Erratum to 'Pooled analysis of trastuzumab deruxtecan retreatment after recovery from grade 1 interstitial lung disease/pneumonitis': [Annals of Oncology. Volume 36, Issue 11, November 2025, Pages 1389-1399

3025 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for pts with unresectable or metastatic HER2+ BC with ≥2 prior anti-HER2–based therapies. T-DXd showed improved progression-free survival vs trastuzumab emtansine (T-DM1) as an earlier-line treatment (tx) for pts with HER2+ metastatic BC in the phase 3 DESTINY-Breast03 trial (Cortes J, et al. Ann Oncol. 2021;32:S1283-S1346. Abstract LBA1). Preliminary antitumor activity of T-DXd was shown in heavily pretreated pts with HER2-low advanced/metastatic BC in the phase 1 DS8201-A-J101 trial (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). We report preliminary results from the dose-finding phase of 2 trials investigating T-DXd combination tx in HER2+ or HER2-low metastatic BC. Methods: DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773) are 2-part, modular, open-label, multicenter trials of T-DXd combined with other anticancer tx in pts with advanced/metastatic BC that is HER2+ (DB-07) or HER2 low (DB-08). Part 1 of each study is an ongoing dose-finding phase; pts must have ≥1 prior tx for metastatic BC. Part 2 of each study is a dose-expansion phase; pts must have no (DB-07) or ≤1 (DB-08) prior tx for metastatic BC. We report preliminary results from the T-DXd + pertuzumab module of DB-07 part 1 (data cutoff: Oct 15, 2021) and T-DXd + anastrozole and T-DXd + fulvestrant modules of DB-08 part 1 (data cutoff: Sep 27, 2021); pts in the DB-08 modules must be hormone receptor positive. The part 1 primary objective was to assess safety and tolerability and determine the recommended phase 2 dose (RP2D) according to the modified toxicity probability interval-2 algorithm. Pts were followed up beyond the 21-day dose-limiting toxicity (DLT) period (28 days for T-DXd + fulvestrant) for safety events. Results: In DB-07, 7 pts were enrolled and received T-DXd 5.4 mg/kg + pertuzumab 420 mg (loading dose: 840 mg) every 3 wk (q3w; not evaluable for DLTs, n = 1). In DB-08, 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + anastrozole 1 mg daily (not evaluable for DLTs, n = 1); another 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + fulvestrant 500 mg every 4 wk (loading dose: 500 mg cycle 1 days 1 and 15). For all 3 modules, no DLTs were reported in any DLT-evaluable pts; the dose levels used in part 1 were approved to be the RP2Ds for use in the dose-expansion part of each corresponding module. No deaths on study or cases of interstitial lung disease/pneumonitis were reported to date. Conclusions: The RP2Ds for the T-DXd combinations were the standard doses for BC of each individual drug. These studies are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway. Clinical trial information: NCT04538742; NCT04556773.

As a newly emerged class of anticancer bioagents in the most precise and selectively targeted way, antibody-drug conjugate (ADC) combines the cancer-targeting abilities of monoclonal antibodies with the cytotoxicity potency of payload, delivering highly cytotoxic drug into tumors via 'targeted chemotherapy'. ADC has revolutionized the treatment landscape of human epidermal growth factor receptor 2 positive and triple negative subtypes in breast cancer. Three ADCs have been approved by U. S. Food and Drug Administration with breast cancer indications, including trastuzumab emtansine (T-DM1; also approved in China), trastuzumab deruxtecan (T-DXd, DS-8201) and sacituzumab govitecan (IMMU-132; also approved in China). Antibodies, cytotoxic drug, linker, and conjugation process are implicated in ADC profile, resulting in unique adverse drug reactions and toxicity heterogeneity within ADC class. For example, more attention should be paid to the management of thrombocytopenia, hepatotoxicity, and reductions in left ventricular ejection fraction (LVEF) in patients treated with trastuzumab emtansine; clinical physicians should pay attention to the risk of neutropenia, interstitial lung disease/pneumonitis, and reductions in LVEF when treated with trastuzumab deruxtecan; sacituzumab govitecan most frequently caused neutropenia, anemia and diarrhea requiring close monitor. ADC has generally favorable safety profiles, and dose modifications and/or symptomatic supporting treatment are effective in terms of toxicity management. This consensus aims at providing guidance for clinical oncologists of early detection, regular assessment, timely management and follow-up monitor of ADC-associated adverse reactions/events.

