Kadcyla (ado-trastuzumab emtansine)

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.

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

Drug-induced lupus is a clinical syndrome that shares similar features with systemic lupus erythematosus (SLE). The majority of patients present with symptoms such as arthralgia and myalgia. Hydralazine and procainamide are high-risk drugs for drug-induced lupus. Symptoms usually develop after months or years of use, but may also develop suddenly. Our patient also received TDM-1 treatment for 18 months. We present a case of TDM-1-associated drug-induced lupus in a patient with metastatic breast cancer. This is the first case of TDM-1-related drug-induced lupus reported in the literature.

The docking results revealed that NSAIDs, including Diclofenac, Mefenamic acid, Celecoxib, Naproxen, and Etoricoxib, significantly suppress resistant cancer cells. Moreover, the possible role of NSAIDs in mitigating T-DM1 resistance presents an intriguing avenue for further investigation. This research contributes significantly to the field and establishes a basis for further research to enhance treatment efficacy for EC patients.

A 54-year-old postmenopausal female patient with recurrent breast cancer and metastasis was treated with trastuzumab and paclitaxel (12 cycles), followed by trastuzumab maintenance therapy (71 cycles)...Oral therapy with lapatinib and letrozole was prescribed for a year to treat the breast cancer, along with the lesions and enhanced nodules observed in the patient's lungs, liver, and bones...This case report demonstrates the long-term efficacy of T-DM1 and its satisfactory safety profile. Overall, it provides valuable insights into the management of and challenges faced during the treatment of recurrent breast cancer with metastasis.

P2, N=176, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2028 --> May 2028 | Trial primary completion date: May 2028 --> Feb 2028

P2, N=87, Not yet recruiting, Jules Bordet Institute

Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively...Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%...Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610).

For patients with residual disease (RD), 3 adjuvant strategies have been shown to improve outcomes: (1) adjuvant trastuzumab emtansine for ERBB2-positive disease, (2) adjuvant capecitabine for triple-negative disease, and (3) adjuvant olaparib for patients with germline BRCA variants. Escalating adjuvant treatment has led to meaningful survival improvements among patients with breast cancer and RD after neoadjuvant therapy. Uncovering the anatomic and biological intricacies of RD will allow for increased precision in postneoadjuvant treatments, moving beyond the binary paradigm of RD vs pathologic complete response, toward more tailored rescue strategies in the adjuvant setting.

Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

In MBC, ADCs have expanded treatment options but their sequential use requires further study. Evidence suggests that sequencing ADCs with similar payloads is ineffective, though current data are inconclusive. More research is needed to optimize treatment strategies, including potential combination therapies.

T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

The patients who progressed after trastuzumab-based chemotherapy and TDM-1 were included in the study...Treatment options are limited in heavily pretreated HER2-positive breast cancer patients. Despite a small number of patients, this study showed that the lapatinib plus capecitabine combination was effective and well-tolerated in heavily pretreated HER2-positive breast cancer patients after TDM-1.

The goal of the study was to evaluate the effectiveness of trastuzumab-based therapy in patients who progressed under trastuzumab emtansine (TDM-1)...Toxicity in all grades was observed in ten (66.7%) patients, and grade 3-4 toxicity (anemia and neutropenia) in two patients (13.3%). This study showed that rechallenge trastuzumab-based therapy was effective and good-tolerated in heavily pretreated patients who had progressed under TDM-1.

Margetuximab plus chemotherapy was used as fourth- or later-line treatment in patients who had received multiple HER2-targeted agents, including trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, tucatinib, and neratinib. Patients responded to margetuximab plus chemotherapy with real-world progression-free survival (PFS) of 3, 4, and 7 months. Clinical outcomes from three heavily pretreated patients with metastatic HER2+/HR+ MBC demonstrated that margetuximab plus chemotherapy resulted in real-world PFS comparable to that reported in the controlled pivotal clinical trial and support use of this targeted therapy option in appropriately identified patients.

P1, N=210, Recruiting, Suzhou Zanrong Pharma Limited | Trial completion date: Oct 2024 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Oct 2025