Rapid Fire 6

S. Loibl¹, Y. Park², Z. Shao³, C. Huang⁴, C. H. Barrios⁵, J. Abraham⁶, A. Prat⁷, N. Niikura⁸, M. Untch⁹, S. Im¹⁰, W. Li¹¹, H. Li¹², Y. Wang¹³, H. Yao¹⁴, S. Kim¹⁵, E. Mathias¹⁶, J. Petschauer¹⁷, W. Lu¹⁸, H. Abdel-Monem¹⁹, C. E. Geyer, Jr.²⁰; ¹Department of Medicine and Research, GBG Neu-Isenburg and Goethe University, Neu-Isenburg, GERMANY, ²Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ³Department of Breast Surgery, Fudan University Cancer Hospital, Shanghai, CHINA, ⁴Department of Surgery, National Taiwan University Hospital, Taipei City, TAIWAN, ⁵Department of Oncology, Hospital São Lucas da PUCRS, Porto Alegre, BRAZIL, ⁶Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, ⁷Department of Medical Oncology, Hospital Clínic de Barcelona, Barcelona, SPAIN, ⁸Department of Breast Oncology, Tokai University School of Medicine, Isehara, JAPAN, ⁹Department of Gynecologic Oncology and Obstetrics, Helios Hospital Berlin-Buch, Berlin, GERMANY, ¹⁰Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Cancer Research Institute, Seoul National University, Seoul, KOREA, REPUBLIC OF, ¹¹Tumor Center, First Hospital of Jilin University, Changchun City, CHINA, ¹²Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, CHINA, ¹³Department of Breast Surgery, Cancer Hospital of Shandong First Medical University, Jinan City, CHINA, ¹⁴Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Guang Zhou, CHINA, ¹⁵Department of Oncology, Asan Medical Center, Seoul, KOREA, REPUBLIC OF, ¹⁶Department of Global Oncology Research and Development, Daiichi Sankyo, Inc., Basking Ridge, NJ, ¹⁷17Clinical Science, Daiichi Sankyo, Inc., Basking Ridge, NJ, ¹⁸Department of Biostatistics and Data Management, Daiichi Sankyo, Inc., Basking Ridge, NJ, ¹⁹Department of Clinical Safety and Pharmacovigilance, Clinical Science, Daiichi Sankyo, Inc., Basking Ridge, NJ, ²⁰Department of Medicine, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA.

Background: In the phase 3 DESTINY-Breast05 study (NCT04622319)of T-DXd vs T-DM1 in patients with residual invasive HER2+BC after neoadjuvant treatment (NAT), T-DXd demonstrated statistically significant and clinically meaningful improvement vs T-DM1 in the primary endpoint of invasive disease-free survival (IDFS) and the key secondary endpoint of disease-free survival (DFS; Geyer, ESMO 2025). ~80% of patients had invasive residual disease in the axillary lymph nodes, 93% received adjuvant radiotherapy (56% concurrent [n = 918]; 37% sequential [n = 605]), and 79%received dual HER2-targeted NAT. Safety was generally manageable with no new safety signals. Here we report additional efficacy and safety data from the DESTINY-Breast05 interim analysis.  Methods: Patients with residual invasive HER2+ BC following NAT consisting of anti-HER2 therapy and taxane-based chemotherapy and at high risk for recurrence (cT4, N0-3, M0 or cT1-3, N2-3, M0 at presentation prior to NAT, or cT1-3, N0-1, M0, with axillary node-positive disease [ypN1-3] following NAT)were randomized 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg once every 3 weeks for 14 cycles. All patients receiving adjuvant radiotherapy (RT) were required to have serial chest computed tomography (CT) scans; details to be presented. RT could be administered concurrently with study therapy or prior to initiating study therapy (sequential). Patients receiving sequential therapy had an additional CT scan at the end of the RT.  Results: At data cutoff (July 2, 2025), 1635 patients were randomized to T-DXd (n = 818) or T-DM1 (n = 817). Median treatment duration was similar in both arms; more than 70% of patients in both arms received 14 cycles of study therapy. Efficacy results in clinically relevant subgroups will be presented. Adjudicated drug-related interstitial lung disease(ILD) and investigator-reported radiation pneumonitis by timing of adjuvant RT are summarized in the Table. Adjudicated drug-related ILD occurred in 9.6% of patients who received T‑DXd; most ILD events were grade 1 or 2, and 0.2% had grade 5 events. No notable differences were observed based on adjuvant RT timing. Incidence of investigator-reported radiation pneumonitis was similar in both arms (31.4% with T-DXd and 30.5% with T-DM1), with no grade ≥3 events and the majority being grade 1.  Conclusions: The additional analyses further characterize the positive benefit of T-DXd over T-DM1 in the post-neoadjuvant HER2+ BC residual disease setting, supporting T-DXd as a potential new standard-of-care in this setting. Timing of adjuvant RT did not impact incidence of adjudicated drug-related ILD with T-DXd. Additional results will be presented.

