T-DM1 demonstrated a manageable safety profile, and the adverse events were consistent with those reported in randomized trials. The data are not yet sufficient to allow for a formal analysis of RFS and OS, and long-term follow-up is required.

This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes.

Furthermore, this treatment may modulate TME immune profiles. Further validation using a larger sample size is warranted.

We searched the FAERS database for reports of cardiovascular adverse events in patients with HER2-positive breast cancer receiving trastuzumab, ado-trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-Dxd). Proportionate analysis showed age and weight were the two key factors contributing to the occurrence of T-DCs induced MACE. HER2-positive breast cancer patients receiving T-DCs require additional cardiac monitoring, particularly for stroke in younger patients.

P2, N=25, Recruiting, Guangdong Provincial People's Hospital

P=N/A, N=178, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=500 --> 178 | Trial completion date: Mar 2025 --> Sep 2025 | Trial primary completion date: Mar 2025 --> Sep 2025

P2, N=23, Not yet recruiting, Guangzhou Women and Children's Medical Center

P2, N=270, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | N=190 --> 270

The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer...Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments.

P3, N=726, Not yet recruiting, Daiichi Sankyo

P1/2, N=36, Not yet recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

In this large French observational study, T-DXd users were older, had more comorbidities, and had more brain metastases than patients included in registration trials. The rapid expansion of clinical indications of T-DXd calls for proactive surveillance and timely management of potentially life-threatening T-DXd-related toxicity.

P=N/A, N=135, Not yet recruiting, AstraZeneca

With the approval of trastuzumab deruxtecan for the treatment of unresectable/metastatic HER2-low breast cancer, human epidermal growth factor receptor 2 (HER2)-low has emerged as a clinically actionable biomarker...Patients with discordant HER2 status had better responses to platinum-based chemotherapy. Therefore, for patients with HER2-0 primary lesions, re-evaluation of HER2 status in metastatic lesions through biopsy may offer new treatment opportunities.

This analysis offers the most comprehensive overview of ado-trastuzumab emtansine induced hemorrhage to date, shedding new light on this severe complication. Understanding the underlying mechanisms of these positive PTs can provide useful insights for further research.

Regarding responses, 5 patients had partial response (including 2 patients that were pretreated with trastuzumab), 1 patient had stable disease at 12 weeks and 4 patients had disease progression at initial assessment. All patients but one that derived clinical benefit had HER2 3 + expression.DiscussionIn the real-world setting, T-DXd showed activity in a cohort of heavily pre-treated patients with HER2-expressing gynecological malignancies.

P1/2, N=74, Not yet recruiting, Fudan University

P1, N=20, Not yet recruiting, Atridia Pty Ltd. | Initiation date: Nov 2024 --> Mar 2025

P1, N=120, Recruiting, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

P1, N=20, Recruiting, Atridia Pty Ltd. | Not yet recruiting --> Recruiting

P2, N=72, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Feb 2025 --> Nov 2024

P=N/A, N=800, Recruiting, Sun Yat-sen University | Trial completion date: Sep 2024 --> Jan 2025 | Trial primary completion date: Sep 2024 --> Jan 2025

P2, N=139, Terminated, Jules Bordet Institute | N=1065 --> 139 | Trial completion date: Mar 2029 --> Nov 2024 | Suspended --> Terminated | Trial primary completion date: Jun 2027 --> Nov 2024; Serious concerns on the slow recruitment of the study that impacts the robustness of the scientific rationale and the study financial provision. It aims to assess carefully the situation and to evaluate the potential solutions to overcome the issues.

P1, N=120, Not yet recruiting, SystImmune Inc.

Future research should focus on a more detailed examination of responses in varied patient populations, long-term outcomes, and a thorough economic evaluation of T-DM1, along with an exploration into treatment resistance. This will provide a more nuanced understanding of T-DM1's role in the treatment landscape of HER2-positive breast cancer.

P1, N=20, Active, not recruiting, Dana-Farber Cancer Institute | Phase classification: P1b --> P1

P2, N=135, Recruiting, Eisai Inc. | Trial completion date: Oct 2026 --> Mar 2026 | Trial primary completion date: Oct 2026 --> Mar 2026

P1, N=32, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

Currently, there are three ADCs available for use in breast cancer: trastuzumab emtansine for HER2 positive breast cancer (early stage and metastatic), trastuzumab deruxtecan for HER2 positive and HER2 low breast cancer (metastatic) and sacituzumab govitecan for triple negative and hormone receptor positive (HR +), HER2 negative breast cancer(metastatic). The future of this class of compounds is very exciting. This field is rapidly evolving with new ADCs being investigated and clinical trials looking at the use of known ADCs in earlier stage disease.

P2, N=74, Not yet recruiting, University of Chicago | Initiation date: Jul 2024 --> Jan 2025

In conclusion, our findings demonstrated that durvalumab and T-DXd synergistically promoted apoptosis in cholangiocarcinoma cells by inhibiting EGR1 expression through inactivation of the p38 MAPK pathway. This study confirmed the potential of durvalumab and T-DXd for the treatment of cholangiocarcinoma.

P2, N=20, Not yet recruiting, Shanghai Hengrui Pharmaceutical Co., Ltd.

Higher levels of HER2 biomarkers in baseline tissue and liquid biopsies, including HER2 status (IHC/ISH), HER2/CEP17 ratio, HER2 ISH signals, HER2 H-score, plasma HER2 (ERBB2) amplification status, HER2 adjusted plasma copy number, and HER2 extracellular domain correlate with antitumor activity (indicated by objective response rate, progression-free survival, and overall survival) of T-DXd. Baseline circulating tumor DNA (ctDNA) analysis suggests antitumor activity of T-DXd in patients who had baseline activating RAS, PIK3CA, or HER2 mutations detected in ctDNA.

This extensive study in China demonstrated that RC48 has excellent therapeutic potential for both HER2-positive and HER2-low MBC with a favorable safety profile. The study also suggests that combination therapy significantly boosts efficacy beyond monotherapy, indicating a promising avenue for future ADC development.

P2, N=36, Not yet recruiting, Laura Huppert, MD, BA | Trial completion date: Feb 2028 --> Jun 2028 | Initiation date: Oct 2024 --> Jan 2025 | Trial primary completion date: Feb 2028 --> Jun 2028

Concurrent SRS and T-DXd has excellent local control, without an increased risk of radiation necrosis. HER2-low disease is associated with worse systemic PFS and DIC with T-DXd compared to HER2+.

The combination of RC48 with platinum+/- bevacizumab resulted in the highest ORR of 71.4% (5 out of 7 patients), with HER2 TKI following at a 50.0% ORR (4 out of 8 patients). RC48, particularly in combination regimens, demonstrates promising efficacy in advanced NSCLC with HER2 alterations. These findings underscore the need for further research to validate RC48's application in clinical practice.

This novel assay outperformed standard CSF cytology in our case. There is an urgent need to develop CSF tumor cell assessment tool that surpasses the capabilities of conventional CSF cytology.

After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months...Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

P3, N=96, Terminated, Hoffmann-La Roche | Completed --> Terminated; Due to low enrollment, the Sponsor decided to prematurely terminate the study

P2, N=42, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

RC48-ADC showcases promising efficacy and manageable safety in patients with both HER2-positive and HER2-low-expression mBC.