Background: Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable antitumor activity in patients (pts) with previously treated HER2-positive (HER2+) and HER2-low/ultra-low mBC. We report interim clinical efficacy and safety for T-DXd plus pembrolizumab (PEM) in pts with previously treated HER2+ or HER2-low mBC enrolled in the breast cancer cohorts of DS8201-A-U106 (NCT04042701). Methods: U106 is an open-label, multicenter, 2-part, phase 1b study. Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus PEM. In part 2, pts with mBC were assigned by centrally determined HER2 expression status to cohort 1 (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in situ hybridization [ISH]+ that progressed on T-DM1) or cohort 2 (HER2-low; IHC 1+ or IHC2+/ISH- that progressed on standard therapy); the primary endpoint was confirmed objective response rate (cORR) by independent central review (ICR). Results: The RDE was T-DXd 5.4 mg/kg and PEM 200 mg intravenously every 3 weeks (Q3W). At data cutoff (DCO; Nov 18, 2023), 56 pts with mBC had received the RDE (30 in cohort 1; 26 in cohort 2). Median age was 58.6 years in cohort 1 and 56.3 years in cohort 2. Most pts in cohort 1 were from Europe (27/30 [90.0%]), most pts in cohort 2 were from the United States (16/26 [61.5%]). 17 pts (56.6%) in cohort 1 and 25 pts (96.2%) in cohort 2 were hormone receptor positive. Pts received a median 3.0 (range, 2-12) and 4.5 (range, 1-12) prior treatment regimens in the metastatic/locally advanced setting in cohorts 1 and 2, respectively. At DCO, T-DXd and PEM treatment was ongoing in 7 and 4 pts in cohort 1 and no pts in cohort 2. Median duration of follow-up was 16.1 mo (range, 3.0-30.2) in cohort 1 and 15.3 mo (range, 1.4-34.1) in cohort 2. The cORR by ICR was 80.0% (24/30; 95% CI, 61.4-92.3) in cohort 1 and 23.1% (6/26; 95% CI, 9.0-43.6) in cohort 2. The disease control rate (complete response + partial response + stable disease) was 100% (95% CI, 88.4-100) in cohort 1 and 80.8% (95% CI, 60.6-93.4) in cohort 2. Median duration of response (mDoR) was not evaluable (NE; 95% CI, 6.9 mo-NE) in cohort 1 and 11.4 mo (95% CI, 2.8-NE) in cohort 2. Median progression-free survival (mPFS) was NE (95% CI, 8.7 mo-NE) in cohort 1 and 12.7 mo (95% CI, 4.0-16.9) in cohort 2. PFS rates at 12 months in cohorts 1 and 2, respectively, were 68.6% (95% CI, 46.7-83.0) and 52.1% (95% CI, 29.7-70.4). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 20 pts (66.7%) in cohort 1 (40.0% related to T-DXd; 26.7% related to PEM; 16.7% related to both) and 16 pts (61.5%) in cohort 2 (23.1% related to T-DXd; 3.8% related to PEM; 3.8% related to both). The most common grade ≥3 TEAEs were neutropenia, anemia, nausea, fatigue, and vomiting. TEAEs associated with discontinuation occurred in 9 pts (30.0%) and 2 pts (7.7%) in cohorts 1 and 2, respectively (including 1 due to grade 2 decreased left ventricle ejection fraction in cohort 1). There were 2 TEAEs associated with death (both in cohort 1; 1 due to general physical health deterioration; 1 due to neurologic decompensation); neither was related to either study treatment per investigator assessment. The overall incidence of adjudicated drug-related (T-DXd and/or PEM-related) interstitial lung disease/pneumonitis was 12.5% (7/56), with 3 events in cohort 1 (all grade 2) and 4 events in cohort 2 (3 grade 2; 1 grade 3). Conclusions: Combination therapy with T-DXd and PEM showed encouraging efficacy in heavily pretreated pts with HER2+ and HER2-low mBC. Prolonged mPFS and mDoR were observed in pts with HER2-low mBC despite lower-than-expected cORR in this cohort. The value of addition of immunotherapy to T-DXd in this setting remains to be determined. The safety profile was consistent with the known profiles of the individual drugs and was generally manageable. Citation Format: Hope S. Rugo, Antonio Anton Torres, Hendrik-Tobias Arkenau, Emma Kipps, Antoine Italiano, Antonio Calles Blanco, Georgia Anguera Palacios, Marie Meurer, Jesus Soberino Gracia, Aditya Bardia, Aixa E. Soyano, Anthony Goncalves, Robert Droder, Michael J. Chisamore, Daniel Barrios, Kodai Abe, Dipica Haribhai, Mitchell Rosen, Brandon Cunningham, Florence Dalenc. Trastuzumab deruxtecan With Pembrolizumab in Previously Treated HER2-Expressing Advanced or Metastatic Breast Cancer: Interim Analyses of the Breast Cohorts from the Open-Label, Multicenter, Phase 1b Study DS8201-A-U106 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-07-29.

Background: HER2+ BC is associated with a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in patients (pts) with HER2+ BC with BM, an unmet medical need remains due to the poor prognosis in this pt population. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, median progression-free survival (PFS) of 19.4 and 18.1 mo, respectively, and median duration of response (DOR) of 20.8 and 16.9 mo, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). Here we describe a trial evaluating T-DXd in pts ± BM with previously treated advanced/metastatic HER2+ BC. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg q3w in pts with HER2+ BC ± BM. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (−BM at baseline) and cohort 2 (+BM at baseline). Pts must have previously treated advanced/metastatic HER2+ BC that has progressed with ≥1 prior anti-HER2-based regimen and received ≤2 lines of therapy in the metastatic setting (excludes pts with prior tucatinib). Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by RECIST version 1.1 per ICR). Secondary endpoints in both cohorts are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL. Incidence of new symptomatic CNS metastasis (CNSM) is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM are secondary endpoints in cohort 2. Citation Format: Nancy U Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Graham Walker, Nadia Harbeck. Open-label, multinational, multicenter, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with previously treated advanced/metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC): DESTINY-Breast12 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-26-01.

Background: Patients (pts) with human epidermal growth factor receptor 2–positive breast cancer (HER2+ BC) have a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in pts with HER2+ BC with BM, an unmet medical need remains. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM (n=24), with a confirmed objective response rate (ORR) of 61.4%, an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, and median progression-free survival (PFS) of 19.4 and 18.1 months, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). T-DXd also demonstrated preliminary efficacy in a subgroup of pts with BM in the DESTINY-Breast03 trial, with an extracranial ORR of 67.4%, intracranial ORR of 63.9%, and median PFS of 15.0 months (Hurvitz S et al. SABCS 2021. Abst GS3-01). However, both trials excluded pts with active/progressive BM. Here we describe a trial evaluating T-DXd in a real-world setting in pts with stable or active BM and pts without BM with previously treated advanced/metastatic HER2+ BC. The data generated by this study will complement previous and ongoing studies, providing a more robust understanding of T-DXd treatment in patients with and without BM. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (91 sites in the US, Europe, Australia, Canada, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg every 3 weeks in pts with HER2+ BC ± BM. As part of prescreening, all pts will provide informed consent for tumor tissue samples (archival tumor tissue or fresh biopsy) to be collected and tested for HER2 status. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (no BM at baseline) and cohort 2 (BM at baseline). Pts must have previously treated HER2-positive BC that has progressed on or after ≥1 prior anti-HER2–based regimen (including disease progression ≤6 months after adjuvant treatment with HER2-targeted therapies) and received ≤2 lines of therapy in the metastatic setting (excluding pts with prior tucatinib). Cohort 1 will be limited to include ≤25% third-line pts. Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 per ICR). Secondary endpoints in both cohorts are overall survival, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and quality of life. Incidence of new symptomatic central nervous system (CNS) metastasis is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNS metastasis are secondary endpoints in cohort 2. Citation Format: Nancy U. Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Manoj Prahladan, Nadia Harbeck. Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-02.

Background Antibody Drug Conjugate (ADCs) therapies combine targeted antibodies with potent drugs. However, systemic toxicities often limit their effectiveness and narrow their therapeutic index (TI). 1 While there are methods...