Table. Key Safety Outcomes by Adjuvant RT

CC, concurrent; ILD, interstitial lung disease; RP, radiation pneumonitis; RT, radiotherapy; Seq, sequential.

^aGrouped term. Includes the preferred terms pulmonary radiation injury, radiation alveolitis, radiation bronchitis, radiation fibrosis – lung, radiation pneumonitis.

G. Curigliano¹, N. Harbeck², J.-F. Boileau³, S. Modi⁴, J. Wu⁵, S. Ohno⁶, C. Kelly⁷, X. Cao⁸, A. Fabi⁹, S. Escrivá-de-Romaní¹⁰, A. Shimomura¹¹, É. Poirier¹², R. Joseph¹³, L. Seneviratne¹⁴, S.-C. Chen¹⁵, M. Tiambeng¹⁶, J. Pedrini¹⁷, M. Schwaederle¹⁸, M. Gufran¹⁹, A. Darilay²⁰, L. Pusztai²¹; ¹Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS & Department of Oncology and Hematology-Oncology, University of Milano, Milano, Italy, ²Breast Center, Department of OB&GYN, LMU University Hospital and CCC Munich, Munich, Germany, ³Departments of Surgery and Gerald Bronfman Oncology, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada, ⁴Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York,, NY, ⁵Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China, ⁶Breast Thyroid Surgery, Sagara Hospital, Kagoshima, Japan, ⁷Department of Medical Oncology, Mater Private Hospital & Cancer Trials Ireland Breast Group, Dublin, Ireland, ⁸The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer & Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China, ⁹Precision Medicine Unit in Senology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, ¹⁰Medical Oncology Department, Breast Cancer Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain, ¹¹Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo, Japan, ¹²Department of Surgery, CHU de Québec, Université Laval, Laval, QC, Canada, ¹³Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, India, ¹⁴Department of Medical Oncology, Los Angeles Cancer Network, Los Angeles, CA, ¹⁵Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyüan, Taiwan, ¹⁶Section of Medical Oncology, Department of Internal Medicine, Cardinal Santos Medical Center, San Juan, Metro Manila, Philippines, ¹⁷Instituto de Medicina Pesquisa & Desenvolvimento, Grupo Hospitalar Conceição, Porto Alegre, Brazil, ¹⁸Clinical Development, Late-Stage Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, ¹⁹Global Medicines Development, Patient Safety Oncology, AstraZeneca, Luton, United Kingdom, ²⁰Biometrics Oncology, Late-Stage Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, ²¹Yale Cancer Center, Yale University School of Medicine, New Haven, CT

Background: Neoadjuvant standard-of-care for HER2+ eBC consists of dual HER2 blockade and cytotoxic agents associated with short- and long-term toxicities. In DB-11, T-DXd-THP showed a statistically significant and clinically meaningful pathologic complete response benefit and improved safety profile vs ddAC-THP. We report data for clinically relevant adverse events (AEs). Methods: Patients (pts) with high-risk (≥T3, node positive [N1-3] or inflammatory), HER2+ eBC were randomized to neoadjuvant T-DXd (8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). Chest HRCT scans were performed every 6 weeks. AEs of special interest were adjudicated interstitial lung disease (ILD)/pneumonitis (systemic steroids recommended) and left ventricular dysfunction (LVD). Clinically relevant AEs (nausea/vomiting [N/V], neutropenia, and peripheral neuropathy) are also described. Outcomes are reported in the safety analysis set (≥1 dose of any study drug). Results: At primary analysis (data cutoff Mar 12, 2025; N=915), all-grade adjudicated drug-related ILD/pneumonitis rates were low across arms (Table) and were maintained (T-DXd-THP) or higher (ddAC-THP) in the THP phase (Cycles 5-8) vs Cycles 1-4. Rates of serious AEs (T-DXd 0.4%; T-DXd-THP 0.6%; ddAC-THP 2.9%), Grade ≥3 adjudicated drug-related ILD/pneumonitis, and all-grade/Grade ≥3 LVD were highest with ddAC-THP (Table). For T-DXd, T-DXd-THP, and ddAC-THP, respectively, steroids were received by 71.4%, 64.3%, and 56.3% of pts with adjudicated drug-related ILD/pneumonitis; 57.1%, 71.4%, and 81.3% of cases resolved. N/V was more common with T-DXd and T-DXd-THP than ddAC-THP, but use of 3 recommended prophylactic antiemetics before Cycle 1 was lower (T-DXd 14.1%; T-DXd-THP 16.9%; ddAC-THP 39.7%); 2 recommended antiemetics were used in 55.5% (T-DXd), 57.2% (T-DXd-THP), and 40.4% (ddAC-THP) of pts. N/V was mainly low grade and nonserious, and rates decreased after Cycles 1-4. Neutropenia rates were highest with ddAC-THP across cycles; granulocyte colony-stimulating factor use was lower with T-DXd (16.1%) and T-DXd-THP (22.7%) than ddAC-THP (87.2%). Peripheral neuropathy rates were lowest with T-DXd; across all treatments, events were predominantly low grade and nonserious, and most occurred during the THP phase. Conclusion: Across arms, adjudicated drug-related ILD/pneumonitis rates were low, with fewer Grade ≥3 events with T-DXd and T-DXd-THP than ddAC-THP. LVD and neutropenia rates were highest with ddAC-THP. Although rates of N/V were higher with T-DXd and T-DXd-THP than ddAC-THP and peripheral neuropathy rates were higher with T-DXd-THP, events were generally low grade and nonserious, demonstrating a safety profile that is manageable with recommended treatment.

