Abstract PS5-02-15: Concurrent Trastuzumab Deruxtecan and Radiation Therapy in HER2- positive and HER2-low Metastatic Breast Cancer: Assessing the efficacy

e13000 Background: Metastatic breast cancer, particularly that which expresses the HER2 receptor, poses a significant therapeutic challenge in oncology, often associated with an unfavorable prognosis. Although therapies targeting HER2, such as trastuzumab, have improved patient outcomes, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, has shown promising efficacy even in heavily pretreated patients. Recent clinical trials, including DESTINY-Breast, demonstrated benefits in progression-free survival (PFS) and overall survival (OS). However, the efficacy of the combination of trastuzumab deruxtecan with radiotherapy (RT) remains to be explored. This study aims to evaluate this combination in patients with HER2-positive and HER2-low metastatic breast cancer. Methods: We conducted a retrospective study including patients treated between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and radiotherapy were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, efficacy and treatment discontinuations were collected. Data on tumor response were collected through imaging examinations, and follow-up was conducted from the last day of radiotherapy until death or the last examination, and toxicities were graded using CTCAE V5.0. Results: The studied population includes 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 14 months. Treatment details indicated that trastuzumab deruxtecan was administered at the recommended dose across various treatment modalities. Of the patients evaluated, 39.4% achieved partial remission, while 9.1% attained complete remission. Additionally, 39.4% experienced stable disease, and 12.1% faced disease progression necessitating a change in therapy. Safety assessment revealed that acute toxicities were mainly associated with systemic treatment. Survival analysis showed 11 deaths (33.3%) during the follow-up period, with a median overall survival of 26 months and median progression-free survival of 12 months. Conclusions: The combination of trastuzumab deruxtecan with radiotherapy in HER2-positive and HER2-low metastatic breast cancer demonstrates promising efficacy with a manageable safety profile. Further studies are warranted to fully elucidate the potential synergistic effects of this treatment regimen and its impact on patient outcomes.

Purpose: Recent DESTINY-Breast trials have demonstrated trastuzumab deruxtecan's effectiveness in HER2-positive and HER2-low metastatic breast cancer. However, safety concerns remain regarding its combination with radiation therapy (RT). The purpose of this work is to assess the toxicity profile of combining trastuzumab deruxtecan and RT in patients with HER2-positive and HER2-low metastatic breast cancer to address these concerns. Materials and Methods We conducted a retrospective study which included patients treated at Institut Curie Paris between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, and treatment discontinuations were collected. Follow-up was conducted from the last day of radiotherapy until death or the last examination and toxicities were graded using the CTCAE V5.0. Results The studied population includes all 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 11 months. The most common acute grade 1 toxicity was nausea. Grade 2 toxicities affected 21.2% of patients, including asthenia, mucositis, cardiac decompensation, and diarrhea. Trastuzumab deruxtecan discontinuation occurred in 5 patients due to systemic treatment-related toxicities, including nausea, thrombocytopenia, neutropenia, and cardiac decompensation. 21.2% of patients reported late toxicities, with nausea being the most prevalent. Conclusion Our series of patients who received concurrent treatment of radiotherapy and trastuzumab deruxtecan are showing acceptable toxicity. Larger prospective studies are needed to evaluate the toxicity and efficacy of this combination. Citation Format: Jihane Bouziane, Pierre Loap, Kim Cao, Sofiane Allali, Yacine Gounane, Loganadane Gokula, Laurence Escalup, Jean-Yves Pierga, Youlia Kirova. Concurrent use of trastuzumab deruxtecan and radiation therapy in HER2-positive and HER2-low metastatic breast cancer: a single-center experience and review of the literature [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 P5-03-26.