Background: The mechanism of T-DXd-related ILD remains unknown. Understanding the pathophysiology of drug-induced ILD and identifying biomarkers for patients (pts) at higher risk of T-DXd-related ILD is crucial. Krebs von den Lungen-6 (KL-6) has been analyzed as a biomarker for ILD, but its relevance to T-DXd-related ILD is undetermined. This exploratory analysis aimed to identify candidate ILD risk biomarkers via proteomic analysis and evaluate KL-6 levels in serum samples from pts in 3 T-DXd studies. Methods: Baseline serum samples were collected from 189 pts in 3 T-DXd clinical trials: DESTINY-Breast01 (DB-01; n = 56; NCT03248492), DESTINY-Breast04 (DB-04; n = 78; NCT03734029), and DESTINY-Lung01 (DL-01; n = 55; NCT03505710). Pts were divided into 3 groups: 94 non-ILD controls, matched 1:1 based on patient characteristics, and 95 pts who later developed ILD, further categorized by worst adjudicated grade (G): G1/2 ILD (n = 74) and G3-5 ILD (n = 21). Available baseline serum samples were analyzed using the SomaScan™ proteomics platform. Baseline and longitudinal serum KL-6 levels were measured by ELISA. Results: From ∼6000 analytes tested, elevated baseline serum interleukin 1 receptor-like 1 (ST2) levels were observed in pts with incident G3-5 ILD in all 3 studies. In DL-01, median levels of baseline ST2 relative fluorescence units (RFU; IQR [Q1-Q3]) in non-ILD pts were comparable to G1/2 ILD cases (n = 27, 3838 RFU [2873-4910] vs n = 20, 4374 RFU [3417-5122]), in contrast, the median baseline ST2 level in G3-5 ILD cases was elevated (n = 8, 8512 RFU [6824-23494]). Elevation of median baseline ST2 levels in G3-5 ILD cases was also observed in DB-01 (n = 6, 7707 RFU [6503-19035]) and DB-04 (n = 7, 5973 RFU [3972-14682]). In DB-01, the median baseline ST2 levels were 3816 RFU (n = 28, [2757-4712]) in non-ILD patients and 3529 RFU (n = 22, [2742-4695]) in G1/2 ILD cases. In DB-04, the median baseline ST2 levels were 4420 RFU (n = 39, [3051-6002]) in non-ILD patients and 4140 RFU (n = 32, [2714-5758]) in G1/2 ILD cases. Baseline KL-6 levels were elevated in G3-5 ILD cases in DB-01. This elevation was not observed in DB-04 or DL-01. Longitudinal sample analysis showed that KL-6 levels decreased with T-DXd treatment, mirroring the reduction in tumor burden observed after treatment. Conclusions: Proteomics analysis revealed elevated baseline serum ST2 levels as a potential baseline marker for T-DXd-related G3-5 ILD in lung and breast cancer. Luminex™ analysis is ongoing to quantify ST2 levels. The utility of KL-6 as a biomarker for T-DXd-related ILD appears to be limited. KL-6 levels decreased after T-DXd treatment, likely due to tumor shrinkage and reduction of tumor-derived KL-6. Given the limited number of clinical studies included and few G3-5 ILD events, the suitability of these candidate biomarkers needs further investigation. Citation Format: Zenta Tsuchihashi, Kevin Contrepois, Kazuishi Kubota, Jing Zhao, Xuya Wang, Vinit Kumar, Nuria Folguera Blasco, Brad Jakubison, Sonia Terrillon, Yingkai Cheng, Tomohiro Kaji, Miho Nakamura, Charles A. Powell, Egbert F. Smit, Shanu Modi, Peter Newham. Baseline serum protein analysis of patients with interstitial lung disease/pneumonitis (ILD) in 3 trastuzumab deruxtecan (T-DXd) trials: DESTINY-Breast01, DESTINY-Breast04, and DESTINY-Lung01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5928.

Trastuzumab deruxtecan (T-DXd) is one of the new generation antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER-2) with bystander effect. T-DXd can not only significantly improve the survival of HER-2-positive advanced breast cancer patients, but also enable advanced breast cancer patients with low HER-2 expression to benefit from HER-2-targeted therapy. T-DXd has been approved by the National Medical Products Administration (NMPA) for the treatment of HER-2-positive or HER-2-low breast cancer patients. It is foreseeable that T-DXd will be widely used in clinical practice in the future. However, T-DXd has also shown different safety characteristics compared to previous HER-2 targeted drugs in clinical trials. How to manage T-DXd adverse events more reasonably and fully utilize the efficacy of T-DXd is an urgent clinical problem. Based on the existing clinical evidence and guideline consensus, combined with clinical practice experience, the expert group finally reached the consensus of clinical care pathway and adverse reaction management of trastuzumab deruxtecan after many discussions. This consensus content includes the clinical use method of T-DXd, pre-treatment patient education, and management of common or noteworthy adverse events of T-DXd. The adverse events include infusion related adverse events, digestive system adverse events (nausea/vomiting, constipation, diarrhea, and decreased appetite), hematological adverse events (neutropenia, febrile neutropenia, anemia, thrombocytopenia), respiratory adverse events (interstitial lung disease/pneumonia), cardiovascular adverse events (decreased left ventricular ejection fraction), adverse events in liver function (elevated transaminases) and other common adverse events (alopecia, fatigue, etc). This consensus focuses on the prevention of adverse events, dose adjustment and treatment when adverse events occur, and recommendations for patients' lifestyle, aiming to improve clinicians' understanding of T-DXd and provide practical guidance for clinical oncologists on T-DXd clinical management.

Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P< 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P< 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-02.

e16468 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated efficacy in treating a variety of gastrointestinal (GI) cancers. However, there is significant variability in its reported efficacy and safety profiles, likely due to differences in trial designs, patient populations, and clinical settings. This systematic review and meta-analysis aims to consolidate current evidence on the efficacy and safety of T-DXd in GI malignancies. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines, utilizing the Medline, Embase, Cochrane Central, and ClinicalTrials.gov databases. Out of 5,594 articles reviewed, ten studies were ultimately included after both primary and secondary screenings, providing data on the outcomes and safety of T-DXd in GI malignancies. The NIH quality assessment tool was employed to evaluate the quality of the studies. Pooled analyses were performed using the 'meta' package (Schwarzer et al., R programming language), and proportions with 95% confidence intervals (CIs) were calculated. Results: We identified ten studies involving 653 patients treated with T-DXd for GI malignancies. The median age of the patients was 64.5 years (27-85), with 53% being male. The median follow-up duration was 5.9 months (0.5-30.5). The median overall survival and progression-free survival were 11.15 months (1.4-20.8) and 5.6 months (2.6-8.7), respectively. The pooled objective response rate (ORR) was 36.9% (95% CI: 31.5%-42.5%, I² = 41%, n = 589), with partial response and complete response rates of 35.2% (95% CI: 31.1%-39.5%, I² = 0%, n = 516) and 1.3% (95% CI: 0.0%-4.7%, I² = 73%, n = 516), respectively. The median duration of response (DoR) was seven months (0.7-22.3). Reported adverse events included anemia, febrile neutropenia, thrombocytopenia, diarrhea, nausea, interstitial lung disease/pneumonitis, heart failure, and hepatitis. Eight out of ten studies noted treatment discontinuation due to toxicities in 77 patients. For the 5.4 mg/kg dose, grade 3/4 adverse events were reported in 67 patients by two studies. For the 6.4 mg/kg dose, a total of 146 grade 3/4 adverse events were reported by six studies. Conclusions: This meta-analysis supports the efficacy of T-DXd in patients with GI malignancies, demonstrating a moderate ORR and a clinically meaningful DoR, even in patients who have experienced disease progression after multiple lines of therapy. Overall, T-DXd is well-tolerated, with minimal severe adverse events. These findings validate existing research and underscore the need for further clinical trials, particularly in earlier lines of treatment. The evolving landscape of ADCs, including T-DXd, highlights the importance of continued research and clinical application across various malignancies.