X. Hu¹, J. Yu², T. Sun³, Q. Zhang⁴, H. Li⁵, J. Yao⁶, Y. Shi⁷, T. Wu⁸, X. Jia⁹, Y. Shi¹⁰, S. Ding¹¹, W. Chen¹², Y. Zeng¹³, X. Zeng¹⁴, Y. Yin¹⁵, J. Wu¹⁶, J. Sun¹⁷, D. Luo¹⁸, J. Nie¹⁹, F. Li²⁰, Y. Liu²¹, Z. Zhang²², C. Yuan²³, C. Yang²⁴, H. Yang²⁵, C. Li²⁶, X. Ling²⁷, X. Wu²⁸, G. Li²⁹, Z. Li³⁰, Z. Pan³¹, J. Zhang³¹, Q. Zhou³¹; ¹Fudan University Shanghai Cancer Center, Shanghai, CHINA, ²Shandong Cancer Hospital, Jinan, CHINA, ³Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Cancer Hospital of Dalian University of Technology, Shenyang, CHINA, ⁴Harbin Medical University Affiliated Cancer Hospital, Shanghai, CHINA, ⁵Beijing Cancer Hospital, Beijing, CHINA, ⁶Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, CHINA, ⁷Sun Yat-sen University Cancer Center, Guangzhou, CHINA, ⁸‌The First People’s Hospital of Changde, Changde, CHINA, ⁹Deyang People’s Hospital, Deyang, CHINA, ¹⁰Tianjin Medical University Cancer Institute Hospital, Tianjin, CHINA, ¹¹The Central Hospital of Yongzhou, Yongzhou, CHINA, ¹²Nanchang People’s Hospital, Nanchang, CHINA, ¹³Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, CHINA, ¹⁴Chongqing University Cancer Hospital, Chongqing, CHINA, ¹⁵Jiangsu Province Hospital, Nanjing, CHINA, ¹⁶Meizhou People’s Hospital, Meizhou, CHINA, ¹⁷Anyang Tumor Hospital, Shanghai, CHINA, ¹⁸The First People’s Hospital of Zunyi, Zuny, CHINA, ¹⁹Yunnan Cancer Hospital, Kunming, CHINA, ²⁰The Second Hospital of Anhui Medical University, Hefei, CHINA, ²¹Jilin Cancer Hospital, Changchun, CHINA, ²²Nanyang First People’s Hospital, Nanyang, CHINA, ²³General Hospital of Ningxia Medical University, Yinchuan, CHINA, ²⁴Yuebei People’s Hospital, Shaoguan, CHINA, ²⁵Affilated Hospital of Hebei University, Shanghai, CHINA, ²⁶AnQing Municipal Hospital, Shanghai, CHINA, ²⁷The First Hospital of Lanzhou University, Lanzhou, CHINA, ²⁸Hubei Cancer Hospital, Wuhan, CHINA, ²⁹Shanghai Tongji Hospital, Shanghai, CHINA, ³⁰Anshan Cancer Hospital, Anshan, CHINA, ³¹CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, CHINA.

