Kadcyla (ado-trastuzumab emtansine)

We named this method the smash method, which is the volleyball term. In volleyball, the ball is raised while low and quickly hits the ground again, just like we do with the HER-2 receptor. The smash method can switch HER-2 negative or HER-2 low tumors into HER-2 overexpressed, iatrogenically. Thus, we can use her2-targeted therapies in all cancer patients instead of a small portion.

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.

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.

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

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.

Hormonal or endocrine therapy includes selective estrogen receptor modulators (SERMs) such as raloxifene, tamoxifen and toremifene, selective estrogen-receptor degraders (SERDs) including elacestrant and fulvestrant, and aromatase inhibitors such as anastrozole, letrozole, and exemestane...These agents include taxanes (docetaxel, nab-paclitaxel, and paclitaxel), anthracyclines (doxorubicin, epirubicin), anti-metabolites (capecitabine, gemcitabine, fluorouracil, methotrexate), alkylating agents (carboplatin, cisplatin, and cyclophosphamide), and drugs that target microtubules (eribulin, ixabepilone, ado-trastuzumab emtansine). Patients with ER-positive tumors are treated with 5-10 years of endocrine therapy and chemotherapy. For patients with metastatic breast cancer, standard first-line and follow-up therapy options include targeted approaches such as CDK4/6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PDL1 immunotherapy, depending on the tumor type and molecular profile.

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.

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

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

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

The patient was treated with ADCs of ARX-788 for third-line treatment, she had ILD. After treatment of ILD, the patient was treated with ADCs of trastuzumab-DM1 (T-DM1) for fourth-line treatment and she had ILD again...Whether other anti-HER2 ADCs can be tried in the later lines is still being cautious. Whether there is a certain relationship between the side effects and efficacy of ADCs, there is no evidence-based data.

For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval.

P3, N=608, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2025 --> Jul 2025

The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

T‑DXd outperformed T‑DM1 regardless of HRD+/- or BRCA1/2 alt status, although HRD+ status and BRCA1/2 alt were poor prognosticators for PFS in both arms. Mutational analysis at DP will be presented.

Patients received neoadjuvant treatment with taxanes and subcutaneous fixed dose combination pertuzumab and trastuzumab (P+T) for a total duration of 12 weeks followed by surgery. Adjuvant treatment was determined according to response at surgery: patients with a pathologic complete response (pCR, defined as pT0/Tis pN0) received adjuvant P+T for additional 14 cycles, while patients with residual disease received adjuvant trastuzumab emtansine (T-DM1) for 14 cycles... Neoadjuvant treatment with an anthracycline-free regimen in patients with HER2-positive, hormone receptor negative, node-negative early breast cancer resulted in a high rate of pCR. The majority of patients achieving pCR had the HER2-enriched PAM50 subtype.

ESMO Breast 2024) and following T-DM1 monotherapy in the second-line setting or beyond (Brasó-Maristany et al. The HER2DX ERBB2 mRNA score is strongly associated with long-term survival outcomes in metastatic HER2+ breast cancer treated with first-line THP. Notably, HER2DX identified patients with ERBB2-low disease, as the subgroup with the poorest outcomes in both PFS and OS. Further analyses will be presented at the conference.

From gemtuzumab ozogamicin to trastuzumab emtansine (T-DM1), and now to third-generation agents such as trastuzumab deruxtecan (DS-8201) and disitamab vedotin (RC48), improvements have been made in target selectivity, potency, linker stability, and reduced off-target effects. ADCs represent a promising frontier in precision cancer treatment, with continued research enhancing their potential in breast cancer and beyond. This review provides a comprehensive exploration of ADCs' evolution in breast cancer therapy, offering a molecular perspective to inform clinical practice and update colleagues on this dynamic field.

To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.

P=N/A, N=50, Enrolling by invitation, Nagoya City University

Dual human epidermal growth factor receptor 2(HER2)blockade with trastuzumab(H)and pertuzumab(P)combined with docetaxel and carboplatin(TCb)is a standard neoadjuvant therapy for HER2-positive breast cancer patients. 4 cycles of T-DM1+P). Simultaneous administration of H and P enables a reduced administration time, which would benefit both patients and healthcare providers.

Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

The patient received neoadjuvant chemotherapy with epirubicin and cyclophosphamide, followed by docetaxel, trastuzumab, and pertuzumab...A liver biopsy following treatment with trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-Dxd) revealed HER2-negative status. Cyclin-dependent kinase (CDK) 4/6 inhibitor combination endocrine therapy has been continued for 16 months to date while maintaining tumor shrinkage. It is essential to perform a rebiopsy during treatment to optimize therapy based on the subtype.

Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies.

Some treatments against human epidermal growth factor 2 (HER2) have been associated with cutaneous and pulmonary vasculitis. We present the first case of Henoch-Schönlein purpura associated with the use of T-DM1 in a patient with HER2 breast cancer.

This report underscores the need for further investigation into the long-term effects of combining SRS with novel systemic therapies, particularly in HER2-positive breast cancer patients with brain metastases. Understanding and mitigating late neurotoxicity are critical for optimizing treatment strategies and improving patient outcomes.

Our results are in line with the CLEOPATRA and EMILIA studies, but long-term responders in the arm A may have impacted our results. The absence of difference in term of PFS in first metastatic line may be explained by a selection bias, as patients in the arm A potentially have more aggressive forms.

HER2-targeted drugs such as HerceptinTM (trastuzumab), PERJETA® (pertuzumab) and KADCYLA® (adotrastuzumab emtansine) are beneficial for HER2-positive breast cancer patients who will inhibit cell signaling pathways. If the FISH results are negative for HER2 IHC equivocal, this is considered HER2-Low. Significantly, Enhertu has shown a promising objective response in HER2-Low breast cancer patients.

T-DM1 therapy in HER2-positive metastatic breast cancer leads to significant spleen enlargement and systemic biochemical changes. Future studies should focus on elucidating the long-term implications of these findings and optimizing monitoring strategies for spleen-related complications.

In addition, moderate hepatotoxicity may be partially explained based on the pharmacological mechanisms of trastuzumab emtansine action involving microtubule disorganisation in hepatocytes via cytoskeleton-associated protein 5 on the cell surface by emtansine. We discuss the mechanism of the development of thrombocytopaenia and liver dysfunction.

P1/2, N=473, Recruiting, Ascendis Pharma Oncology Division A/S | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: May 2026 --> Aug 2027

P2, N=20, Suspended, University of Rochester | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2025 --> Jun 2026

Administration of NPs-T-DM1 not only significantly inhibits tumor growth but also reduces damage to megakaryocytes, inhibits T-DM1-induced thrombocytopenia, and remarkably improves the safety of antibody-conjugated drugs. This work presents a promising strategy to enhance the safety and efficacy of T-DM1 in antitumor therapy, offering significant potential for advancing clinical application in HER2-positive breast cancer patients.

Ipatasertib+paclitaxel demonstrated more encouraging activity. The tolerability of both regimens was consistent with previous experience.

P1, N=68, Completed, Otto Metzger, MD | Active, not recruiting --> Completed

Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

P2, N=512, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2024 --> Dec 2024

P2, N=253, Completed, Daiichi Sankyo | Active, not recruiting --> Completed