiro Nakayama,5 Kenichi Inoue,6 Hiroji Iwata, 7 Tatsuya Toyama,8 Yutaka Yamamoto,9 Damien Hansra, 10 Masato Takahashi, 11 Akihiko Osaki, 12 Kumiko Koyama, 13 Tatsuya Inoue, 14 Takatoshi Yonekura, 13 Joseph Mostillo, 15 Shoichi Ohwada, 13 Yoshimi Tanaka, 13 David Sternberg, 15 Kan Yonemori 16 1 Yale University, Hartford, CT; 2 Nagoya University Graduate School of Medicine, Nagoya, Japan; 3 National Cancer Center Hospital East, Kashiwa, Japan; 4 The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5 Osaka International Cancer Institute, Osaka, Japan; 6 Saitama Cancer Center, Saitama Japan; 7 Aichi Cancer Center Hospital, Nagoya, Japan; 8 Nagoya City University, Nagoya, Japan; 9 Kumamoto University Hospital, Kumamoto, Japan; 10 Piedmont Physicians Medical Oncology, Fayetteville, GA; 11 National Hospital Organization, Hokkaido Cancer Center, Sapporo, Japan; 12 Saitama Medical University International Medical Center; Hidaka, Japan; 13 Daiichi Sankyo Co., Ltd., Tokyo, Japan; 14 Daiichi Sankyo RD Novare Co., Ltd., Edogawa-Ku, Japan; 15 Daiichi Sankyo, Inc., Basking Ridge, NJ; 16 National Cancer Center Hospital, Tokyo, Japan ASCO 2022 #1002 Oral On behalf of the investigators 82 22 Daiichi-Sankyo#83Patritumab Deruxtecan (HER3-DXd) • HER3-DXd is an ADC with 3 components 1-6: • • A fully human anti-HER3 IgG1 mAb (patritumab), covalently linked to A topoisomerase I inhibitor payload, an exatecan derivative, via A tetrapeptide-based cleavable linker 7 Key Attributes of HER3-DXd Payload mechanism of action: topoisomerase I inhibitor a,1-4 High potency of payload a,1-4 Human anti-HER3 IgG1 mAb1-4 Deruxtecan 1-4 High drug to antibody ratio = 8 a,1,2 Payload with short systemic half-life a,b,2,3 NH H Stable linker-payload a,2-4 H3C- HO-CH3 Cleavable Tetrapeptide-Based Linker Tumor-selective cleavable linker a,1-5 Topoisomerase I Inhibitor Payload (DXd) Bystander antitumor effect a,2,6 HER, human epidermal growth factor receptor; IgG1, immunoglobulin G1; mAb, monoclonal antibody. a The clinical relevance of these features is under investigation. b Based on animal data. 1. Hashimoto Y, et al. Clin Cancer Res. 2019;25:7151-7161. 2. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 3. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 4. Koganemaru S, et al. Mol Cancer Ther. 2019;18:2043-2050. 5. Haratani K, et al. J Clin Invest. 2020;130(1):374-388. 6. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039-1046. ASCO 2022 #1002 Oral Daiichi-Sankyo 83#84Background · • HER3 is overexpressed in many types of cancer, including 30% to 50% of breast cancers Overexpression of HER3 in breast cancer is associated with poor prognosis 4,5 • No HER3-directed therapies have been approved for the treatment of any cancer Daiichi-Sankyo • . U31402-A-J101 (NCT02980341/JapicCTI-163401) is an ongoing phase 1/2 study of HER3-DXd in patients with HER3-expressing metastatic breast cancer Early data from the dose escalation, dose finding, 6 and dose expansion parts showed promising antitumor activity and a manageable safety profile in heavily pretreated patients • Here we report mature data across all study cohorts, providing consolidated data among patients with a range of breast cancer subtypes • As of the August 16, 2021, data cutoff, the median follow-up for all patients was 31.9 months (range, 15-56 months) BC, breast cancer. 1. Naidu R, et al. Br J Cancer. 1998;78(10):1385-1390. 2. Travis A, et al. Br J Cancer. 1996;74(2):229-233. 3. Kogawa T, et al. ASCO 2018. Poster 2512. 4. Witton CJ, et al. J Pathol. 2003;200(3): 290-297. 5. Ocana A, et al. J Natl Cancer Inst. 2013;105(4):266-273. 6. Masuda N, et al. SABCS 2018. Poster PD1-03. 7. Krop IE, et al. SABCS 2020. Poster PD1-09. ASCO 2022 #1002 Oral 84 ==#85Study Design Daiichi-Sankyo Patritumab Deruxtecan: U31402-A-J101 KEY ELIGIBILITY CRITERIA Advanced/unresectable or metastatic breast cancer HER3-positivea DE/DF & HR+/HER2- DEXP •≥2 and ≤6 lines of prior chemotherapy; ≥2 for advanced disease Dose expansion: TNBC . • 1 to 2 prior chemotherapy regimens for advanced disease Dose Escalation (DE)b Any BC Subtype Dose Finding (DF) Any BC Subtype 8.0 mg/kg IV Q3W n=6 6.4 mg/kg IV Q3W n=15 4.8 mg/kg IV Q3W n=15 3.2 mg/kg IV Q3W n=3 4.2 mg/kg IV Q2W x 3 cycles then 6.4 mg/kg IV Q3W (n=12) | 1.6 mg/kg IV Q3W n=3 Data for all 3 phases were pooled • • 3.2 4.8 6.4 mg/kg Q3W then 6.4 mg/kg Q3W (n=12) Dose Expansion (DEXP) HER3-High HR+/HER2- 6.4 mg/kg IV Q3W (n=31) 4.8 mg/kg IV Q3W (n=33) TNBC 6.4 mg/kg IV Q3W (n=31) HER3-Lowc HR+/HER2- 6.4 mg/kg IV Q3W (n=21) Efficacy is reported by BC subtype: HR+/HER2- (n=113) TNBC (n=53), and HER2+ (n=14) Safety is reported for patients who received HER3-DXd 4.8 mg/kg (n=48), 6.4 mg/kg (n=98), and all patients (N=182d) DE, dose escalation; DEXP, dose expansion; DF, dose finding; EWOC, escalation with overdose control; HR, hormone receptor; IHC, immunohistochemistry; mCRM, modified continuous reassessment method; Q2W, once every 2 weeks; Q3W, once every 3 weeks; R, randomized; TNBC, triple-negative breast cancer. a HER3 status was determined by IHC; HER3-positive was defined as IHC 2+ and IHC 3+ for DE/DF cohorts and as ≥25% membrane positivity at 10x for DEXP cohorts. b Guided by mCRM with EWOC. CHER3- high was defined as >75% membrane positivity at 10x; HER3-low was defined as ≥25% and ≤75% membrane positivity at 10x. d Includes two patients with unknown BC subtype. ASCO 2022 #1002 Oral 55 85#86Baseline Characteristics Median age (range), years Country, % ECOG PS, % Japan HR+/HER2- (n=113) HER3-High and -Low 55.0 (30-83) TNBC (n=53) HER3-High a 59.0 (30-81) HER2+ (n=14) HER3-High 58.0 (37-70) 70.8 86.8 100.0 USA 29.2 13.2 0.0 0 75.4 62.3 85.7 1 24.6 37.7 14.3 HER2 zero 34.5 35.8 0.0 HER2 Low 51.3 54.7 0.0 HER2 status, %b HER2 High 0.0 0.0 100.0 HER2+ ISH Unknown 11.5 9.4 0.0 Unknown 2.7 0.0 0.0 Lung and/or Liver 90.3 64.2 85.7 Lung 43.4 47.2 42.9 Presence of metastasis (BICR), % Liver 75.2 34.0 57.1 Brain 10.6 9.4 28.6 Bone 60.2 35.8 50.0 Median sum of diameters (BICR; range), mm 54.0 (10, 182) 44.4 (11, 186) 44.6 (17, 85) All regimens 7.0 (2-14) 3.0 (1-13) 6.5 (2-11) Median number of prior cancer regimens (range), n In advanced setting 6.0 (2-13) CT in advanced setting 3.0 (1-7) 2.0 (1-13) 2.0 (1-6) 5.5 (2-11) 4.0 (2-8) Patients with HER3-expressing metastatic BC with poor prognostic characteristics were heavily pretreated ASCO-CAP, American Society of Clinical Oncology-College of American Pathologists; BICR, blinded independent central review; CT, chemotherapy; DE/DF, dose escalation/dose finding; ECOG PS, Eastern Cooperative Oncology Group performance status; ISH, in situ hybridization. a HER3-high was defined as >75% membrane