Background: Despite advances in anti-HER2 therapy, treatment options remain limited for patients (pts) with HER2-positive (HER2+) advanced breast cancer (ABC) who have progressed on at least trastuzumab and taxane in China. DP303c is a novel antibody-drug conjugate targeting HER2, composed of a humanized anti-HER2 monoclonal antibody conjugated to monomethyl auristatin E. This phase III study compared the efficacy and safety of DP303c with T-DM1 in pts with HER2+ ABC who had received prior trastuzumab and taxane therapy. Methods: Adult pts with HER2+ ABC previously treated with trastuzumab and taxane were randomly assigned (1:1) to receive DP303c (3.0 mg/kg Q3W) or T-DM1 (3.6 mg/kg Q3W). Pts were stratified by number of lines of previous systemic therapy (≤1 vs. >1), prior pertuzumab treatment (Yes vs. No), and visceral metastasis(Yes vs. No). The primary endpoint was PFS assessed by a blinded independent review committee (BIRC). Secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Results: Between Mar 28, 2024 and April 25, 2025, 448 pts were randomized (DP303c, n=226; T-DM1, n=222). Baseline characteristics were well balanced. Median age was 54 (range:25, 78) years; median weight 60.0 (range:36, 99.5) kg; 78.8% were HER2 IHC 3+, 52.0% were hormone receptor-positive, 68.8% had visceral metastasis and 11.4% had intracranial metastases in intent-to-treat population. Overall, 59.8% had received ≥2 lines of advanced systemic therapy, with 51.1% previously treated with pertuzumab and 55.8% with HER2 tyrosine kinase inhibitors . At interim analysis (cut-off date: July 8, 2025; median follow-up: 7.4 months), BIRC-assessed PFS was significantly improved with DP303c (median PFS 8.8 months; 95% CI: 7.20, 9.92) vs T-DM1 (median PFS 5.8 months; 95% CI: 4.67, 7.10) (p<0.0001), with a stratified hazard ratio (HR) of 0.56 (95% CI: 0.42, 0.75). Investigator-assessed PFS showed consistent results (median PFS 9.7 vs 6.9 months; p<0.0001; HR 0.55, 95% CI: 0.41, 0.73). The confirmed ORR per BIRC was significantly higher with DP303c (62.8%; 95% CI: 56.17, 69.15) vs T-DM1 (42.8%; 95% CI: 36.19, 49.59), with a rate difference of 20.0% (95% CI: 10.93, 29.16). CBR per BIRC was 68.6% (95% CI: 62.10, 74.58) vs 50.9% (95% CI: 44.13, 57.65). OS was immature at this analysis. Treatment-emergent adverse events (TEAEs) occurred in 99.6% of DP303c and 99.1% of T-DM1 pts. The most common TEAEs (≥20%) with DP303c included corneal disorder, vision blurred, dry eye, peripheral sensory neuropathy, hyperlipidemia, alopecia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and weight decreased. Only 1 pt had ulcerative keratitis, with no corneal perforation or blindness in DP303c group. The most common TEAEs (≥20%) with T-DM1 were AST increased, platelet count decreased, ALT increased, corneal disorder, dry eye, vision blurred, neutrophil count decreased, white blood cell count decreased, hyperlipidemia, anemia, Gamma-glutamyltransferase increased, and hypercholesterolaemia. Permanent discontinuation due to treatment-emergent adverse events was observed in 2 pts (0.9%) receiving​​ DP303c and 3 (1.4%) receiving​​ T-DM1. One on-treatment death occurred in each group, judged to be unrelated to study treatment per investigator. Conclusion: DP303c demonstrated statistically significant and clinically meaningful improvement in PFS compared with T-DM1 in pts with HER2+ ABC who had been previously treated with trastuzumab and taxane. The safety profile of DP303c was manageable. These results support DP303c as a potential new treatment option for HER2+ ABC.

J. L. Wright¹, K. Ko², W. Kenworthy², W. Bosch³, L. Braunstein⁴, G. Freedman², E. Gillespie⁵, R. Jimenez⁶, S. Pugh⁷, H. Lu², M. Pankuch⁸, N. Remmes⁹, W. Straube³, W. Zou², E. Berlin², L. Fang¹⁰, S. MacDonald¹¹, N. Taunk², J. Kim⁵, A. Thukral⁸, A. Taghian⁶, M. Mishra¹², R. Mutter⁹, V. Croog¹³, D. Boggs¹⁴, J. Urbanic¹⁵, N. Ohri¹⁶, A. Chawla¹⁷, T. Meier¹⁸, L. Rosen¹⁹, M. Fegundes²⁰, O. Cahlon²¹, K. Hoffman²², A. Ferriozzi², J. Bekelman², A. Lin², B. Ky²; ¹University of North Carolina, Chapel Hill, NC, ²University of Pennsylvania, Philadelphia, PA, ³Washington University, St Louis, MO, ⁴Memorial Sloan-Kettering Cancer Center, New York, NY, ⁵University of Washington, Seattle, WA, ⁶Massachusetts General Hospital, Boston, MA, ⁷American College of Radiology, Reston, VA, ⁸Northwestern University, Evanston, IL, ⁹Mayo Clinic-Rochester, Rochester, MN, ¹⁰Swedish Cancer Institute, Seattle, WA, ¹¹Southwest Florida Proton, Ft Meyers, FL, ¹²University of Maryland, College Park, MD, ¹³Johns Hopkins University, Baltimore, MD, ¹⁴University of Alabama, Tuscaloosa, AL, ¹⁵University of California- San Diego, San Diego, CA, ¹⁶Rutgers Cancer Institute, New Brunswick, NJ, ¹⁷Inova Schar Cancer Center, Fairfax, NJ, ¹⁸University of Cincinnati, Cincinnati, OH, ¹⁹Willis Knighton, Shreveport, LA, ²⁰Baptist Health, Miami, FL, ²¹New York University, New York, NY, ²²MD Anderson Cancer Center, Houston, TX

