Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1]. A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020

TotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236

TotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2][56.7; 79.8][22.7; 45.4]16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI][6.2; 9.7][5.4; NR][4.4; 8.7][2.8; 8.3]Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7][8.4; NR][4.6; 8.5][2.1; 6.9]

Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [abstract]. In …