positivity at 10x; HER3-low was defined as ≥25% and ≤75% membrane positivity at 10x. In DE/DF cohorts, IHC 2+ and 3+ were considered HER3-high. b HER2 status definitions: HER2 zero, IHC 0; HER2 low, IHC 1+ or 2+ (ISH-); HER2 high, IHC 2+ (ISH+), IHC 3+. Patients with clinically active brain metastases were excluded. ASCO 2022 #1002 Oral Daiichi-Sankyo 86#87Disposition, Follow-Up, and Treatment Duration Discontinued from treatment, n (%) PD (RECIST version 1.1) Clinical progression AE Death Withdrawal by patient Other Ongoing on study treatment, n (%) Median follow-up (range), months Median treatment duration (range), months Data cutoff: August 16, 2021 AE, adverse event; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors. a All patients received ≥1 dose. ASCO 2022 #1002 Oral All Patients (N=182) 178 (97.8) 133 (73.1) 15 (8.2) 15 (8.2) 3 (1.6) 6 (3.3) 6 (3.3) 4 (2.2) 31.9 (15-56) 5.9 (0.7-30.6) Daiichi-Sankyo 87#88Clinical Activity of HER3-DXd Across BC Subtypes Outcomes (BICR per RECIST 1.1) Confirmed ORR, % (95% CI³) HR+/HER2- (n=113) HER3-High and -Low 30.1 (21.8-39.4) TNBC (n=53) HER3-High HER2+ Best overall response, %b PR SD PD NE DOR, median (95% CI), mo 30.1 22.6 22.6 (12.3-36.2) 42.9 (n=14) HER3-High 42.9 (17.7-71.1) 50.4 56.6 50.0 11.5 17.0 7.1 8.0 3.8 0.0 7.2 5.9 8.3 (5.3-NE) PFS, median (95% CI), mo 6-month PFS rate, % (95% CI) 7.4 (4.7-8.4) 53.5 (43.4-62.6) 14.6 (11.3-19.5) (3.0-8.4) 5.5 (3.9-6.8) 38.2 (24.2-52.0) 14.6 (11.2-17.2) (2.8-26.4) 11.0 (4.4-16.4) 51.6 (22.1-74.8) 19.5 (12.2-NE) OS, median (95% CI), mo HER3-DXd demonstrated durable antitumor activity across BC subtypes • Confirmed ORR for all patients (N=182), 28.6% (95% CI, 22.1%-35.7%); median DOR, 7.0 mo (95% CI, 5.5-8.5 months) CR, confirmed response; DOR, duration of response; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease. a 95% exact binomial confidence interval (by Clopper-Pearson method). b No patients had a CR. ASCO 2022 #1002 Oral 88 88 Daiichi-Sankyo#89Best Percent Change From Baseline Change in Tumor Size From Baseline 60' 622 40 20 0 -20 -40 -60° -80 -100 Best Percent Change From Baseline -60 -80 ® ¥ ° ॰ ༠ Ş ྣ ཚྭ -20 -40 -100 HR+/HER2- TNBCa HER3 Expression High Low Patients (n=106) 60 HER2+a Patients (n=51) -40 -60 82202788 -100 Daiichi-Sankyo Patients (n=13) HER3-DXd induced a clinically meaningful decrease in tumor size by BICR in most patients across BC subtypes b a Patients with TNBC and HER2+ were all HER3-high. b Best percentage change from baseline in sum of diameters based on BICR for all target lesions identified is represented by patient. If any lesion measurement is missing at a post-baseline tumor assessment visit, that visit is not taken into consideration for best percent change from baseline in sum of diameters. ASCO 2022 #1002 Oral 89#90Baseline HER3 Membrane Expression by BOR HR+/HER2- cohorta n=74 (blue lines represent the mean) 100- HER3 membrane positivity, %b 75- 50 25 25 0 PR n=20 SD n=38 PD n=10 NE n=6 BOR TNBC cohorta n=26 (blue lines represent the mean) 100- HER3 membrane positivity, %b 75. 50 50 25 PR n=3 SD n=18 PD n=3 NE n=2 BOR Antitumor responses across a broad range of baseline HER3 membrane expression BOR, best overall response. a Pre-treatment HER3 positivity from patients in the dose expansion cohorts. b Percent HER3 membrane positivity was centrally assessed by HER3 IHC. ASCO 2022 #1002 Oral Daiichi-Sankyo 90 90#91HER3 Membrane Expression Over Time HR+/HER2- cohort n=85 TNBC cohort n=31 PR SD PD NE PR SD PD NE 100- 100- HER3 membrane positivity, %b 25 25. 50 75 75 0 Archival Pre-treatment Visit HER3 membrane positivity, %b 50 25- 75- 0- Archival Pre-treatment Visit HER3 membrane expression changed dynamically, but this was not associated with clinical activity EOT, end of treatment. a On-treatment biopsy taken at cycle 2 day 3 or cycle 3 day 3. b Percent HER3 membrane positivity was centrally assessed by HER3 IHC. ASCO 2022 #1002 Oral 91 Daiichi-Sankyo#92Overall Safety Profile of HER3-DXd Daiichi-Sankyo • HER3-DXd was associated with a • • manageable safety profile There was a low rate of TEAEs associated with treatment discontinuation (9.9%) • 18 patients had TEAEs associated with treatment discontinuation across all doses: pneumonitis (n=6), disease progression (n=2), ejection fraction decreased (n=2), ILD, malaise, peripheral edema, hepatotoxicity, gastric cancer, mental status changes, extradural hematoma, and general physical health deterioration (all n=1) 6.6% of patients had treatment-related ILD eventsa Patients, n (%) Median treatment duration: 5.9 mo (range 0.7-30.6 mo) Any TEAE Associated with death 4.8 mg/kg n=48 6.4 mg/kg n=98 47 (97.9) 98 (100) All Doses N=182 181 (99.5) Associated with discontinuation Associated with dose reduction Associated with drug interruption 5 (10.4) 8 (8.2) 18 (9.9) 6 (12.5) 22 (22.4) 35 (19.2) 23 (47.9) 57 (58.2) 100 (54.9) Associated with death 1 (2.1)b 6 (6.1)b 7 (3.8)b Grade ≥3 TEAE 31 (64.6) 80 (81.6) 130 (71.4) Treatment-related TEAE 47 (97.9) 97 (99.0) 180 (98.9) 0 1 (1.0) 1 (0.5)c Grade ≥3 27 (56.3) 76 (77.6) 120 (65.9) Serious TEAE 7 (14.6) 23 (23.5) 38 (20.9) Adjudicated treatment-related ILDd Grade 1 0 2 (2.0) 3 (1.6) Grade 2 1 (2.1) 2 (2.0) 5 (2.7) Grade 3 0 2 (2.0) 3 (1.6) • Most were grade 1 and 2 (4.4%) • There was one grade 5 ILD event (0.5%) Grade 4 0 0 0 Grade 5 Total 0 1 (1.0) 1 (0.5) 1 (2.1) 7 (7.1) 12 (6.6) ILD, interstitial lung disease; TEAE, treatment-emergent adverse event. a As determined by an independent adjudication committee. b TEAEs associated with death included disease progression (n=4), neutropenic sepsis (n=1), extradural hematoma (n=1), and choking (n=1). Treatment- related TEAE associated with death was neutropenic sepsis (n=1). d Median time to onset, 141.5 days (95% CI; 36-584 days). ASCO 2022 #1002 Oral 92 22#93• • • TEAEs in Patients Treated with 4.8 mg/kg and 6.4 mg/kg Daiichi-Sankyo Gl and hematologic toxicity were the most common TEAES TEAES (≥25% of all patients), (%) 4.8 mg/kg n=48 All grade Grade ≥3 All grade 6.4 mg/kg n=98 Grade ≥3 • Rates of non-hematologic toxicity were similar at both doses and generally low grade Rates of grade ≥3 neutropenia, thrombocytopenia and leukopenia were numerically higher at 6.4 mg/kg vs 4.8 mg/kg • All events were managed by dose delay or reduction and were not associated with treatment discontinuation No grade ≥3 TEAE of thrombocytopenia resulted in a grade ≥3 bleeding event TEAES Nausea Alopecia Malaise 97.9 64.6 100 81.6 68.8 4.2 80.6 5.1 Platelet count decreaseda 60.4 27.1 71.4 38.8 Neutrophil count decreaseda 62.5 27.1 66.3 52.0 Decreased appetite 56.3 6.3 53.1 6.1 Vomiting 47.9 4.2 46.9 1.0 White blood cell count