Objectives: In the RadComp randomized trial, we compared radiation dose to cardiac substructures in patients treated with proton versus photon radiation therapy (RT) ; evaluated changes in cardiac-specific health-related quality of life (HRQOL) outcomes from baseline to 6 months following RT; and determined associations between radiation dose volume histogram (DVH) parameters and changes in cardiac-specific HRQOL. Methods: The study cohort included patients with locally advanced breast cancer enrolled on RadComp who completed treatment per protocol, had available radiation DVH metrics for all cardiac substructures, and completed both the baseline and at least one follow-up cardiac-specific HRQOL over the 6 months post-RT. Cardiac-specific HRQOL measures included PROMIS fatigue, PRO-CTCAE shortness of breath (SOB) (severity and interference with daily activities), and PRO-CTCAE chest pain, chest tightness, and angina (frequency, severity, and interference). Detailed dose volume histograms (DVH) for cardiac substructures included the whole heart, left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), and left anterior descending artery (LAD) were derived. The Wilcoxon rank-sum test was used to compare dose distributions between photon and proton RT. Associations between DVH metrics and HRQOL outcomes were evaluated using repeated-measures linear regression via generalized estimating equations with an independent working correlation structure. All models were adjusted for RT type, age, cardiovascular risk factors, surgery type, laterality, ethnicity, education, timepoint, and race. Additional stratified analyses was performed according to laterality (right versus left + bilateral). Results: Across 1160 RadComp participants, RT exposure to cardiac substructures differed significantly between proton and photon RT and by laterality. Median mean heart dose was lower with protons, 0.9 Gy (Q1, Q3 0.49, 1.46), compared to photons 2.83 Gy (Q1, Q3 1.49, 4.52) (p< 0.001), and lower for right-sided disease, 0.91 Gy (Q1, Q3 0.44, 1.55), compared to left and bilateral 1.99 Gy (Q1, Q3 1.11, 3.63) (p<0.001). Similarly, for the LAD, LA, LV, and RA, mean proton dose was significantly lower (p<0.001). However, for the whole heart, RA, and RV, maximum doses to small-volume parameters and dose to 0.03cc were higher with proton RT. PRO-CTCAE measures of HRQOL were generally favorable at all timepoints across all participants, and grade ≥3 toxicity was rare (≤5.5%) for all measures. The PROMIS Fatigue T-Score increased from baseline (median 49 [Q1, Q3 46, 57]) to end of RT (55 [Q1, Q3 49, 63]), and returned to baseline levels at 6 months (p<0.001). While there were no significant differences in PRO-CTCAE SOB severity (p=0.24) and interference (p=0.11) over time, PRO-CTCAE chest pain worsened compared to pre-RT with respect to frequency (p<0.001), severity (p<0.001), and interference (p=0.008). However, the absolute changes were small. No DVH metrics were significantly associated with any cardiac-specific HRQOL outcomes. Stratification by laterality yielded similar results. Conclusions: Proton RT generally conferred significantly lower doses to the heart and cardiac substructures compared to photon RT. HRQOL outcomes were favorable across all participants, with fatigue returning to baseline, no change in SOB parameters, and a slight worsening of chest pain outcomes over 6 months following RT. Cardiac-specific HRQOLs appear not to be significantly affected by RT dose to cardiac substructures within the first 6 months post-RT. Other organs at risk that could also impact cardiac HRQOL endpoints, longer follow-up, and major cardiac events will be evaluated in future analyses.