569 Background: TDxD is a human epidermal growth factor 2 (HER2) directed antibody-drug conjugate (ADC) utilized in the treatment of metastatic breast cancer (mBC) and is currently approved for HER2+ and HER2 low breast cancer. In the DESTINY-Breast trials, TDxD prolonged both progression-free survival (PFS) and overall survival (OS) compared with physician’s choice chemotherapy. This benefit carries the risk of rare but significant toxicities such as interstitial lung disease/pneumonitis and heart failure. Cancer drug dosing is traditionally based on the maximum tolerated dose, which may not apply to targeted therapies such as ADCs. A lower TDxD dose may offer comparable efficacy and less toxicity than the FDA approved dose. This study aimed to assess treatment patterns and clinical outcomes in mBC patients (pts) who received TDxD. Methods: This retrospective single institutional chart review study was performed to obtain de-identified patient data. Study population included all mBC pts who received at least 1 cycle of TDxD between 2/10/2020 -12/27/2024. TDxD treatment parameters and patient characteristics were obtained. Real-world progression-free survival (PFS) and overall survival (OS) from date of TDxD initiation and the date of last follow-up was assessed using Kaplan-Meier methods. Differences of OS, PFS between groups were examined by log-rank. Results: This analysis included 66 eligible mBC pts (median age of 67 at TDxD initiation; 29% non-White). 37 pts received TDxD at the initial SD (5.4 mg/kg); 29 received a median RD of 4.4 mg/kg. In the overall cohort, 40.9% had HER2+ mBC (16/37 SD vs. 11/29 RD) and 59.1% HER2-low (21/37 SD vs 18/29 RD). In the overall cohort: 44% were stage IV at time of diagnosis; 74% had baseline visceral metastases, 28% brain metastases, and a median of 3 metastatic sites of disease. Overall, pts had received a median of 4 prior lines of therapy for metastatic disease. 90.6% of ER+/HER2-low pts had received prior CDK4/6 inhibitors. The median treatment duration for SD and RD were similar (251 vs 301 days; p = ns). Among HER2+ and ER+/HER2-low pts, ORR were 18.5% (60% SD & 40% RD) and 17.2% (20% SD & 80%), respectively. The median PFS (10.4 vs 11.2 months; p = 0.8) and OS (18.3 vs 28.1 months; p > 0.09) were similar for SD and RD, respectively. The median PFS (11.5 vs. 20.1 months; p = 0.05) for HER2+ and for ER+/HER2-low (7.6 vs 10.0 months; p = 0.05) between SD and RD were similar. Median OS for HER2+ (not reached vs. 28.1 months; p > 0.09) and ER+/HER2-low (14.1 vs. 19.1; p = 0.5) were similar between SD and RD, respectively. The reported pneumonitis rate for SD was 8% vs 0% for RD. At the end of the follow-up period, 50% of patients were alive. Conclusions: In this small real world data set, PFS, and OS were similar between SD and RD groups in HER2 positive and HER2 low groups. These data provide rationale for dose reduction of ADCs in the metastatic setting.

Trastuzumab deruxtecan (T-DXd) - antibody - drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) - has demonstrated high efficacy in clinical studies, with high rates of durable responses and improved outcomes in HER2-positive and HER2-low metastatic breast cancer (mBC) patients. T-DXd has demonstrated a generally manageable safety profile across the DESTINY trials, but there is an emerging unmet need for additional real-world clinical practice information. Italian experts conducted a Delphi panel and several roundtables to develop recommendations for the prevention and practical management of T-DXd-related AEs and toxicities, including nausea and vomiting (N/V), neutropenia, anemia, cardiovascular events, interstitial lung disease/pneumonitis (ILD/P), and treatment safety. ILD/P and N/V are the most challenging AEs associated with T-DXd. Being T-DXd now classified as a Highly Emetogenic Chemotherapy, Italian experts recommend pre-treatment with the triplet (NK1 RA + 5-HT3 RA + dexamethasone) in all patients to prevent acute N/V. Patients must be monitored early on treatment for signs/symptoms of ILD/P and any clinical suspicion should be promptly investigated and managed according to guidelines. These recommendations and proactive surveillance may substantially improve the management of T-DXd-related AEs, maximizing the benefit of this treatment for HER2-positive and HER2-low mBC, and potentially increasing treatment acceptance.