Recent DESTINY-Breast trials have demonstrated trastuzumab deruxtecan's effectiveness in HER2-positive and HER2-low metastatic breast cancer. However, safety concerns remain regarding its combination with radiation therapy (RT). The purpose of this work is to assess the toxicity profile of combining trastuzumab deruxtecan and RT in patients with HER2-positive and HER2-low metastatic breast cancer to address these concerns. We conducted a retrospective study which included patients treated at Institut Curie Paris between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, and treatment discontinuations were collected. Follow-up was conducted from the last day of radiotherapy until death or the last examination and toxicities were graded using the CTCAE V5.0. The studied population includes all 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 11 months. The most common acute grade 1 toxicity was nausea. Grade 2 toxicities affected 21.2% of patients, including asthenia, mucositis, cardiac decompensation, and diarrhea. Trastuzumab deruxtecan discontinuation occurred in 5 patients due to systemic treatment-related toxicities, including nausea, thrombocytopenia, neutropenia, and cardiac decompensation. There were 21.2% reported with late toxicities, with nausea being the most prevalent. Our series of patients who received concurrent treatment of radiotherapy and trastuzumab deruxtecan are showing acceptable toxicity. Larger prospective studies are needed to evaluate the toxicity and efficacy of this combination.

Background. Reducing malignant mortality to 185 cases per 100,000 by 2030 is one of goals of the state program “Healthcare development” in Russia.Aim. To assess potential impact of using trastuzumab deruxtecan in patients with breast cancer on reducing cancer mortality.Materials and methods. Three indications of trastuzumab deruxtecan were considered: adult patients with HER2-positive unresectable or metastatic breast cancer that were previously treated with trastuzumab and a taxane in the advanced or metastatic setting (referred as “Second line”); adult patients with HER2-positive unresectable or metastatic breast cancer who previously received at least two lines of therapy in the metastatic setting including trastuzumab emtansine (referred as “Third line”); adult patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy (referred as “HER2-low metastatic breast cancer”). The set of comparators for each clinical situation was formed based on the clinical guidelines and clinical trials of trastuzumab deruxtecan. Overall survival and treatment duration were modelled on the clinical trials basis. The model was used to estimate number of lives saved in case of transitioning all eligible patients to trastuzumab deruxtecan within a three-year horizon.Results. Up to 3,609 patients p. a. in the “Second line” situation, 1,300 patients p. a. in the “Third line” situation and 2,260 patients p. a. in the “HER2-low breast cancer” situation can initiate trastuzumab deruxtecan treatment. In that case mortality from neoplasms could be reduced by 1,461 deaths in case of “Second line”, by 427 deaths in case of “Third line” and by 801 deaths in case of “HER2-low metastatic breast cancer” over three years. Reduction in mortality will contribute to achieving the target mortality rate from neoplasms of 21.61–24.81 %, 4.31–12.57 % and 5.91–20.89 %, respectively.Conclusion. Using trastuzumab deruxtecan for breast cancer treatment in different clinical situations leads to quantitate reduction in cancer mortality in Russia.

Introduction Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)–targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non–small cell lung cancer, colorectal cancer, and HER2-low tumors. Areas covered The current treatment and investigational landscape of HER2-positive and HER2-low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify relevant literature, a search was performed on English-language publications and congress abstracts. Expert opinion T-DXd is likely to become the standard of care for second-line treatment of HER2-positive mBC, and it may play a role in the treatment of hormone receptor–positive and triple-negative mBC with HER2-low expression. Because it was recently approved in the United States and Japan to treat HER2-positive metastatic GC, it holds promise for the treatment of other HER2-positive solid tumors, including colorectal cancer, non–small cell lung cancer, and HER2-low BC.