K. Punie¹, S. M. Tolaney², A. Bardia³, S. A. Hurvitz⁴, C. Barrios⁵, A. Schneeweiss⁶, J. Sohn⁷, E. Tokunaga⁸, A. Brufsky⁹, Y. Park¹⁰, B. Xu¹¹, R. Hegg¹², M. Oliveira¹³, A. Fabi¹⁴, Y. Zhang¹⁵, H. Wang¹⁵, Y. Mu¹⁶, R. Delaney¹⁵, J. Cortés¹⁷; ¹Oncology Center Antwerp, Ziekenhuis aan de Stroom, Antwerp, BELGIUM, ²Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, ³David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, ⁴UW Medicine, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, ⁵Latin American Cooperative Oncology Group (LACOG), Porto Alegre, BRAZIL, ⁶Heidelberg University Hospital and German Cancer Research Center, Heidelberg, GERMANY, ⁷Yonsei Cancer Center, Seoul, KOREA, REPUBLIC OF, ⁸National Hospital Organization Kyushu Cancer Center, Fukuoka, JAPAN, ⁹Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburg, PA, ¹⁰Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ¹¹Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, CHINA, ¹²University of São Paulo, São Paulo, BRAZIL, ¹³Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, SPAIN, ¹⁴Precision Medicine Unit in Senology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, ITALY, ¹⁵Gilead Sciences, Inc., Foster City, CA, ¹⁶Thermofisher Scientific, Cambridge, MA, ¹⁷IBCC, Pangaea Oncol, Quiron Gp, Barcelona, SPAIN; IOB Madrid, Inst of Oncol, Hosp Beata María Ana, Madrid, SPAIN; Oncol Dept, Hosp Universitario Torrejón, Ribera Gp, Madrid, SPAIN; Universidad Europea de Madrid, Madrid, SPAIN; MEDSIR, Barcelona, SPAIN and, Ridgewood, NJ.

Background: In the ASCENT-03 study (NCT05382299), SG led to a statistically significant improvement in progression-free survival vs chemotherapy in patients with previously untreated advanced TNBC who are not candidates for PD-(L)1 inhibitors. We report PROs from this study. Methods: Patients were randomized to SG or chemotherapy (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel). Patients completed the EORTC QLQ-C30 at baseline, each cycle, and end of treatment. The key PRO-related secondary endpoints were change from baseline to week 25 in physical functioning and Time To first meaningful Deterioration (TTD) in fatigue. Changes from baseline and TTD in other domains, and Time To first meaningful Improvement (TTI) in all domains were assessed as exploratory endpoints. The meaningful within-patient changes from baseline for TTD and TTI analyses were defined as 13.33 points for physical functioning and 10 points for all other domains. Comparison between treatment arms was analyzed using a mixed-effect model for repeated measure for changes from baseline, the stratified Cox regression model for TTD, and the Fine-Gray subdistribution hazard regression model for TTI. Results: Analyses included 558 patients (279 in each arm). LS mean change from baseline favored SG for physical functioning, role functioning, global health status/quality of life (QOL), fatigue, pain, and dyspnea and favored chemotherapy for diarrhea; differences exceeded the minimum important differences (MID) for physical and role functioning (Table). TTD was comparable across most domains, including fatigue, but favored SG for dyspnea, and chemotherapy for nausea/vomiting and diarrhea, consistent with the known SG safety profile (Table). TTI favored SG for physical, role, cognitive, and social functioning, as well as fatigue, insomnia, appetite loss, and constipation and was comparable in both treatment arms for other domains (Table). Conclusions: The key secondary endpoints of LS mean changes from baseline to week 25 in physical functioning favored SG vs chemotherapy, while TTD in fatigue was similar in both treatment arms. These data, along with additional exploratory results reported here, suggest that SG was associated with more favorable and sustained benefits in QOL vs chemotherapy. The known gastrointestinal side effects of SG did not negatively impact global health status/QoL or functional domain scores in this analysis. Along with ASCENT-03 efficacy data, these data support SG as a potential new standard of care for patients with previously untreated advanced TNBC who are not candidates for PD-(L)1 inhibitors.