decreaseda 45.8 10.4 45.9 23.5 Diarrhea 41.7 4.2 43.9 3.1 Anemiaa 43.8 20.8 43.9 21.4 Aspartate aminotransferase increased Stomatitis 43.8 4.2 34.7 6.1 25.0 0.0 34.7 1.0 Fatigue 31.3 0.0 33.7 3.1 Alanine aminotransferase increased 41.7 2.1 31.6 7.1 Constipation 22.9 0.0 29.6 0.0 20.8 NA 28.6 ΝΑ 22.9 0.0 26.5 1.0 Gl, gastrointestinal; NA, not applicable. a Grouped terms: platelet count decreased (platelet count decreased, thrombocytopenia); neutrophil count decreased (neutrophil count decreased, neutropenia); white blood cell count decreased (leukopenia, white blood cell decreased); anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased). ASCO 2022 #1002 Oral 93#94Conclusions Daiichi-Sankyo HER3-DXd demonstrated clinically meaningful and durable antitumor activity in a heavily pretreated population of patients with HER3-expressing BC • Durable antitumor activity was demonstrated across BC subtypes: HR+/HER2- (ORR, 30%; median DOR, 7.2 months), TNBC (ORR, 23%; median DOR, 5.9 months), and HER2+ (ORR, 43%; median DOR, 8.3 months) • Antitumor activity was also demonstrated across the range of HER3 expression • The safety profile was manageable with a low rate of discontinuation due to TEAES (10%) • • • • The rate of adjudicated treatment-related ILD was 7%; most cases were grade 1 and 2 Grade ≥3 hematological toxicities were manageable; no grade ≥3 thrombocytopenia resulted in treatment discontinuation nor in a grade ≥3 bleeding event As a similar safety profile was seen with 4.8 mg/kg and 6.4 mg/kg, a 5.6 mg/kg dose, currently used in NSCLC, is being evaluated in BC to refine dose optimization These data provide encouraging evidence of antitumor efficacy with a manageable safety profile and warrant further evaluation of HER3-DXd across clinical and histopathological BC subtypes ASCO 2022 #1002 Oral 94 94#95Abstract 9017 Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations Conor E. Steuer,1 Hidetoshi Hayashi,² Wu-Chou Su,³ Makoto Nishio,4 Melissa L. Johnson, 5 Dong-Wan Kim,6 Marianna Koczywas, Enriqueta Felip,8 Kathryn A. Gold,⁹ Haruyasu Murakami, 10 Christina S. Baik,11 Sang-We Kim, 12 Egbert F. Smit, 13 Mark Gigantone, 14 Ben Kim, 14 Pang-Dian Fan, 11 Zhenhao Qi,14 Elaine Y. Wu,14 David Sternberg, 14 Pasi A. Jänne 15 *Winship Cancer Institute of Emory University, Atlanta, GA; Kindai University, Osaka, Japan; ³National Cheng Kung University Hospital, Tainan, Taiwan; "The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; "Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN; "Seoul National University Hospital, Seoul, South Korea; "City of Hope, Duarte, CA; "Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; "Moores Cancer Center at UC San Diego Health, San Diego, CA; 10Shizuoka Cancer Center, Shizuoka, Japan; "University of Washington/Seattle Cancer Care Alliance, Seattle, WA; 12Asan Medical Center, Seoul, South Korea; 13Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; 14Daiichi Sankyo, Inc, Basking Ridge, NJ; 15Dana-Farber Cancer Institute, Boston, MA Background • Human epidermal growth factor receptor 3 (HER3) is expressed in 83% of NSCLC tumors¹ - Overexpression of HER3 in NSCLC has been associated with poor clinical outcomes¹ • Patients with advanced NSCLC without EGFR-activating mutations (EGFRM) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO)2,3 ⚫ Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate (Figure 1) Figure 1. HER3-DXd Structure and Attributes HER3-DXd is an antibody drug conjugate with 3 components14 ⚫ A fully human anti-HER3 IgG1 mAb (patritumab), covalently linked to . A topoisomerase I inhibitor payload, an exatecan derivative, via A tetrapeptide-based cleavable linker Human anti-HER3 IgC1 mAb4-7 Deruxtecan4-7 Cleavable tetrapeptide-based linker Topoisomerase I inhibitor payload (DXd) The 7 Key Attributes of HER3-DXd Payload mechanism of action: topoisomerase I inhibitor4- High potency of payload- High drug-to-antibody ratio 84,5, Payload with short systemic half-life 56, Stable linker-payload5-7 Tumor-selective cleavable linker*** Bystander antitumor effect** *The dinical relevance of these features is under investigation. Eased on animal data ⚫ We previously reported efficacy and safety data for HER3-DXd in heavily pretreated patients with EGFRm NSCLC (all had prior EGFR TKI therapy and 80% had prior PBC)10 - In 57 patients receiving HER3-DXd 5.6 mg/kg IV every 3 weeks (Q3W), the confirmed objective response rate (ORR) by blinded independent central review (BICR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was 39% (95% CI, 26.0%-52.4%), and median progression-free survival (PFS) was 8.2 months (95% CI, 4.4-8.3 months) - Clinical activity was observed across a broad range of HER3 membrane expression levels and mechanisms of EGFR TKI resistance • Here we describe the efficacy and safety results of HER3-DXd in patients with advanced NSCLC without common EGFRm whose disease progressed after treatment with PBC ± 10 Conclusions • Similar to the previously reported observations in patients with EGFRm NSCLC, HER3-DXd showed promising clinical activity in heavily pretreated patients with advanced NSCLC with or without identified variant genomic alterations - Durable antitumor activity was seen in patients with variant identified driver genomic alterations and patients without such genomic alterations ⚫ The overall safety profile of HER3-DXd was manageable and similar to that previously reported in patients with EGFRm NSCLC ⚫ These results demonstrate the promising clinical activity of HER3-DXd in patients with NSCLC harboring a broad range of genomic alterations or without identified driver genomic alterations, and they warrant further clinical evaluation Poster presented at: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL, and virtual. Corresponding author email address: [email protected] Methods • U31402-A-U102 is an ongoing phase 1 dose-escalation and dose-expansion study in patients with NSCLC (Figure 2; ClinicalTrials.gov, NCT03260491; EudraCT, 2017-000543-41; JapicCTI, 194868) - Here we report data from the dose-expansion part, cohort 2; all patients had squamous or nonsquamous NSCLC without the common Ex19del, L858R, L861Q, or G719X mutations -Patients with stable brain metastases were eligible - Patients with non-EGFR oncogenic alterations were eligible provided that they had prior treatment with ≥1 targeted therapy, if available - All patients received HER3-DXd 5.6 mg/kg IV Q3W • The primary endpoint was confirmed ORR by BICR per RECIST 1.1 Secondary endpoints included disease control rate, time to response, duration of response, PFS, and safety Results • At the January 28, 2022, data cutoff, 47 patients