(DS-8201A) in Subjects with HER2-Low Expressing Breast Cancer

Home , Targeted therapy, Trastuzumab deruxtecan

Poster # P6-17-02 – San Antonio Breast Cancer Symposium® – December 4–8, 2018 Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study Shanu Modi,1 Junji Tsurutani,2,3 Kenji Tamura,4 Haeseong Park,5 Yasuaki Sagara,6 Rashmi K. Murthy,7 Hiroji Iwata,8 Ian E. Krop,9 Toshihiko Doi,10 Charles Redfern,11 Alvaro Moreno-Aspitia,12 Rebecca Redman,13 Caleb Lee,14 Masahiro Sugihara,15 Yoshihiko Fujisaki,15 Shunji Takahashi16

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Kindai University Faculty of Medicine, Osaka, Japan; 3Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan; 4National Cancer Center Hospital, Tokyo, Japan; 5Washington University School of Medicine, St Louis, MO, USA; 6Social medical corporation Hakuaikai Sagara Hospital, Kagoshima City, Japan; 7University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 8Aichi Cancer Center Hospital, Nagoya, Japan; 9Dana-Farber Cancer Institute, Boston, MA, USA; 10National Cancer Center Hospital East, Chiba, Japan; 11Sharp HealthCare, San Diego, CA, USA; 12Mayo Clinic, Jacksonville, FL, USA; 13The University of Louisville, Louisville, KY, USA; 14Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 15Daiichi Sankyo Co., Ltd., Tokyo, Japan; 16The Cancer Institute Hospital of Japanese Foundation For Cancer Research, Tokyo, Japan

FIGURE 4. Best Percentage Change in Tumor Size from Baseline by IHC Status TABLE 4. TEAEs (≥20%) in All Breast Cancer Subjects, Regardless of HER2 Status, BACKGROUND METHODS RESULTS (October 12, 2018 Data Cutoff) Who Received 5.4 or 6.4 mg/kg Doses of [Fam-] Trastuzumab Deruxtecan (N = 170) • Approximately 15%–20% of breast cancer tumors are human epidermal growth receptor 2 Study Design and Population • As of October 12, 2018, 54 subjects with heavily pretreated (median of 7.5 prior 1-3 Adverse events All grades Grade ≥3 (HER2)-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH]-positive), • This is an ongoing, first-in-human, 2-part, open-label, multiregional (Japan and US), anticancer regimens) HER2-low breast cancer were enrolled and received ≥1 dose [fam-] 80 N = 50 Hematologic but potentially many more patients with breast cancer have tumors with low levels of phase 1 study (ClinicalTrials.gov NCT02564900) (Figure 3) trastuzumab deruxtecan 5.4 or 6.4 mg/kg (Table 2) HER2 expression (ie, IHC 1+ or 2+/ISH-negative) which do not reach the threshold for Anemia 68 (40.0) 25 (14.7) • Subjects with advanced breast or gastric cancer who had failed prior therapy were TABLE 2. Demographics and Baseline Characteristics (Safety Analysis Population) 60 HER2-positive disease4 White blood cell count decreased 43 (25.3) 16 (9.4) included in the dose-escalation (Part 1) and treated with doses ranging from 0.8 to 8.0 HER2-low breast cancer 40 Neutrophil count decreased 42 (24.7) 19 (11.2) • Although HER2-targeted therapies have improved survival for advanced HER2-positive mg/kg of [fam-] trastuzumab deruxtecan, given intravenously once every 3 weeks10 Characteristics (N = 54) Platelet count decreased 41 (24.1) 11 (6.5) breast cancers, none have been approved for patients with HER2-low breast cancer * —— In Part 1, no dose-limiting toxicities were observed and the maximum tolerated dose 20 (Figure 1)5-7 Age, median (range), years 56.5 (33–75) Gastrointestinal was not reached10 ECOG performance status, n (%) 0 * * * * Nausea 135 (79.4) 6 (3.5) FIGURE 1. Overview of Breast Cancer Treatment Strategies with HER2-Targeted —— Based on Part 1 results, 5.4 and 6.4 mg/kg were selected as the recommended dose Vomiting 78 (45.9) 5 (2.9) 5-7 0 29 (53.7) Therapy Based on HER2 Status 10 –20 for expansion (RDE) in Part 2 Diarrhea 