TPS1102 Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in HER2+ breast cancer (BC). However, there are many more BC patients with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/ in situ hybridization-negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and a topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of ~8 and the membrane permeability of the cleaved payload enables a cytotoxic bystander effect. In an ongoing phase 1 trial, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Oct 2018 data cutoff; Modi et al, SABCS 2018). Methods: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter study comparing efficacy and safety of T-DXd vs physician’s choice in HER2-low, unresectable and/or metastatic BC. Approximately 540 subjects will be randomized 2:1 to T-DXd (5.4 mg/kg intravenous every 3 weeks) or physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization is stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/hormone receptor (HR) status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per mRECIST v1.1 determined by blinded independent central review. Secondary efficacy endpoints are investigator-assessed PFS, overall survival, confirmed ORR, and duration of response. Safety endpoints include serious adverse events (AEs), treatment-emergent AEs, and AEs of special interest (interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). Primary PFS analysis will occur when 318 events are observed in HR+ subjects; providing 90% power to detect a hazard ratio of 0.68 with 1-sided α of 0.025. Enrollment began in Dec 2018. Clinical trial information: NCT03734029.

Pooled analysis by best confirmed response to trastuzumab deruxtecan and related biomarkers in patients with HER2-positive metastatic breast cancer from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03.

Background: Trastuzumab deruxtecan (T-DXd) has been evaluated in numerous solid tumors and has been approved for metastatic HER2-positive breast and gastric/gastroesophageal cancers. We aimed to provide a precise estimate of toxicity of T-DXd observed in clinical trials. Methods: A systematic literature search was performed in PubMed and supplemented by review of abstracts from ASCO and ESMO. Eligible studies were clinical trials (dose-expansion phase 1, phase 2, and phase 3) investigating single agent T-DXd. The search was performed in June 2022. For single-arm trials, meta-analysis comprised one-sample proportions to obtain the random effects estimates of toxicity and respective 95% confidence intervals (CI) for T-DXd, while for randomized trials, the Mantel-Haenszel odds ratio method was utilized. Results: Fifteen trials comprising 1566 participants were evaluable for toxicity. ECOG Performance Status (PS) was reported in 11 studies and was ≥ 2 in only a single patient. The median age at enrollment was reported for 13 studies and was 57.5 years. Seven trials comprising 1023 (65.3%) participants evaluated T-DXd for breast cancer. From available data, 1209/1440 (84%)of participants were female and 735/1551 (47%) were from East Asia. The median follow-up time was 11.1 months (13 studies) and median previous lines of treatment were 3 (12 studies). All-grade toxicity rate of ≥10% was reported for most toxicities; however, grade ≥3 toxicity rate of ≥10% was reported only for neutropenia and anemia; 17.4% (95%CI 12-22.8) and 14.8% (95%CI 8.6-21), respectively (Table 1). Interstitial lung disease/pneumonitis (ILD) was reported in 203 (12.4%) patients, including 160 (9.41%) grade 1-2, and 23 (1.1%) grade 3-4. Treatment-related death was reported in 20 (1%) patients, and all were due to grade 5 ILD. No significant difference in ILD was identified in subgroup analysis of trials conducted in east Asia vs. the rest of the world, breast vs. other solid tumors, 5.4mg/kg vs. other doses, median follow-up < 12 months vs. ≥12 months or median previous lines ≥3 vs. < 3. In the three randomized clinical trials, grade ≥3 toxicity was significantly higher for nausea (OR: 9.32, 95%CI: 2.53-34.32), ILD (OR: 5.35, 95%CI: 0.97, 29.48), fatigue (OR:2.5, 95%CI: 1.11-5.66), and anemia (OR:1.77 95%CI: 1.14-2.74). Conclusions: T-DXd was associated with infrequent grade ≥3 toxicities across clinical trials. Grade 1-2 ILD was more common; however, grade 3-4 ILD occurred in 1.1%. This may be related to active monitoring of this toxicity in clinical trials and discontinuation of treatment in participants with G2 ILD. There is lack of evidence for the safety of T-DXd in patients with ECOG PS ≥ 2. Citation Format: Faris Tamimi, Abhenil Mittal, Consolacion Molto Valiente, Massimo Di Iorio, Laith Al-Showbaki, Michelle Nadler, Eitan Amir. Toxicity profile of single agent trastuzumab deruxtecan in solid tumors: A meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-02.