in cohort 2 had been treated with HER3-DXd 5.6 mg/kg IV Q3W (Tables 1 and 2) In this heavily pretreated cohort, all patients had prior PBC and 45 of 47 had prior IO (Table 1) -Most patients had adenocarcinoma (74%; Figure 3) - 21 patients had identified driver genomic alterations (Figure 3) ⚫ Median follow-up was 19.7 months (range, 13.8-29.2 months) • Confirmed responses by BICR were observed in patients with NSCLC harboring a range of driver genomic alterations and also with NSCLC without such genomic alterations (Figures 4 and 5) Table 1. Patient Characteristics and Treatment History Age, median (range), years Female, n (%) ECOG performance status 0/1, n (%) Sum of diameters at baseline, median (range), mm² History CNS metastases, n (%) Patients with identified driver genomic alterations, n (%) Patients without identified driver genomic alterations, n (%) Prior lines of systemic therapy, median (range) Prior cancer regimens, n (%) PBC 10 Anti-PD-1/anti-PD-L1 Anti-CTLA-4 Genomic-directed therapy Data cutoff: January 28, 2022. *By BICR per RECIST 1.1. In the localy advanced or metastatic setting. Table 2. Disposition Patients, n (%) Median (range) follow-up: 19.7 mo (13.8-29.2 mo) Treated Ongoing study treatment Discontinued from study treatment Primary reason for discontinuation PD Clinical progression Adverse event Withdrawal of consent by patient Death Data cutoff: January 28, 2022. Figure 2. Study Design (This Poster Presents Cohort 2) Dose escalation Locally advanced/metastatic NSCLC with EGFR mutations EGFR TKI treatment HER3-DXd IV Q3W Dose expansion Squamous or nonsquamous NSCLC without common EGFRM 6.4 mg/kg (N=5) EGFRM NSCLC (adenocarcinoma with prior EGFR TKI and prior PBC 5.6 mg/kg (N=12) Progression on prior 4.8 mg/kg (N=15) 5.6 mg/kg (N=47) 3.2 mg/kg (N=4) NSCLC with EGFR mutations including any histology other than combined small and non-small cell; with prior EGFR TKI and prior PBC Recommended dose for expansion: HER3-DXd 5.6 mg/kg IV Q3W Figure 4. Clinical Activity With Durable Responses Observed in Patients With Variant Genomic Alterations or Without Identified Driver Genomic Alterations Prior chemotherapy Prior PBC Prior genomic-directed KRASINRAS mutations RAS G1Z KRAS G120 Driver genomic alteration Brain metastases at baseline (BICR) KRAS G12D KRAS G120 Π NEAS 0611 Π Fusions ALK EMLA ALK RET fusion CO ROS CD74:ROST GOPC::ROS! Other driver alterations EGFR L8615 EGFR 1751 1759deiraN ERBB2A715 776YWMA ERBB2 AMP CGFR Cx2018 EGFR-Cor HER3-DXd 5.6 mg/kg (N=47) No Identified driver alteration 62 (29-79) 25 (53.2) 16 (34.0)/31 (66.0) 67 (18-205) ☐ Π Π ☐ Π Π ㅁ 15 (31.9) 21 (44.7) ☐ +1 26 (55.3) ☐ 3 (1-8) Π ☐ ☐ ☐ 47 (100) 45 (95.7) 45 (95.7) 1 (21) 9 (19.1) Data cutor. January 28, 2022. HER3-DXd 5.6 mg/kg A (N=47) 47 (100) 5 (10.6) 42 (89 4) 24 (51.1) 6 (12.8) 5 (10.6) 4 (8.5) 3 (6.4) Figure 3. Histology and Driver Genomic Alterations Large cell (n=1 [2%]) Squamous (n=8 [17%]) Histology (N=47) Adenocarcinoma Other (n=35 [74%]) (n=3 [6%]) *Adenosquamous, neuroendocrine, NSCLC with neuroendocrine features (n-1 each) *RET rearrangement was identified in the CRF Information on the partner gene was not obtained. Identified Driver Genomic Alterations (N=21) RET sion RET EMLA ALK ALK GOPC FUSION 1751 1750 EGFR L861R FRBB2 AMP MUTATION EGFR ROS1 ROS CD74 Rost Best percentage change in sum of diameters 40 20 ྴ ྨ ཋ 8 ཤཿ པྟཱཿ -20 ㅁ ☐ ☐ ☐ Months 12 ㅁ Duration Treatment → Ongoing Assessments (BICR) CR PR First occurrence of confirmed response SD PD Investigator felt the patient was deriving benefit Including unconfirmed PR -> Safety Data cutoff January 28, 2022 • The overall safety profile was manageable (Table 3), and similar to that in patients with EGFRm NSCLC10 - 5 patients (11%) had TEAEs associated with treatment discontinuation The most common grade 23 TEAEs were neutropenia (26%), fatigue (17%), thrombocytopenia (15%), hypokalemia (13%), anemia (11%), leukopenia (11%), and pneumonia (11%) - Drug-related interstitial lung disease by central adjudication occurred in 5 patients (11%; all grade 1 or 2; median time to onset, 140 days [range, 43-331 days]) - No drug-related deaths occurred in this cohort Table 3. Manageable Safety Profile TEAEs by patient, n (%) Median (range) treatment duration: 4.2 mo (0.7-19.8 mo) Any TEAE Associated with treatment discontinuation² Associated with treatment dose reduction Associated with treatment dose interruption Associated with death Grade =3 Serious AE Treatment-related TEAE Associated with death Grade 23 Serious AE Grade 1 Adjudicated treatment-related interstitial lung disease Grade 2 Grade ≥3 5.6 mg/kg (N=47) 47(100) 5 (10.6) 11 (23.4) 24 (51.1) 7 (14.9) 34 (72.3) 19 (40.4) 47(100) 24 (51.1) 6 (12.8) 5 (10.6) 1 (2.1) 4 (8.5) *The protocol allowed treatment after PD if the Data cutoff January 28, 2022. *TEAEs associated with treatment discontinuation were pneumonitis (n-2) and pneumonia, platelet count decreased, red blood cell court decreased, and pericardial effusion (n-1 each). "TEAES associated with death were disease progression (n-2); pneumonia (n-2); and COVID-19, malignant neoplasm progression, physical deconditioning, and white blood cell count decreased (n-1 each). BOR by BICR CR PR PD NE + Treatment ongoing 15 18 References Figure 5. Antitumor Activity in Patients With (A) or Without (B) Identified Driver Genomic Alterations 1. Scharpenseel H, et al. Sci Rep. 2019:9(1):7406. 2. Brueckl WM, et al. Transl Lung Cancer Res. 2021;10(7):3093-3105. 3. Santos ES. Expert Rev Anticancer Ther. 2020;20(3):221-228 4. Hashimoto Y, et al. Clin Cancer Res. 2019,25(23):7151-7161. 5. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 6. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 7. Koganemaru S, et al. Mol Cancer Ther. 2019;18(11):2043-2050. 8. Haratani K, et al. J Clin Invest. 2020;130(1):374-388. 9. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039–1046. 