65 (38.2) 5 (2.9) 1 18 (33.3) • The dose-expansion (Part 2) enrolled subjects in 5 cohorts, including those with heavily –40 Constipation 65 (38.2) 1 (0.6) IHC 0 HER2-negativeb HER2 expression (IHC), n (%) pretreated HER2-low breast cancer (IHC 1+ or 2+/ISH-negative), with the goal of Stomatitis 40 (23.5) 1 (0.6) –60 evaluating safety/tolerability and efficacy of [fam-] trastuzumab deruxtecan at the RDE 1+ 29 (53.7) Other (Table 1) * : HR negative 2+ 25 (46.3) –80 Decreased appetite 92 (54.1) 5 (2.9) IHC 1+ HER2-negativeb No approved HER2-targeted therapy • Efficacy outcomes included objective response rate (ORR), disease control rate, duration HR status, n (%) IHC 2+ IHC 1+ Alopecia 79 (46.5) 0 of response (DOR), time to response, and progression-free survival (PFS) –100 HER2-low BCa Positive 47 (87.0) Fatigue 72 (42.4) 7 (4.1) • The present analysis included all subjects from Part 1, Part 2c, and Part 2e who had Best percentage change in tumor size from baseline HER2 testing with AST increased 43 (25.3) 3 (1.8) IHC 2+ Negative 7 (13.0) validated IHC ISH– HER2-negativeb Dotted lines denote 30% decrease and 20% increase in tumor size cutoffs for partial response and progressive disease, respectively. (further testing) HER2-low breast cancer and were treated with ≥1 dose of [fam-] trastuzumab deruxtecan Malaise 40 (23.5) 0 assay Number of prior cancer regimens, median (range) 7.5 (2–18) HR, hormone receptor; IHC, immunohistochemistry. No previous anti-HER2 therapy: 5.4 or 6.4 mg/kg (Figure 3) Pyrexia 35 (20.6) 2 (1.2) • Trastuzumab + pertuzumab plus a Prior therapy, n (%) FIGURE 5. Percentage Change in Tumor Size from Baseline by IHC Status ISH+ taxane ALT increased 34 (20.0) 1 (0.6) Progression on trastuzumab regimen: TABLE 1. Phase 1 Study Objectives (October 12, 2018 Data Cutoff) IHC 3+ HER2-positiveb HER2-targeted therapy 10 (18.5) All values are n (%). • T-DM1 monotherapy 120 Part 1 (Dose escalation) Part 2 (Dose expansion) Data cutoff October 12, 2018. Other HER2-targeted therapy CDK4/6 inhibitor 16 (29.6) ALT, alanine aminotransferase; AST, aspartate aminotransferase; HER2, human epidermal growth factor receptor 2; TEAEs, treatment-emergent adverse events. • Lapatinib 100 • Neratinib Primary objectives Primary objectives Sum of RECIST target lesion diameters, median (range), cm 5.5 (1–19) 1. To assess the safety and tolerability 1. To assess the safety and tolerability at Data cutoff October 12, 2018. ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, 80 aHER2-low breast cancer population assessed in current study; currently undefined by HER2-testing guidelines. immunohistochemistry; RECIST, response evaluation criteria in solid tumors. CONCLUSIONS bHER2 status according to ASCO/CAP guidelines.4 2. To determine the MTD or RDE the MTD/RDE IHC 2+ ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; BC, breast cancer; HER2, human epidermal growth 60 receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; T-DM1, ado-trastuzumab emtansine. 2. To evaluate the efficacy at the MTD/RDE IHC 1+ • In this phase 1 study, [fam-] trastuzumab deruxtecan demonstrated promising antitumor Efficacy activity in heavily pretreated subjects with HER2-low breast cancer • [Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody- Secondary objectives Secondary objectives 40 • The ORR with confirmation of complete/partial response was 19/43 (44.2%) in the —— In these subjects with HER2-low breast cancer, efficacy was also observed in the drug conjugate with a humanized HER2-targeted antibody, a proprietary peptide- 1. To assess the PK 1. To assess the PK efficacy evaluable subjects, with a median DOR of 8.1 months and a median PFS of 7.6 20 subgroups of subjects with HR-negative disease, in those receiving