S. Modi¹, J. Boileau², J. Wu³, L. Pusztai⁴, S. Ohno⁵, G. Curigliano⁶, C. Kelly⁷, J. Asselah⁸, S. Im⁹, L. Coltelli¹⁰, M. Chaudhari¹¹, S. Blau¹², A. Martínez Bueno¹³, B. Czartoryska-Arlukowicz¹⁴, J. Pedrini¹⁵, C. Zhang¹⁶, S. Safdar¹⁷, S. Mannix¹⁸, N. Harbeck¹⁹; ¹Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, ²Surgery and Gerald Bronfman Oncology, Segal Cancer Centre, Jewish General Hospital, Montreal, QC, CANADA, ³Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, CHINA, ⁴Yale Cancer Center, Yale University School of Medicine, New Haven, CT, ⁵Breast Thyroid Surgery, Sagara Hospital, Kagoshima, JAPAN, ⁶Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS & Department of Oncology and Hematology-Oncology, University of Milano, Milano, ITALY, ⁷Department of Medical Oncology, Mater Private Hospital & Cancer Trials Ireland Breast Group, Dublin, IRELAND, ⁸Gerald Bronfman Department of Oncology, Cedars Cancer Centre, McGill University Health Centre, Montreal, QC, CANADA, ⁹Department of Internal Medicine, Seoul National University Hospital, Seoul, KOREA, REPUBLIC OF, ¹⁰Medical Oncology Unit ATNO, Pontedera Hospital, Pisa, ITALY, ¹¹Medical Oncology Department, HCG Manavata Cancer Centre, Nashik, INDIA, ¹²Exigent Research Network, Tacoma, WA, ¹³Instituto Oncológico Rosell, Hospital Quiron Dexeus, Barcelona, SPAIN, ¹⁴Breast Cancer Unit, Białostockie Centrum Onkologii im.M.Skłodowskiej-Curie, Białystok, POLAND, ¹⁵Instituto de Medicina Pesquisa & Desenvolvimento Grupo Hospitalar Conceição, Porto Alegre, BRAZIL, ¹⁶Biometrics, Late-Stage Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, ¹⁷Clinical Development, Late-Stage Oncology, Oncology R&D, AstraZeneca, Toronto, ON, ¹⁸Clinical Outcomes Assessment Measurement Science, Evinova, AstraZeneca Group, Gaithersburg, MD, ¹⁹Breast Center, Department of OB&GYN, LMU University Hospital and CCC Munich, Munich, GERMANY.

Background: In the DESTINY-Breast11 Phase 3 study, NAT with T-DXd-THP showed a statistically significant and clinically meaningful improvement in pathologic complete response rate and improved safety profile vs ddAC-THP in high-risk, HER2+ eBC. We report physical functioning (PF) and patient-reported tolerability during NAT. Methods: Patients with high-risk (≥T3, node positive [N1-3], or inflammatory), HER2+ eBC were randomized to NAT T-DXd (8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). PF was measured on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire Core 30 (QLQ-C30) PF subscale. Twenty symptomatic adverse events (AEs) were measured using select items from the PRO version of the Common Terminology Criteria for Adverse Events, EORTC-QLQ-C30, and EORTC item library. The Patient Global Impression of Treatment Tolerability measured overall side-effect bother. Descriptive PRO analyses included all patients who received ≥1 dose of study intervention. Results: In the T-DXd, T-DXd-THP, and ddAC-THP arms, respectively, 283, 320, and 312 patients began treatment. More patients had maintained or improved PF during NAT with T-DXd and T-DXd-THP vs ddAC-THP (range across weeks, respectively: 42.7-75.5%, 43.7-75.7%, and 24.0-62.4%; Table). Overall side-effect bother during NAT was generally lower with T-DXd and T-DXd-THP than ddAC-THP, with a numerically lower proportion of patient-weeks with high side-effect bother (T-DXd 45.8%; T-DXd-THP 43.0%; ddAC-THP 49.5%). Of the 20 symptomatic AEs measured, 14 and 13 AEs, respectively, were generally better with T-DXd and T-DXd-THP than ddAC-THP (both: diarrhea, appetite loss, taste changes, mouth/throat sores, numbness/tingling, muscle pain, joint pain, chest pain, cough, dyspnea, rash, hot flashes, insomnia; T-DXd: nosebleed). Although present in all arms, five AEs were generally worse with T-DXd and/or T-DXd-THP vs ddAC-THP (both: hair loss, headache, nausea, vomiting; T-DXd: constipation; T-DXd-THP: nosebleed). For symptomatic AEs for which impact on daily activities was assessed (headache, insomnia, joint pain, mouth/throat sores, muscle pain, numbness/tingling), limited interference on daily activities was observed across all arms. Conclusion: More patients had maintained or improved PF with T-DXd or T-DXd-THP vs ddAC-THP. T-DXd and T-DXd-THP demonstrated a lower patient-reported treatment burden (tolerability, symptomatic AEs) than ddAC-THP. These findings, together with the favorable safety and efficacy profile of T-DXd-THP vs ddAC-THP, support T-DXd-THP as a tolerable therapy in high-risk HER2+ eBC.  Table. Patient-reportedPF by EORTC-QLQ-C30 PF subscale