10. Jänne PA, et al. Cancer Disc. 2022;12(1):74-89. Abbreviations BICR, blinded independent central review, BOR, best overall response; CNS, central nervous system; CR, complete response; CRF, case report form; ECOG, Eastem Cooperative Oncology Group; EGFRM, EGFR-activating mutations; HER3; human epidermal growth factor IV, intravenous; mAb, monoclonal antibody; NE, not evaluable; receptor 3; 10, immunotherapy, NSCLC, non-small cell lung cancer, ORR, objective response rate; PBC, platinum-based chemotherapy; PD, progressive disease; PR, partial response; PFS, progression-free survival; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TEAE, treatment-emergent adverse event. B Best percentage change in sum of diameters Confirmed ORR (95% CI), % -40 Outcomes (BICR per RECIST 1.1) Disease control rate (95% CI), % Time to response, medan (range), mo -60 -80 བྷུ སྨཱ ॰ སྨཱ ༈༙ ཋ N-21 28.6(11.3, 52.2) 76.2 (52.8, 91.8) 2.8 (1.3-4.6) Duration of response, median (95% CI), mo PFS, median (95% CI), mo 9.4 (4.2-NE) 10.8 (2.8-16.0 EGFR ERBB2 MET EGFR KRAS EGFR ERBB2 AMP AMP Ex20ins G12C Exin EGFR CD74 KRAS CD74 EGFR Ex20ins ROST ROS1 Ex20ins 7751 759 L861R G12C EGFR KRAS 775 G776 ERBB2 RET fusion NRAS EML4: KRAS ALK GIF ALK ALK ROS1 ROST ALK G12125 02033N 02032R L1196M 31296F $1226Y BRAF V600E Outcomes (BICR per RECIST 1.1) Confimed ORR (95% CI), % BOR by BICR CR PR SD PD NE + Treatment ongoing Funding This study is sponsored by Daiichi Sankyo, Inc. Acknowledgments We thank the patients, their families, and their caregivers for their participation and study staff for their contributions. Medical editorial assistance was provided by Amos Race, PhD, CMPP, (ArticulateScience LLC) and funded by Daiichi Sankyo, Inc. Data cutoff: January 28, 2022. Twenty of 21 patients with identified driver mutations, and 24 of 26 patients without, had best percentage change in sum of diameters data available. Please scan this quick response (QR) code with your smartphone camera or app to obtain additional materials. Alternatively, please use the link below. https://bit.ly/36L30fB Materials obtained through the QR code are for personal use only. Copies of the poster may not be reproduced without permissions from ASCO and the authors of this poster. N-25 26.9 (11.5, 47.8) -60 Disease control rate (95% CI), % 73.1 (522, 88.4) Time to response, median (range), mo 2.1 (1.2-6.0) -80 Duration of response, median (95% CI), mo 9.6 (1.5-NE) PFS, median (95% CI), mo 4.2 (2.5-10.8) -100 95#96Phase I, Two-Part, Multi-Center, First-in-Human Study of DS-6000a in Subjects with Advanced Renal Cell Carcinoma and Ovarian Cancer Erika P. Hamilton, MD1,2; Shekeab Jauhari, MD1,3; Kathleen Moore, MD4; Brian Rini, MD5; Robert McLeod, MD; Jie Lin, MD6; Nanae Izumi6; Madan G. Kundu, PhD; Yusuke Myobatake; Abderrahmane Laadem, MD6; Yutaka Noguchi7; Julius Kirui¹; David R. Spigel, MD1,2 1Sarah Cannon Research Institute, Nashville, TN; 2Tennessee Oncology, PLLC, Nashville, TN; ³Florida Cancer Specialists and Research Institute, Lake Mary, FL; 4University of Oklahoma College of Medicine, Oklahoma City, OK; 5Vanderbilt-Ingram Cancer Center, Nashville, TN; ‘Daiichi Sankyo, Inc, Basking Ridge, NJ; 7Daiichi Sankyo Co, Ltd, Tokyo, Japan ASCO 2022 #3002 Oral On behalf of the investigators 96 96 Daiichi-Sankyo#97Background Cadherin 6 (CDH6) is part of the cadherin family, which is involved with cell-cell adhesion, organ development, and epithelial-mesenchymal transition CDH6 is found to be overexpressed in various cancers, particularly ovarian cancer (OVC) and renal cell carcinoma (RCC) 1 In preclinical studies, DS-6000a inhibited tumor growth and induced tumor regression in CDH6- expressing OVC and RCC1 Here, we report initial results from the dose- escalation portion of a first-in-human trial in patients. with advanced OVC and RCC (NCT04707248) PDX, patient-derived xenograft. 1. Hirokazu S, et al. ESMO 2021. Abstract 10P. ASCO 2022 #3002 Oral Tumor volume, mm³ H score 100 200 300 CDH6 Expression in RCC/Serous OVC1 Clear cell RCC Papillary RCC Serous OVC Antitumor Activity of DS-6000a in RCC and OVC PDX Model¹ 1400 CDH6 RCC 1200 1000 800 Vehicle 600 400 DS-6000a 200 0 0 20 40 40 Day Tumor volume, mm³ Median 1200 CDH6 OVC 1000 800 Vehicle 600 400 200 DS-6000a 0 0 20 40 Day 97 Daiichi-Sankyo#98Daiichi-Sankyo DS-6000a Was Designed With 7 Key Attributes DS-6000a is a cadherin 6 (CDH6) directed ADC composed of 3 components:1-3 A humanized anti-CDH6 IgG1 monoclonal antibody covalently linked to: A topoisomerase I inhibitor payload, an exatecan derivative, via A tetrapeptide-based cleavable linker Humanized anti-CDH6 IgG1 mAb Deruxtecan1,2 Payload mechanism of action: topoisomerase I inhibitora,1,2 High potency of payload a,1,2 High drug-to-antibody ratio =8a,1,2 Payload with short systemic half-life a,b,1,2 H NH H Stable linker-payload a,1,2 H,C- HOCH Cleavable tetrapeptide-based linker Tumor-selective cleavable linkera,1,2 Topoisomerase I inhibitor payload (DXD) Bystander antitumor effect a,1,2 ADC, antibody-drug conjugate; DXd, a novel topoisomerase 1 inhibitor that is a derivative of exatecan; IgG1, immunoglobulin G1; mAb, monoclonal antibody. a The clinical relevance of these features is under investigation. b Based on animal data. 1. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 3. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039-1046. ASCO 2022 #3002 Oral 88 98#99Study Design Dose Escalation (Part A) DS-6000a IV q3w RCC and serous OVC Dose Expansion (Part B) DS-6000a IV q3w at RDE Cohort B-1 RCC 9.6 mg/kg 8.0 mg/kg RDE 6.4 mg/kg 4.8 mg/kg 3.2 mg/kg Cohort B-2 Serous OVC 1.6 mg/kg Enrollment criteria Primary objectives Safety and tolerability Determine MTD and RDE Daiichi-Sankyo • Advanced/metastatic RCC or OVC not amenable to SOC therapya . • ECOG PS 0 to 1 • Ability to provide archived tissue for correlative testing Secondary objectives • No previous treatment with CDH6-targeting agents or ADCs with a linked topoisomerase I inhibitor . • PK of DS-6000a, total anti-CDH6 antibody, and the DXd payload Antitumor activity per RECIST 1.1 • Immunogenicity ADC, antibody drug conjugate; CDH6, cadherin 6; DXd, topoisomerase I inhibitor payload; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; MTD, maximum tolerated dose; OVC, ovarian cancer; PK, pharmacokinetics; q3w, every 3 weeks; RCC, renal cell carcinoma, RDE, recommended dose for expansion; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SOC, standard of care. a Patients with OVC must have also had prior treatment with platinum and taxane therapy. ASCO 2022 #3002 Oral 99 99#100Baseline Patient and Disease Characteristics DS-6000a Dose Escalation OVC (N=20) Age, median (range), years 65.5 (51-78) RCC (N=9) 60.0 (41-72) Total (N=30)a 64.5 (41-78) Sex, n (%) Female 20 (100) 4 (44.4) 25 (83.3) Male 0 5 (55.6) 5 (16.7) Baseline ECOG PS, n (%) 0 10 (50) 6 (66.7) 16 (53.3) 1 10 (50) 3 (33.3) 14 (46.7) Tumor type, n (%) Renal cell carcinoma Clear cell RCC Non-clear cell RCC Serous ovarian cancer Platinum-resistant disease - 8 (88.9) 1 (11.1) 8 (26.7) 1 (3.3) 20 (100) 20 (66.7) 17 (85) 17 (56.7) No. of prior systemic regimens Median (range) 4.0 (1-12) Baseline CDH6 expression H score, range 0-250 2.0 (1-6) 17-218 3.0 (1-12) 0-250b Data cutoff: February 25, 2022. CDH6, cadherin 6; ECOG PS, Eastern Cooperative Oncology Group performance status; OVC, ovarian cancer; RCC, renal cell carcinoma. a One missing primary diagnosis of OVC. b Membrane