DESTINY-Breast03 Phase 3 Study Results

Abstract 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