*Change from baseline score <10 or increase ≥10

M. Rimawi¹, S. Loibl², Z. Jiang³, R. Barroso-Sousa⁴, Y. Park⁵, C. Saura⁶, A. Schneeweiss⁷, M. Toi⁸, Ç. Arslan⁹, W. Chen¹⁰, J. Sohn¹¹, W. Li¹², H.-C. Wang¹³, M. Şendur¹⁴, J. Asselah¹⁵, A. Roborel de Climens¹⁶, J. Liu¹⁷, D. Huang¹⁸, J. Shetty¹⁹, S. Tolaney²⁰; ¹Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, ²University Hospital Goethe, University Frankfurt/M, GBG, Neu-Isenburg, Germany, ³Department of Breast Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China, ⁴Hospital Brasilia, Rede Américas, DF, Brazil, ⁵Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of, ⁶Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, ⁷National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany, ⁸Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan, ⁹Department of Medical Oncology, Izmir University of Economics, Izmir, Turkey, ¹⁰Department of Breast Oncology, The Third Hospital of Nanchang, Nanchang, China, ¹¹Division of Medical Oncology, Yonsei Cancer Center, Seoul, Korea, Republic of, ¹²Department of Cancer Center, The First Hospital of Jilin University, Chaoyang District, Changchun, Jilin, China, ¹³Department of Surgery, China Medical University Hospital, Taichung City, Taiwan, ¹⁴Department of Medical Oncology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara Bilkent City Hospital, Ankara, Turkey, ¹⁵Gerald Bronfman Department of Oncology, McGill University Health Centre, Cedars Cancer Center, Montreal, QC, Canada, ¹⁶Patient-Centered Solutions, IQVIA, Paris, France, ¹⁷Biometrics Oncology, Late-Stage Development, Oncology R&D, AstraZeneca, South San Francisco, CA, ¹⁸Global Medicines Development, Oncology R&D, AstraZeneca, Mississauga, ON, Canada, ¹⁹Clinical Development, Late-Stage Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, ²⁰Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Background: In the Phase 3 randomized trial, DESTINY-Breast09 (NCT04784715), T-DXd + P significantly improved progression-free survival (PFS) compared with standard-of-care THP as 1L therapy for pts with HER2+ a/mBC, with no new safety signals. Here, we present PROs for the T-DXd + P and THP arms. The T-DXd monotherapy arm remains blinded until the final PFS analysis. Methods: Eligible pts had HER2+ a/mBC and no prior systemic therapy for a/mBC (1 line of endocrine therapy [ET] allowed). (Neo)adjuvant HER2-directed therapy/chemotherapy with a disease-free interval of >6 months was permitted. Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg once every 3 weeks (= one cycle), T-DXd + P, or THP. Pts with hormone receptor-positive disease could add ET after taxane discontinuation or six cycles of T-DXd. PRO secondary endpoints included: time to deterioration (TTD) in pain via the EORTC QLQ-C30; the proportion of pts experiencing treatment-related symptoms via selected scales/items of the QLQ-C30, EORTC QLQ-BR45, and PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE); the proportion of pts with ‘maintained or improved’ physical function via the QLQ-C30; and side effect burden via the Patient Global Impression of Treatment Tolerability (PGI-TT). PROs were assessed on Day 1 of each cycle until Cycle 9, with the QLQ-C30/-BR45 assessed every second cycle thereafter until progression. Results: In total, 383 pts were randomized to T-DXd + P and 387 to THP. Median TTD in pain was not reached in either arm; the risk of pain deterioration was similar in both arms (hazard ratio 0.95; 95% CI 0.74, 1.21; maturity 35%). On the QLQ-C30/-BR45, more pts in the T-DXd + P arm reported deterioration in nausea/vomiting, constipation, and appetite loss, whereas fewer pts reported deterioration in skin/mucosal symptoms compared with THP (Table). On the PRO-CTCAE, fewer pts in the T-DXd + P arm experienced nosebleeds and extremity swelling vs those in the THP arm. PGI-TT outcomes were comparable between arms. Most pts had ‘maintained or improved’ physical function: 82.9% with T-DXd + P vs 82.4% with THP at Cycle 2; and 75.4% vs 77.7%, respectively, at Cycle 27 (~18.7 months, the expected median PFS in the THP arm). Conclusions: T-DXd + P was associated with more gastrointestinal symptoms but fewer skin/mucosal, nosebleed, and extremity swelling symptoms vs THP. Pain, fatigue, physical function, and overall patient-reported treatment impact were similar between regimens. Complementing the efficacy and safety results, PRO data support T-DXd + P as a new 1L treatment in HER2+ a/mBC providing durable pain control and maintenance of physical function, with distinct quality of life advantages compared with THP.