prior CDK4/6 based cleavable linker that is stable in plasma and selectively cleaved by cathepsins 2. To evaluate the efficacy 2. To assess antidrug antibodies months (Table 3) inhibitors, and in those with HER2 IHC 1+ upregulated in tumor cells, and a potent topoisomerase I inhibitor payload (Figure 1)8 0 3. To assess antidrug antibodies —— The ORR was 14/34 (41.2%) in HER2-low breast cancer subjects who had not • The safety profile of [fam-] trastuzumab deruxtecan was consistent with what would be • The [fam-] trastuzumab deruxtecan high drug-to-antibody ratio of approximately 8, MTD, maximum tolerated dose; PK, pharmacokinetics; RDE, recommended dose for expansion. received prior HER2-targeted therapy –20 expected for a HER2-targeted antibody-drug conjugate that utilizes a topoisomerase I together with the bystander effect of the released payload due its membrane permeability, • Efficacy was also observed in those subjects with hormone receptor (HR)-negative inhibitor as its payload can potentially allow for targeting tumors with heterogeneous or low HER2 expression8,9 FIGURE 3. Phase 1 Study Design –40 disease, in those receiving prior CDK4/6 inhibitors, and in those with HER2 IHC 1+ —— The 2 most common classes of TEAEs were gastrointestinal and hematologic in nature —— The bystander effect occurs when released payload crosses the cell membrane of • Best percentage change in tumor size from baseline and percentage change in tumor targeted cells and affects cells in close proximity, regardless of their level of HER2 Dose escalation (Part 1) Dose expansion (Part 2) –60 • Drug-related ILD/pneumonitis, including fatal cases, have been reported in the overall

size over time in individual subjects are shown in Figures 4 and 5 changePercentagein tumorsize from baseline study population; all suspected cases of ILD/pneumonitis are reviewed by an independent expression –80 ILD adjudication committee (see Poster #P6-17-06 at SABCS 2018) HNSTD TABLE 3. Efficacy Outcomes in HER2-low Breast Cancer Subjects FIGURE 2. Structure of [Fam-] Trastuzumab Deruxtecan Part 2a HER2-positive (Efficacy Analysis Population) –100 —— A robust monitoring and management plan has been established and implemented T-DM1 pretreated BC 10 20 30 40 50 60 70 80 90 100 110 120 across all studies of [fam-] trastuzumab deruxtecan Proprietary drug-linker and payload Breast cancer or gastric/GEJ adenocarcinomaa (IHC 3+ or ISH +) 8.0 mg/kg TTR, DOR, PFS, Weeks O mCRM with EWOC a a • A phase 3 trial to assess the efficacy and safety of [fam-] trastuzumab deruxtecan O Confirmed Confirmed median median median Dotted lines denote 30% decrease and 20% increase in tumor size cutoffs for partial response and progressive disease, respectively. O H Part 2b Administered IV Q3W 6 pts IHC, immunohistochemistry. in subjects with HER2-low breast cancer has been initiated (DESTINY-Breast04; RDE HER2-positive ORR, n/N (%) DCR, n/N (%) (95% CI), mo (range), mo (95% CI), mo 3 6 O Trastuzumab pretreated GC ClinicalTrials.gov NCT03734029) N 6.4 mg/kg O (IHC 3+ or IHC 2+/ISH+) 2.8 9.4 7.6 Safety O O O N All (N = 51) 19/43 (44.2) 34/43 (79.1) H H H 6 pts 6 pts (1.6, 3.0) (1.5+, 23.6+) (4.9, 13.7) 4 5 CysS N N N N RDE 1 8 N N N O • Among the 170 breast cancer subjects, regardless of HER2-status, treated with ≥1 dose H H H O O O O 2 7 F 5.4 mg/kg Part 2c of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg, 99.4% experienced a treatment- HER2-low BC Subgroups Pharmacologically active level (IHC 2+/ISH–, IHC 1+/ISH–) emergent adverse event (TEAE) regardless of causality, 22.9% experienced a serious REFERENCES 2.8 7.9 5.7 IHC 1+ (n = 27) 7/21 (33.3) 14/21 (66.7) TEAE, 50.0% experienced a grade ≥3 TEAE, and there were 5 drug-related TEAEs 1) Rakha EA, et al. J Clin Pathol. 