CDH6 expression of 23 evaluable archival tissues. ASCO 2022 #3002 Oral Daiichi-Sankyo 100#101Patient and Treatment Summary As of data cutoff, 30 patients enrolled in part A (dose escalation) had received DS-6000a (OVC, n=21; RCC, n=9) - 17 patients (56.7%) were receiving ongoing treatment with DS-6000a (OVC, n=12; RCC, n=5) - 13 patients (43.3%) discontinued treatment - 9 of 13 patients discontinued due to disease progression - 1 patient (3.3%) discontinued due to TEAE . Median treatment duration was 12.1 weeks (range, 3.0-54.1 weeks) Data cutoff: February 25, 2022. OVC, ovarian cancer; RCC, renal cell carcinoma; TEAE, treatment-emergent adverse event. ASCO 2022 #3002 Oral Daiichi-Sankyo 101#102Treatment Related TEAEs (Any Grade) Occurring in ≥10% of Patients Daiichi-Sankyo 1.6 mg/kg (n=1) 3.2 mg/kg 4.8 mg/kg (n=6) 6.4 mg/kg (n=6) (n=8) 8.0 mg/kg (n=6) 9.6 mg/kg (n=3) Any treatment-related TEAE, n (%) 1 (100) 4 (66.7) 4 (66.7) 7 (87.5) 6 (100.0) 3 (100.0) Total (N=30) 25 (83.3) Nausea 0 3 (50.0) 3 (50.0) 5 (62.5) 5 (83.3) 2 (66.7) 18 (60.0) Fatigue 0 2 (33.3) 3 (50.0) 4 (50.0) 6 (100.0) 2 (66.7) 17 (56.7) Vomiting 0 2 (33.3) 1 (16.7) 2 (25.0) 2 (33.3) 2 (66.7) 9 (30.0) Neutrophil count decreased 0 0 0 1 (12.5) 3 (50.0) 3 (100.0) 7 (23.3) Decreased appetite 1 (100) 0 0 4 (50.0) 1 (16.7) 0 6 (20.0) Diarrhea 0 0 0 2 (25.0) 1 (16.7) 1 (33.3) 4 (13.3) · Treatment-related TEAES occurred in 25 patients (83.3%) The most common treatment-related TEAEs of any grade were nausea, fatigue, and vomiting One patient in the 9.6-mg/kg arm experienced grade 2 pneumonitis, which led to treatment discontinuation Data cutoff: February 25, 2022. TEAE, treatment-emergent adverse event. ASCO 2022 #3002 Oral 102#103Treatment-Related TEAEs (Grade ≥3) 1.6 mg/kg 3.2 mg/kg 4.8 mg/kg 6.4 mg/kg 8.0 mg/kg 9.6 mg/kg (n=1) (n=6) (n=6) (n=8) (n=6) Any grade ≥3 treatment-related TEAE, n (%) 0 0 0 2 (25.0) 2 (33.3) (n=3) 3 (100) Total (N=30) 7 (23.3) Neutrophil count decreased Anemia 0 0 0 0 2 (33.3) 3 (100) 5 (16.7) 0 0 0 1 (12.5) 0 1 (33.3) 2 (6.7) Febrile neutropenia 0 0 0 1 (12.5) 0 1 (33.3) 2 (6.7) Decreased appetite 0 0 0 0 1 (16.7) 0 1 (3.3) Platelet count decreased 0 0 0 0 0 1 (33.3) 1 (3.3) Grade ≥3 treatment-related TEAEs occurred in 7 patients (23.3%) The most common treatment-related TEAEs (nausea, fatigue, and vomiting) had no grade ≥3 events Two patients experienced DLTs in the 9.6-mg/kg arm (grade 3 febrile neutropenia and grade 4 platelet count decreased) Two patients experienced grade 3 treatment-related SAES (anemia and febrile neutropenia) Data cutoff: February 25, 2022. DLT, dose-limiting toxicity; SAE, serious adverse event; TEAE, treatment-emergent adverse event. ASCO 2022 #3002 Oral Daiichi-Sankyo 103#104Best change from baseline in sum of diameters, % Change From Baseline in Target Lesions: OVC and RCC Evaluable Populationa 80- RCC renal cell carcinoma OVC = serous ovarian cancer 60- 40- 20- -20- OVC OVC RCC OVC OVC RCC OVC OVC OVC OVC OVC RCC OVC 0- RCC OVC OVC RCC OVC RCC OVC -40- -60- -80- -100- Starting dose level 1.6 mg/kg 13.2 mg/kg 4.8 mg/kg 6.4 mg/kg 18.0 mg/kg 19.6 mg/kg 100 80 60- 40- 20 0- -20- Change from baseline in sum of diameters of target lesions, % -40- Daiichi-Sankyo (1.6 mg/kg; N=1, n=1) (4.8 mg/kg; N=6, n=4) ● (8.0 mg/kg; N=6, n=3) (3.2 mg/kg; N=6, n=4) (6.4 mg/kg; N=8, n=5) (9.6 mg/kg; N=3, n=3) -60- -80 -100- T T 0 1 2 3 4 5 6 7 8 9 10 11 12 Time from first dose of study drug, months Among 20 evaluable patients with measurable disease, there were 6 PRS (platinum-resistant OVC, n=5; RCC, n=1) 4 confirmed PRs (platinum-resistant OVC, n=3; RCC, n=1) 2 unconfirmed PRs (1 patient still in the trial) 12 patients had stable disease Data cutoff: February 25, 2022. OVC, ovarian cancer; PR, partial response; RCC, renal cell carcinoma. a Patients who received ≥1 dose of study treatment and have completed ≥1 postbaseline tumor assessment or discontinued treatment for any reason. ASCO 2022 #3002 Oral 104#105Change From Baseline in CA-125 Levels Among 17 evaluable patients with OVC, a 8 CA-125 responses were observed 80- Best change from baseline in CA-125, % 60- 40- 20 20 0 SD PD SD ΝΑ PR -20- -40- 28 -60- -80- -100 Data cutoff: February 25, 2022. b b b b b b b b PR SD--- Non-CR/ Non-PD SD SD SD PR SD Non-CR/ Non-PD PR SD PR Starting dose level 1.6 mg/kg 13.2 mg/kg 14.8 mg/kg 16.4 mg/kg 8.0 mg/kg 9.6 mg/kg CA-125, cancer antigen 125; CR, complete response; GCIG, Gynecologic Cancer InterGroup; NA, not available; OVC, ovarian cancer; PD, progressive disease; PR, partial response; SD, stable disease. a Patients with baseline CA-125 value and ≥1 postbaseline CA-125 value were included. b According to the GCIG criteria, patients can be evaluated for response only if they have a baseline sample that is ≥2 × the upper limit of normal obtained within 2 weeks prior to starting treatment. CA-125 response is defined as a ≥50% reduction in CA-125 levels from a pretreatment sample. The response must be confirmed and maintained for ≥28 days. ASCO 2022 #3002 Oral Daiichi-Sankyo 105#106• · Case Summary: Patient With Serous OVC 67-year-old woman with stage IV platinum-resistant OVC Treated with DS-6000a 6.4 mg/kg intravenously q3w 3 prior therapies • . • Paclitaxel + carboplatin with olaparib maintenance Carboplatin + gemcitabine + bevacizumab Pegylated liposomal doxorubicin Cycle 14 treatment ongoing Baseline 18 weeks Overall SD (-26.2%) 36 weeks Overall PR (-35.7%) OVC, ovarian cancer; PR, partial response; q3w, every 3 weeks; SD, stable disease. ASCO 2022 #3002 Oral Daiichi-Sankyo 106#107Case Summary: Patient With Clear Cell RCC 60-year-old man with stage IV RCC Treated with DS-6000a 3.2 mg/kg intravenously q3w 3 prior therapies • Sorafenib . Nivolumab Telaglenastat + cabozantinib Cycle 18 treatment ongoing Baseline 19 weeks 48 weeks Overall PR (-45.2%) Overall PR (-64.3%) PR, partial response; q3w, every 3 weeks; RCC, renal cell carcinoma. ASCO 2022 #3002 Oral Daiichi-Sankyo 107#108Conclusions ● DS-6000a was generally well tolerated, and the recommended dose for expansion (RDE) was declared 8.0 mg/kg DS-6000a demonstrated early clinical signals (RECIST and CA-125 responses) in heavily pretreated patients with advanced platinum- resistant OVC and RCC Expansion cohorts (part B) opened at 8.0 mg/kg are enrolling patients with OVC and RCC ASCO 2022 #3002 Oral Daiichi-Sankyo 108#109Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor Suzanne George, MD', Michael Heinrich, MD², Neeta Somaiah, MD³, Brian A Van Tine, MD, PhD, Robert McLeod, MD5, Abderrahmane Laadem, MD, PhD, Ben Cheng, MD5, Satoshi Nishioka, Madan G Kundu, PhD, Xiaozhong Qian, PhD, Yvonne Lau, PhD, Brittany Tran, PharmD5, Prasanna Kumar, PhD, Ololade Dosunmu, MD, Julia Shi, Yoichi Naito, MD8 'Dana-Farber Cancer Institute, Boston, MA; 2OHSU Knight Cancer Institute, Portland, OR; ³The University of Texas MD Anderson Cancer Center, Houston TX;" Washington University in Saint Louis, St. Louis, MO; "Daiichi Sankyo, Inc., Basking Ridge, NJ; "Daiichi Sankyo, Co., Ltd, Tokyo, Japan; 'Sarah Cannon Research Institute, Nashville, TN; "National Cancer Center Hospital East, Kashiwa, Japan BACKGROUND ⚫GPR20 is selectively and abundantly expressed in gastrointestinal stromal tumors (GISTS), the most common sarcoma of the digestive tract. • DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd) which target the drug-to-antibody ratio (DAR) of -8. • In nonclinical pharmacology studies, DS-6157a inhibited the growth of GPR20-expressing GIST xenografted mouse models'. • Here, we report the results from a Phase I trial of DS-6157a in patients (pts) with advanced GIST (NCT04276415). STUDY OBJECTIVES Primary .Dose Escalation (Part 1): Investigate the safety and tolerability of the DS-6157a, and determine the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) Secondary ⚫ Characterize the pharmacokinetic (PK) properties of DS-6157a, total anti-GPR20 antibody, and the drug component (MAAA-1181a) • Investigate the efficacy of DS-6157a (Part 1 only) STUDY DESIGN ⚫The dose-escalation portion of this study (Part 1) enrolled pts with advanced GIST. DS-6157a was administered IV as monotherapy on Day 1 of 21-day cycles. • Part 1 assessed safety, tolerability, and MTD or RDE using Bayesian logistic regression model (BLRM), with at least 3 dose-limiting toxicity (DLT)-evaluable pts per dose level. Age (years) Medlan Sex n(%) Male Race n(%) Asian Black or African American Other 12.273 TEAEs Table 4. TEAEs in ≥10% of Patients Fatigue Constipation Platelet count decreased Vomiting Abdominal pain Neutrophil count decreased White blood cell count decreased Alanine aminotransferase i 0 (n=4) (n=34) PHARMACOKINETIC RESULTS 1.6 MG/KG 3.2 MG/KG 4.8 MG/KG ■6.4 MG/KG 9.6 MG/KG 12.8 MG/KG DS-6157a MAAA-1181a Total Anti-GPR20 Antibody RESPONSE KIT.PDOPRA WT with Tumor viage DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS Table 1. Demographics and Baseline Disease Status Total Number of Patients 34 Primary Site Location n(%) DS-6157a dose, mg/kg Stomach 13 (38.2) Small Intestine Jejunum 5 (14.7) Parameter 1.6 4.8 64 12.8 Total (n=5) (n=13) (n=2) 100000 Small intestine leum 3 (8.8) 60.5 Small Intestine Duodenum 2 (5.9) Rectum 2 (5.9) Any Adverse Events n(%) 4(100) 4(100) 5(100) 13 (100) 8 (100) 2(100) 34 (100) 10000 Other 9 (26.5) 19 (55.9) Female 15 (44.1) Nausea 375.0) 3 (75.0) 3(60.0) 11 (84.6) 6 (100) 2(100) 28 (824) Metastatic Site at Study Entry n(%) Decreased appetite 3(75.0) 250.0 360.0) 8(48.2) 4 (88.7) 2/100 20 (58.8) 1000- Country of Enrollment n(%) 24 (70.6) Anaemia 375.0) 250.0 3 (80.0) 8(48.2) 3 (50.0) 0 17 (50.0) 18 (52.9) Peritoneum 22 (64.1) 22 (64.7) Japan 16 (47.1) 3 (75.0) 1 (25.0) 2 (40.0) 8(48.2) 1(18.7) 2(100) 15 (44.1) 100 Bone 3 (8.8) Lung 8 (23.5) 1 (25.0) 2 (50.0) 2(40.0 5 (38.5) 2 (33.3) 2(100) 14/41.2) Other 13 (38.2) 125.0 2(400) 4130.8) 5 (83.3) 16 (47.1) 1 (50.0) 13 (38.2) 10 1 (2.9) 1 (25.0) 2 (50.0) 2 (40.01 4 (30.8) 1(16.7) 2(100) 12 (35.3) 16 (47.1) GPR20 H-score at screening 1 (2.9) Median 1 (25.0) 250.0) 1(20.0) 2(15.4) 1 (18.7) 2(100) 9 (28.5) Min. Max 5 (38.5) 4(88.7) 0 9 (28.5) Starting Dose Level 1.5 mg kg 3.2 mg/kg 4.8 mg/kg 8.4 mg/kg 9.5 mg kg 12.8 mg/kg 3(23.1) 5 (83.3) 1 (50.0) 9 (28.5) 18 (52.9) GPR20 H-score values n(%) 2(50.0) 1(25.0) 1 (20.0) 3 23.1) 118.7 8 23.5 0.1 16 (47.1) O to 100 5 (14.7) >100 to $200 14 (41.2 Aspartate aminotransferase increased 1 (25.0) 1(25.0) 1 (20.0) 323.1) 1/18.7) 1 (50.0) 8 (23.5) Figure 3. Waterfall Plot of Best Percentage Change in Sum of Diameters from Baseline in Target Lesions Number of Prior Systemic Regimens Median >200 to $300 Missing 11 (324) Dizziness 4 30.8) 1/18.7) 2(100) 0.01 4 (11.8) Insomnia 2/33.3 5.0 Oedema peripheral 17.7) 2 (100) Dry skin 21400 Headache 4(30.8) 1 (50.0) 1 (500) 817.6) 0 7 14 21 28 35 42 49 56 63 0 7 14 21 28 35 42 49 56 63 0 7 14 21 28 35 42 49 56 63 Nominal time since first dose (d) 1.6 moko 17.7) 1(18.7) 2 (100) 5 14.7) 3.2 mg/kg 2(154) 150.0) 4.8 mg 1 (20.0) 177) 2 (33.3) 5114.7) 2(15.4) 118.7) 1 (50.0) 5 14.7 6.4 mg/kg 3/23.11 514.7) 4 11.8) 3 23.1) 1(50.0) 4 11.8) 2 15.4) 4(11.8) 1(18.7) 1(20.0) 2/15.4) 4 11.8) 3 23.1 1(18.71 4 11.8) 1/18.7 1 (500) 4/11.8) 1 (25.0) 1(25.0) 118.7) 4 11.8) ECOG Performance status n(%) 0-Normal activity 1 - Symptoms. but ambulatory PATIENT DISPOSITION SUMMARY Table 2. Patient Disposition Parameter Treatment Status Ongoing on the Study Treatment Discontinued from Study Treatment Primary Reason for discontinuation from Study Treatment Adverse Event Clinical Progression Other Physician Decision Progressive Disease Withdrawal by Subject "Other, finished per Dehydration Hypertension Hyperuricaemia DS-6157a dose, mg/kg Hypokalaemia Pyrexia 1.6 32 4.8 (n-4) (n-4) (n-5) 64 (n-13) 9.6 (n-6) (n-2) 12.8 Total Cough (n-34) Diarrhoea Dysgeusia 2 (40.0) 0 0 2(5.9) 4 (100) 4 (100) 3 (60.0) 13 (100) 6 (100) 2 (100) 32 (94.1) Infusion related reaction Lymphocyte count decreased Rash maculopapular 0 0 0 3 (23.1) 0 0 3 (8.8) 1 (25.0) 1 (25.0) 0 1 (16.7) 0 3 (8.8) 0 0 1 (7.7) 0 0 1 (2.9) 0 0 2 (15.4) 1 (16.7) 0 3 (8.8) 3 (75.0) 3 (75.0) 3 (60.0) 6 (46.2) 2 (33.3) 2 (100) 1 (7.7) 2 (33.3) 19 (55.9) 3 (8.8) 0 0 • At time of data cut-off, 34 pts were exposed to a median of 3.0 treatment cycles (range 1-18) with DS-6157a. The median treatment duration was 9.9 weeks (wks) (range 3-56 wks). Two pts (5.9%) continued to receive study treatment, having completed 17 and 18 cycles, respectively. • There were 2 on-treatment deaths. A TEAE of hepatic function abnormality was the primary cause of death in 1 pt at 6.4 mg/kg and progressive disease in a second pt at 9.6 mg/kg, respectively. ADVERSE EVENTS Table 3. Adverse Events Summary Dyspnoea Hypoalbuminaemia 0 The most common (≥35%) of all AEs were nausea (82%), decreased appetite (59%), anemia (50%), fatigue (44%), constipation (41%), decreased platelets (38%), and vomiting (35%). CTCAE GRADE ≥3 TREATMENT RELATED TEAE Table 5. CTCAE Grade ≥3 Treatment Related TEAE Blood and lymphatic system disorders D3-8167a doce, maka Parameter 1.8 3.2 48 8.8 12.8 Total Maximum CTCAE Grade -3 Treatment-Related TEAE 1 (25.0) 1 (20.0) 8 (61.5) 1 (50.0) 15 (47.1) 1 (20.0) 3 (23.1) 1 (16.7) 1 (50.0) 7 (20.6) 1 (20.0) 3 (23.1) 1 (16.7) 6 (17.6) 1 (16.7) 1 (50.0) 2 (5.9) 1 (50.0) 1 (50.0) 1 (77) 1 (50.0) 2 (5.9) 1 (7.7 1 50.0) 150.0 1 (29) Anaemia Febrile neutropenia Gastrointestinal