Background The current standard of care for neoadjuvant treatment of HER2-positive early-stage breast cancer consists of dual HER2-blockade with trastuzumab (H) plus pertuzumab (P) and polychemotherapy with a pathological complete response (pCR) rate of 31%~50%. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. T-DXd significantly prolonged progression-free and overall survival vs trastuzumab emtansine in HER2-positive unresectable and/or metastatic breast cancer (mBC) previously treated with H and taxane in DESTINY-Breast03 study. HER2-low breast cancer is currently treated as HER2-negative (HER2-low and HER2-zero) breast cancer, with patients stratified according to hormone-receptor (HR) status. In DESTINY-Breast04 study, T-DXd resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy in HER2-low mBC. Given the efficacy of T-DXd monotherapy in HER2-positive or HER2-low mBC, we conduct an exploratory study to evaluate the efficacy and safety of T-DXd in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy, and to identify sensitive biomarkers for T-DXd neoadjuvant therapy. Methods Eligible patients were women aged 18 years to 75 years with clinical stage cT2–cT4/cN0–cN3/cM0 (stage II–III) invasive breast cancer (>2 cm in size) confirmed as HER2-positive (immunohistochemistry [IHC] 3+) or HER2-low (IHC2+ or IHC1+/situ hybridization-negative). Patients are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of at least 55% (as measured by echocardiogram). Patients are also required to have adequate organ function and bone marrow function. Patients with HER2-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, carboplatin, and H plus P for 2 cycles. Patients with HER2-low and HR-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and cisplatin or carboplatin for 2 cycles. Patients with HER2-low and HR-negative breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and anthracycline (epirubicin, pirarubicin or liposomal doxorubicin) for 2 cycles. For patients who have responses of stable disease assessed by magnetic resonance imaging will receive T-DXd neoadjuvant therapy. T-DXd will be administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight for 4 cycles. Peripheral blood and biopsy tissue will be collected before neoadjuvant chemotherapy and T-DXd neoadjuvant therapy, and peripheral blood and surgical tissue will be collected after the surgery. Lipid metabolites in peripheral blood and mass spectrometry-based protein quantification in tissue will be detected to find sensitive biomarkers for T-DXd neoadjuvant therapy. The primary endpoint is pCR rate (ypT0/Tis ypN0) and identify sensitive biomarkers for T-DXd neoadjuvant therapy. Secondary endpoints include objective response rate, breast-conserving rate and invasive disease-free survival. Citation Format: Jin Zhang, Zhendong Shi, Jingjing Liu. An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy [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 PO4-18-04.

DESTINY-Breast03 trial: some questions remain – Authors' reply

Background: Trastuzumab deruxtecan (T-DXd) is a standard of care as 2nd line and after prior chemotherapy for HER2 positive and low metastatic breast cancer (MBC), respectively, based on Destiny Breast03 and 04 results. However, biopsies over time during treatment have shown that HER2 expression is variable. The predictive factors of trastuzumab deruxtecan (T-DXd) for MBC with HER2 positive and low are unclear. The HER2 extracellular domain (HER2-ECD) has been confirmed as a prognosis marker and predictive marker of treatment for HER2-positive MBC. Especially, HER2-ECD is considered a promising biomarker in cases where HER2 expression in metastases is unconfirmed. We hypothesized that HER2-ECD could serve as a biomarker for T-DXd. Patients and methods: A retrospective study of consecutively treated patients in a single center between 2019-2023 with HER2-low and HER2-positive MBC was performed using chart review. HER2 status was diagnosed according to 2020 ASCO-CAP guidelines. HER2-ECD high was defined as >15.0 ng/ml. HER2-ECD was collected prior to T-DXd treatment. We compared overall response (ORR), progression-free survival (OFS), overall survival (OS), and disease control rate (DCR) at HER2-ECD high and low groups. Cox regression analyses were performed to assess the ORR. We used the Kaplan-Meier method to estimate the PFS and OS and the log-rank test to compare each treatment group. Results: A total of 41 MBC patients were included in this study. Patients with HER-positive and HER2-low were 34 and 7, respectively. Among HER2 positive (n=34), HER2-ECD high and low are 14 (41%) and 20 (59%) patients, respectively. Among HER2 low (n=7), HER2-ECD high and low are 3 (43%) and 4 (57%) patients, respectively. Twenty-six patients received T-DM1 prior to T-DXd treatment for MBC with HER2 positive, but no patients received CPT-11 before T-DXd for MBC with HER2 positive and low. The ORR of T-DXd was 89% and 52% in the HER2-ECD high and low groups, respectively (p< 0.001). All 6 cases with CR were HER2-ECD high. Among HER2 low group (n=7), ORR of T-DXd was 67% (2/3) and 25% (1/4) in HER2-ECD high and low groups, respectively. The median PFS in the HER2-ECD high group showed longer than the HER2-ECD low group, 21.8 vs. 8.0 months (HR 0.31; 95%CI, 0.13-0.78, p=0.012). Although there were no significant differences in OS, HER2 ECD high group tended to show longer OS (HR 0.23; 95%CI, 0.04-1.16, p=0.07). The DCR was 100% in the HER2 ECD high group and 87% in the low group. Conclusion: T-DXd showed significantly better response and prolonged PFS in the group with high HER2-ECD. HER2-ECD has the potential to become a biomarker for T-DXd. Further study is warranted to assess the HER2-ECD as a biomarker, especially for HER2 low MBC patients treated with T-DXd. Table. Association between the response and the HER2 status or HER2-ECD status Citation Format: Kazuki Nozawa, Maho Kusudo, Nari Kureyama, Akira Nakakami, Rie Komaki, Yuka Endo, Ayumi Kataoka, Haruru Kotani, Akiyo Yoshimura, Masaya Hattori, Masataka Sawaki, Hiroji Iwata. Impact of Serum HER2 Extracellular Domain in Metastatic Breast Cancer Patients Treated with Trastuzumab Deruxtecan (T-DXd) [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 PO4-14-06.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial

Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM. 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health related quality of life will also be measured. The primary analysis for PFS will be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, Lee C, Wang K, Cortes J. Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-03.

Background: Although patients (pts) with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently experience disease response to neoadjuvant therapy, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an unmet need. HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved in the US for HER2-positive and HER2-low metastatic BC (with boxed warnings for interstitial lung disease). However, the efficacy of T-DXd in the neoadjuvant setting is not known. The primary objective of TALENT (TRIO-US B-12, NCT04553770) is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in pts with HR+/HER2-low early BC. Methods: Men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) BC measuring > 2 cm were eligible. In stage 1 of clinical trial, participants were randomized 1:1 to receive T-DXd (5.4 mg/kg IV q21 days) alone, Arm A, or in combination with anastrozole AI (1 mg PO QD), Arm B. Originally 6 cycles (cy) were given but in 02/2022, an amendment increased the number of treatment cy from 6 to 8 for newly enrolled pts, or those who had not yet had surgery. Men and pre/peri-menopausal women randomized to Arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumor tissue collected at baseline, cy 1 day 17-21, and at surgery. Breast imaging performed at baseline, cy 2 and pre-surgery/EOT. Primary endpoint is pCR rate (ypT0/is ypN0) at surgery. In stage 1, intent was to randomize 58 pts (if at least 2 pCR occurred in an arm, arm progresses to Stage 2 and an additional 15 pts to be enrolled). Other endpoints include safety, objective response rate (ORR), changes in Ki67 expression, Residual Cancer Burden index, exploratory biomarker analysis, and health-related quality of life. Here we present results from stage 1 of the trial. Results: From 09/21/2020 to 10/13/2022, 58 pts were enrolled and treated (29 Arm A, 29 Arm B) in stage 1 of trial. Five pts came off study before completing study therapy (2 after cy 1, 2 after cy 2, 1 after cy 3). As of data cut-off (10/05/2022), 33 pts completed study treatment and have had surgery (17 Arm A, 16 Arm B), 13 are on treatment and 7 are pending surgery; 27 pts completed 6 cy and 13 completed 8 cy. Baseline characteristics were balanced between arms. 19/58 pts were Stage IIA, 26/58 Stage IIB, 12/58 Stage IIIA, and 1/58 Stage IIIB at baseline. 46/58 pts had baseline HER2 expression (from central review) of 1+, 4/58 were 0, 6/58 were 2+, 1/58 had multicentric lesion 1+ and 2+, and 1/58 had a single lesion with 1+ and 2+. In Arm A, 1/17 pt had pCR after 8 cy, 2/17 pts had RCB-I after 6 cy (17.6% RCB 0/1). In Arm B, 1/16 pt had RCB-I after 8 cy (6.3%). The ORR for response-evaluable pts in Arm A was 75% (12/16, 1 CR, 11 PR) and in Arm B was 63.2% (12/19, 2 CR, 10 PR); 1 patient (Arm B) had PD. ILD occurred in 1 pt (1.7%), Gr 2 and resolved 11 days after stopping therapy. Most common treatment-related Grade ≥ 3 AEs in Arms A and B, respectively, include hypokalemia (1.7%, 5.2%), diarrhea (3.4%, 3.4%), neutropenia (3.4%, 1.7%), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%). Conclusions: This is the first report of a trial evaluating neoadjuvant T-DXd in HER2 low breast cancer. T-DXd +/- endocrine therapy demonstrates promising clinical activity for pts with HR+ BC. Updated study results will be provided at the time of presentation. Citation Format: Aditya Bardia, Sara Hurvitz, Michael F. Press, Lisa S. Wang, Nicholas P. McAndrew, David Chan, Vu Phan, Deborah Villa, Merry L. Tetef, Erin Chamberlain, Nihal Abdulla, Thomas Lomis, Laura M. Spring, Steven Applebaum, Shaker Dakhil, Brian DiCarlo, David D. Kim, Evangelia Kirimis, William E. Lawler, Aashini K. Master, Kelly McCann, Edwin Hayashi, Christine Kivork, James Chauv. GS2-03 TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [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 GS2-03.