2015; 68:93-9; 2) Howlader N, et al. J Natl Cancer Inst. 2014; 106; 3) (1.2, 3.0) (2.1+, 11.3) (1.4, 7.9) 3.2 mg/kg 3 pts leading to death Kohler BA, et al. J Natl Cancer Inst. 2015; 107:djv048; 4) Wolff AC, et al. J Clin Oncol. 2018; 36:2105– Cysteine residue Part 2d 22; 5) Cardoso F, et al. Annals of Oncology. 2017; 28:16–33; 6) Giordano SH, et al. J Clin Oncol. 2014; HER2-expressing non-BC/GC and/or 2.7 11.0 13.6 • There were 4 fatal cases of interstitial lung disease (ILD)/pneumonitis in breast cancer 32:2078–99; 7) NCCN Clinical Practical Guidelines in Oncology. 2017; 8) Ogitani Y, et al. Clin Cancer Res. Drug-linker any tumor with HER2 mutation IHC 2+ (n = 24) 12/22 (54.5) 20/22 (90.9) (1.2, 3.9) (1.5+, 23.6+) (NA) 2016; 22:5097–108; 9) Ogitani Y, et al. Cancer Sci. 2016; 107:1039–46; 10) Doi T, et al. Lancet Oncol 2017; O 3 pts subjects, including 2 fatal cases in HER2-low breast cancer subjects, and all suspected H O 1.6 mg/kg 18:1512–22. 2.8 11.0 7.9 N H HR+ (n = 45) 18/38 (47.4) 31/38 (81.6) cases of ILD/pneumonitis are reviewed by an independent ILD adjudication committee Minimum effective level Part 2e (PK cohort) (2.6, 3.0) (1.5+, 23.6+) (4.4, 13.7) O N HER2-expressing BC, including HER2-low BC —— For further detail on the results of the ILD/pneumonitis adjudication, please see Poster F N (IHC 1+, IHC 2+, IHC 3+ and/or ISH+) Prior CDK4/6 2.7 7.1 3 pts 4/12 (33.3) 9/12 (75.0) NR #P6-17-06 at SABCS 2018 Conjugation chemistry O 0.8 mg/kg inhibitor (n = 15) (1.4, 3.0) (NA) ACKNOWLEDGMENTS The linker is connected to the cysteine residue of the antibody O H O Data cutoff October 12, 2018. • Frequent grade ≥3 TEAEs (≥10% regardless of causality) included anemia (14.7%) and This study was sponsored by Daiichi Sankyo Co., Ltd. We thank the patients who are participating in this The present analysis included all subjects from Part 1, Part 2c, and Part 2e with HER2-low BC who were treated with ≥1 dose of aEvaluable subjects for confirmed response had ≥2 postbaseline scans or progressive disease at the first scan and/or discontinued treatment decreased neutrophil counts (11.2%) ( ) study, as well as their families and caregivers. Medical writing and editorial support for this poster was [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg. for any reason. Table 4 Payload (DXd) aSubjects in Part 1 included both HER2-positive (IHC 3+ or IHC2+/ISH-positive) and HER2-low expressing tumors. +, indicates that the values contain censored observations. provided by Marie-Louise Ricketts, PhD and Stefan Kolata, PhD of AlphaBioCom, LLC, and funded by Exatecan derivative BC, breast cancer; CRC, colorectal cancer; EWOC, escalation with overdose control; GC, gastric cancer; GEJ, gastroesophageal junction; BC, breast cancer; CI, confidence interval; DCR, disease control rate; DOR, duration of response; HER2, human epidermal growth receptor 2; • The safety profile of [fam-] trastuzumab deruxtecan among subjects with HER2-low Daiichi Sankyo, Co., Ltd. HER2, human epidermal growth factor receptor 2; HNSTD, highest non-severely toxic dose; IHC, immunohistochemistry; ISH, in situ HR, hormone receptor; IHC, immunohistochemistry; ORR, objective response rate; NA, not available; NR, not reached; PFS, progression-free hybridization; IV, intravenous; mCRM, modified continuous reassessment method; PK, pharmacokinetics; pts, patients; Q3W, once every 3 survival; TTR, time to response. breast cancer was consistent with safety profile among all subjects with breast cancer weeks; RDE, recommended dose for dose expansion; T-DM1, ado-trastuzumab emtansine.

This presentation is the intellectual property of the authors. Please contact Dr. Modi at [email protected] for permission to reprint and/or distribute.