disorders Vomiting General disorders and administration site conditions Fatigue Oedema peripheral Hepatobiliary disorders Hepatic function abnormal Infections and infestations 122 1 (50.0) 12.8 mg kg Ryndall Legend CR & PR = ED PONEDarth Treatment Duration (Most) Figure 4. A Swimmer Plot of Tumor Response over Time Figure 2. Mean (SD) Plot of Plasma Concentration-Time Profiles of DS-6157a, MAAA-1181a, anti-GPR20 Antibody, PK Analysis Set ⚫ PK results from 34 patients indicate that intact DS-6157a, total anti-GPR20 antibody, and cytotoxic payload (MAAA-1181a) plasma concentrations increased in a dose dependent manner. ⚫Mild accumulation for AUC 21 between Cycle 3 (at steady state) and Cycle 1 (after a single dose) at 1.6 mg/kg and 6.4 mg/kg doses was observed for both intact DS-6157a (1.3 and 1.6, respectively) and MAAA-1181a (1.1 and 1.5, respectively). On a molar basis, MAAA-1181a Cin Cycle 1 across 1.6 mg/kg to 9.6 mg/kg dose range were approximately 42-fold to 83-fold lower than those for intact DS-6157a. • Total anti-GPR20 antibody and intact DS-6157a have a similar PK profile, indicating DS-6157a is stable in circulation. • Preliminary immunogenicity results showed no treatment-emergent ADA. RESPONSE PER RECIST v1.1 Table 6. Best Overall Response (BOR) per RECIST v1.1 9.6 maka 10 11 12 13 Image courtesy of Dr. Yoichi Naito Figure 5b. Cycle 3 CT scan 26 August 2021 Pneumonia 6.4 9.6 mg/kg 12.8 mg/kg Injury, poisoning and procedural complications Infusion related reaction 183 DS-6157a dose, makg DS-6157a dose, mg/kg Investigations 5 (38.5) 5 (83.3) 1 (50.0) 11 (324) 1.6 32 48 64 9.6 128 Total Lymphocyte count decreased 1 (7.7) 1 (29) Parameter (n=4) (TF) (n=13) (2) (n=34) Neutrophil count decreased 3 (500) 5 (14.7) Platelet count decreased 4 (66.7) 1 (50.0) 1.6 3.2 8 (23.5) 3.2 4.8 mg/kg mg/kg Treatment-Emergent Adverse Events (TEAE) 4(100) 4 (100) 5(100) 13 (100) 6(100) 2(100) 34 (100) White blood cell count decreased 4 (66.7 5(14.7) Parameter (n=4) (n=4) 4.8 (n=5) TEAE associated with Drug Discontinuation* 0 0 0 3(23.1) 1(16.7) 0 4(11.8) Musculoskeletal and connective tissue disorders TEAE associated with Dose Interruption 0 0 0 0 1(16.7) 2(100) 3(88) Muscular weakness 1 (77) 1 (29) BOR, n (%) 1.6 mg/kg mg/kg Figure 1. Dose Level Cohorts TEAE associated with Dose Reduction 0 0 0 1(50.0) 1(28) Renal and urinary disorders 1 (16.7) 1 (29) Renal disorder 1 (16.7) 1 (29) CR 0 0 0 0 TEAE associated with Death as Outcome 0 17.7) 0 0 1(28) PR 0 0 0 1 (7.7) Related Treatment-Emergent Serious Adverse 0 0 17.7) 2(33.3) 1(50.0) 4(11.8) Event (TESAE) Adverse Events of Special Interest (AESIF Interstitial lung disease (ILD/Pneumonitis Infusion-related reactions (IRR) D Dose-Limiting Toxicities (Any Grade by Pasent 0 KEY INCLUSION CRITERIA .Histopathologically-documented unresectable and/or metastatic GIST, Part 1 • Enrollment in Part 1 was allowed regardless of GPR20 expression • At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 • Adequate organ function • Consent to provide fresh tumor biopsy tissue samples before and on DS-6157a treatment for correlative testing a Four pts (11.8%) experienced a TEAE leading to drug discontinuation. Three pts at 6.4 mg/kg discontinued; 1 each for interstitial lung disease, infusion- related reaction, and hepatic function abnormality, while 1 pt discontinued at 9.6 mg/kg for white blood cell count reduction. bOne pt death was related to an adverse event of hepatic function abnormality. cOne IRR event at 6.4 mg/kg was Grade 3, while the others were Grade 1. One ILD event at 6.4 mg/kg was Grade 1, which occurred after Cycle 6 and the pt recovered in 1 month. d Four pts experienced 1 or more DLTs during Cycle 1 at dose levels 6.4 mg/kg and above as follows: a pt receiving 6.4 mg/kg experienced Grade 3 anemia, Grade 4 hepatic function abnormality, Grade 4 platelet decrease and Grade 5 hepatic function death, a pt at the 9.6 mg/kg dose experienced Grade 3 anemia, Grade 3 febrile neutropenia, Grade 4 hepatic function abnormality, and Grade 4 platelet decrease and recovered, a pt at the 12.8 mg/kg dose experienced Grade 3 neutropenic fever and recovered, and a second pt at the 12.8 mg/kg dose experienced Grade 2 dehydration, diarrhea, nausea and vomiting and recovered. The MTD for DS6157a was determined to be 6.4 mg/kg, per the DLT information. We thank all of the patients and family members for their participation in this trial. We thank all of the investigators and their support staff who participated in this work. REFERENCES SDa 2 (50.0) 3 (75.0) 3 (60.0) 7 (53.8) 0 0 4(308) 1(16.7) 0 5(14.7) 0 1(7.7) 0 0 1(28) 1. Ilda K, et al. Poster presented at: Annual American Association for Cancer Research Meeting; June 22-24, 2020. Abstract 5181. PD 2 (50.0) 0 2 (40.0) 3 (23.1) NE 0 1 (25.0) 0 2(15.4) 0 0 3(23.1) 1(16.7) 0 4(11.8) 0 0 1 (9.1) 1/16.7) 2 (100) 4(12.9) ACKNOWLEDGMENTS Copies of this [poster/slide deck] obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO or the author of this (poster/slides]. *BOR for 30 is considered confimed resoonseen assesment occured >5 weeks from starting treatment Tumor shrinkage was observed in 4 pts with KIT/PDGFRA wild-type GIST who had at least one restaging scan, and were treated at different doses. These included a confirmed PR at the MTD of 6.4 mg/kg in a patient with SDH-deficient GIST with both SDH B and NF1 mutations (See Figure 5). Figure 5a. Screening CT scan 22 June 2021 Figure 5. SDH-deficient GIST Patient with Pathological PR ⚫A 29 y/o female pt with SDH-deficient GIST diagnosed in 2020 without any prior cancer systemic therapies, demonstrated a maximum 87% decrease in tumor size, following treatment with DS-6157a, at the MTD confirmed dose of 6.4 mg/kg. •The target lesion, an abdominal mass, was 150 mm at baseline (Figure 5a) which decreased to 33 mm in Cycle 3, and decreased further to 20 mm 4 weeks later (Figure 5b). • The pt discontinued from study to undergo a surgical resection of the remaining small lesion to become tumor-free. The resected tumor showed a pathological CR per the Investigator's assessment. CONCLUSIONS DS-6157a was generally well-tolerated with early signs of moderate clinical activity. Tumor shrinkage was observed in only 4 pts with KIT/PDGFRA wild-type GIST treated at different doses. One pt with SDH-deficient GIST with both SDH-B and NF1 mutations achieved a PR per CT scan, and then complete pathological response after surgical resection. The study did not proceed to the Part 2 expansion phase, because the efficacy targets were not met in Part 1. 6.4 (n=13) (n=6) 9.6 12.8 Total (n=2) (n=34) 0 0 0 0 0 1(29) 2 (33.3) 0 17 (50.0) 1 (16.7) 2 (100) 10 (29.4) 3 (50.0) 0 6 (17.6) 109