Background: Trastuzumab deruxtecan (T-DXd) has demonstrated promising outcomes in patients with breast cancer brain metastases (BMs), as evidenced by the results from the DEBBRAH, ROSET-BM, and TUXEDO-1 trials, as well as pooled analyses from the DESTINY-Breast01/02/03 studies. However, limited data exist regarding the treatment of BMs patients with T-DXd in real-world clinical settings in China. Therefore, this study aims to evaluate the impact of T-DXd therapy on HER2-positive and HER2-low metastatic breast cancer patients with BMs in the real-world context. Methods: We conducted a single-institution retrospective real-world analysis and obtained a total of 30 patients with HER2-positive and HER2-low metastatic breast cancer with BMs who were treated with T-DXd between July 2023 and July 2024. Results: Thirty patients were included in this study, 26 with HER2 positive and 4 with HER2-low status. At data cutoff (July 7, 2024), patients were followed up for a median of 3.6 months (95%CI [2.0; 5.2]). Patients had received a mean of three prior lines of therapy (range 1-10) and the median age was 52.5 (range 32-72). All the patients were active BMs, 17% of whom had leptomeningeal disease, and 33% received prior radiotherapy for BMs. In the HER2-positive cohort, 65% received prior TKI and 38% prior T-DM1. The ORR was 76.9%, and the intracranial (IC)-ORR was 80.8%. The DCR was 92.3%, and the IC-DCR was 84.6%. The median PFS was 8.8 months (95%CI [1.8; 15.7]). The IC-ORR for patients with the largest lesion >2cm, those treated with TKI, those treated with T-DM1, and those with prior radiotherapy for BMs was 83.3% (5/6), 81.0% (17/21), 90.9% (10/11), and 85.7% (6/7), respectively. In the HER2- low cohort, the ORR, IC-ORR, DCR and IC-DCR were all 75%. Median PFS was not evaluable due to small patient numbers. Toxicities were in line with what previously reported in larger registered clinical trials. Conclusions: Our real-world analysis indicated a clinically meaningful intracranial activity of T-DXd in HER2-positive and HER2-low breast cancer patients with active BMs, with ORR and IC-ORR higher than 70% in the real-world clinical practice. Citation Format: Chunfang Hao, Jie Zhang, Xiaochen Jia, Chao Xu, Yuehong Zhu. Trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer brain metastasis: Results from a single-institution retrospective study [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 P5-05-17.

BackgroundTrastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)–positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear.MethodsWe conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety.ResultsFor this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. At the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P<0.00001 [P-value boundary for superiority, 0.00043]). The incidence of a confirmed response was 85.1% with trastuzumab deruxtecan plus pertuzumab and 78.6% with THP (complete responses in 15.1% and 8.5%, respectively), with a median duration of response of 39.2 months and 26.4 months. Safety was consistent with the known profiles of the individual treatments. The incidence of grade 3 or higher adverse events was 63.5% with trastuzumab deruxtecan plus pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab and neutropenia, leukopenia, and diarrhea with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan plus pertuzumab (grade 1 or 2 in 44 patients and grade 5 [death] in 2 patients) and in 1.0% of those receiving THP (all grade 1 or 2).ConclusionsTrastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast09 ClinicalTrials.gov number, NCT04784715.)

Background: Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate approved for the treatment of HER2-positive (HER2+) and HER2-low metastatic breast cancer (mBC). Currently, there is limited evidence assessing how T-DXd is used in a Canadian real-world (RW) setting. The aim of this observational study was to describe RW treatment-related outcomes using data collected from patients with HER2+ mBC who enrolled in AstraZeneca Canada’s patient support program (PSP) for treatment with T-DXd, following regulatory approval based on the DESTINY-Breast03 (DB-03) trial. Methods: This interim analysis included all patients enrolled in the PSP from June 2022 to August 2023 and initiated T-DXd therapy. The index date was the date of treatment initiation with follow-up until treatment discontinuation or close of the PSP. Primary objectives included rates of treatment discontinuation and dose modifications (dose reduction or discontinuation or dose interruptions &amp;gt;1 cycle length). Secondary objectives included time to treatment discontinuation (TTD), reasons for discontinuation (reported by physicians), and duration of treatment (excluding cumulative length of dose interruptions). Time-to-event outcomes were analyzed using the Kaplan-Meier method; other outcomes were summarized descriptively. Results: A total of 347 patients were included with a mean age of 60 years (SD, 13.2); 6% (n=19) had no prior lines of therapy in the metastatic setting, 64% (n=222) had 1, 9% (n=30) had 2, and 4% (n=14) had 3+, with 18% (n=62) missing data; 30% (n=103) had stable brain metastases at enrollment. Median follow-up was 5.6 months (range 0.2-29.7). Among patients that started at a dose of 5.4 mg/kg (84.4%, n=293) or a lower dose of 4.4 or 3.2 mg/kg (n=20, 5.8%), 32% (n=101) had a dose reduction, 28% (n=87) had a discontinuation, 51% (n=161) had either a dose reduction or discontinuation, and 51% (n=161) had a dose interruption. Some patients (n=34, 9.8%) received a dose not specified in the label (neither 5.4, 4.4, or 3.2 mg/kg). Cumulative probabilities of treatment discontinuation at 3, 6 and 9 months were 10.2% (95% CI, 6.8-13.4), 18.2% (95% CI, 13.6-22.6), and 29.7% (95% CI, 23.3-35.6), respectively. Overall median TTD was 14.3 months (95% CI, 12.4-18.4); median TTD among patients with stable brain metastases was 15.2 months (95% CI, 15.2-not reached). Median duration of treatment (excluding dose interruptions) was 12.7 months (95% CI, 10.3-18.4). Of the total observed discontinuations (28%, n=98) progression was the most common reason (44%, n=43) followed by prescriber decision (23%, n=22), death (16%, n=15), patient decision (12%, n=12), or other/unknown/missing data (6%, n=6). Conclusion: RW use of T-DXd in the Canadian PSP, designed for patients eligible under the regulatory authorization based on DB-03, reflected a largely second-line setting, with a median TTD consistent across the overall population and patients with stable brain metastases. Due to the short duration of follow-up, TTD may be underestimated. During the PSP enrollment period, T-DXd use was still in its early stage of experience in Canada and as such, understanding of optimal therapy management may have still been evolving. Citation Format: C. Brezden-Masley, S. Shokar, A. Nam, R. A. Qadeer, Z. Senhaji Mouhri, B. Salvo, N. Bonar, B. Suero. Interim results: Real world study of treatment discontinuations and modifications for patients with HER2-positive metastatic breast cancer on trastuzumab deruxtecan on a Canadian patient support program [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-04-02.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial