Enhertu (fam-trastuzumab deruxtecan-nxki)

HER2-low showed different clinicopathologic features from HER2-positive cases, with no prognostic differences observed in patients who underwent curative treatment. Still, HER2-low may be associated with the efficacy of AR-targeted therapy.

Introduction: Tucatinib is an oral human epidermal growth factor receptor 2 (HER2)-targeted therapy approved by the European Medicines Agency (EMA) for use in combination with trastuzumab and capecitabine for patients with HER2 + locally advanced or metastatic breast cancer (MBC) treated with ≥2 prior HER2-directed regimens. Median (95% confidence interval) rwTTD was 5.9 (5.0-9.4) months, rwTTNT was 8.4 (6.2-11.8) months, and rwOS was 24.9 (15.6-not reached [NR]) months; in the post-T-DXd subgroup, these results were 6.4 (3.6-11.6), 6.4 (4.5-11.9), and 12.6 (11.9-NR) months. Treatment persistence was 43.9% (overall) and 33.3% (post-T-DXd) at 12 months and 15.4% at 24 months (overall). Tucatinib administered after ≥2 HER2-targeted therapies in the metastatic setting is an effective treatment option in patients with HER2 + MBC, including those treated with prior T-DXd.

P2, N=70, Active, not recruiting, Seagen, a wholly owned subsidiary of Pfizer | Trial completion date: Jul 2025 --> Dec 2025

This study reveals a worse 3-year DFS in HER2 +2/FISH negative patients across both early and advanced disease stages. The findings highlight the prognostic importance of HER2-low status and may guide future therapeutic strategies, including the use of targeted therapies like T-Dxd in non-metastatic patients.

Recent clinical trials of agents like trastuzumab deruxtecan, datopotamab deruxtecan, and sacituzumab govitecan have demonstrated meaningful objective response rates and manageable toxicity, offering hope for patients with advanced NSCLC and SCLC. ADCs are transforming the treatment landscape for lung cancer, offering a blend of targeted delivery and potent therapeutic effects. With ongoing efforts to improve safety, efficacy, and antigen targeting, ADCs have the potential to become a cornerstone of lung cancer therapy and pave the way for innovative multimodal approaches in the future.

Younger age, longer time from MBC diagnosis to start of ADC1, and receipt of SG as ADC1 were associated with longer rwOS from start of ADC1. This cohort represents one of the first multicenter retrospective series of patients treated with sequential ADCs for HER2-low MBC, which may inform clinical practice.

P=N/A, N=100, Recruiting, Seoul National University Hospital

P1, N=55, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P3, N=726, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.

While ADCs like trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, and efflux of cytotoxic payloads challenge their effectiveness. The potential of combination therapies, such as ADCs with immune checkpoint inhibitors (ICIs), further highlights the evolving landscape of breast cancer treatment. As ADC technology advances, personalized approaches integrating biomarkers and optimized sequencing protocols offer promising avenues to enhance treatment outcomes and combat resistance in breast cancer.

The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse...Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1-14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1-5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles...Enrollment is active and ongoing. TRINITY is registered at ClinicalTrials.gov (NCT06253650).

HIF-2α inhibition represents a breakthrough in targeting the fundamental pathobiology of clear cell RCC, with belzutifan demonstrating significant clinical benefit in both von Hippel-Lindau disease and sporadic RCC...ADCs have become a cornerstone of UC treatment, with enfortumab vedotin plus pembrolizumab now approved as first-line therapy. Multiple human epidermal growth factor receptor 2 (HER2)-directed ADCs have shown efficacy in HER2-expressing UC, including trastuzumab deruxtecan, which recently received tumor-agnostic approval. While ADC development in RCC faces unique challenges, novel approaches including immunostimulatory payloads and bispecific antibodies are being explored. The integration of these advances in molecular imaging and therapeutics offers opportunities for more personalized treatment approaches in RCC and UC.

The advent of highly effective HER2-targeted antibody-drug conjugates with clinical activity at low levels of HER2 expression, such as trastuzumab deruxtecan, has necessitated the re-evaluation of HER2 testing, particularly for HER2-low tumours...We discuss the importance of accurately defining HER2-low expression for therapeutic decision-making and how newer diagnostic approaches, such as quantitative immunofluorescence and RNA-based assays, might address the limitations of traditional immunohistochemistry-based methods. As the use of HER2-targeted therapies continues to expand to a wider range of tumour types, ensuring the precision and accuracy of HER2 testing will be crucial for guiding treatment strategies and improving patient outcomes.

P1, N=124, Recruiting, QuantumLeap Healthcare Collaborative | N=54 --> 124 | Trial completion date: Dec 2027 --> Dec 2029 | Trial primary completion date: Dec 2026 --> Dec 2028

P=N/A, N=200, Not yet recruiting, The First Hospital of Jilin University

Pathologists can reproducibly score HER2-low and HER2-ultralow when supported by training. Findings may aid decision-making for patients with breast cancer who are potentially eligible for HER2-directed therapy.

P2, N=72, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting

Within NSCLC, 26% of activating mutations were not included in clinical trials that led to approval of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd)...We identified substantial populations of patients with diverse ERBB2/ERBB3 activating alterations, which represent unmet therapeutic needs. We demonstrate that CGP provides additional genomic information, inclusive of ERBB2 amplification and mutation status together with potential resistance/response-modifying co-alterations, allowing for more nuanced HER2 status interpretation than is possible with IHC/FISH alone.

However, the detection methods and evaluation criteria for HER2-low breast cancer have not yet been standardised, and the toxicity and resistance mechanisms associated with T-DXd therapy are still unclear. This article focuses on these issues and describes the progress and challenges of T-DXd-related therapy in the treatment of advanced breast cancer patients with low HER2 expression.

Notably, T-DXd cytotoxicity also upregulates tumor CD47 expression, dampening immune activation. Combining T-DXd with CD47 checkpoint blockade significantly enhances anti-tumor immune responses in a HER2-transgenic BC mouse model, while also inducing durable CD8+ T cell memory to prevent tumor recurrence after therapy cessation.

P=N/A, N=170, Not yet recruiting, Affiliated Hospital of Guangdong Medical University; Affiliated Hospital of Guangdong Medical University

P=N/A, N=992, Recruiting, Institut du Cancer de Montpellier - Val d'Aurelle | N=620 --> 992

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

A major landmark was recently reached when trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, became the first Food and Drug Administration (FDA)-approved therapy for pretreated HER2-mutant NSCLC, following the promising efficacy demonstrated in the DESTINY-Lung trials...In this review, the authors describe the different HER2 alterations and their clinical consequences, including their impact on prognosis and response to standard therapies. They provide an up-to-date overview of the current treatment landscape and add a comprehensive review of pivotal and ongoing clinical trials of HER2-targeted therapies, including tumor-agnostic drug development strategies.

P=N/A, N=100, Not yet recruiting, The First Hospital of Jilin University; The First Hospital of Jilin University

Our CRISPR screening approach with T-DM1 in HER2-positive breast cancer cell lines identified genes not previously implicated in T-DM1 sensitivity or resistance, including TSC1 and TSC2. These genes may inform new strategies to enhance T-DM1 therapy in the clinic.

After chemotherapy with Trastuzumab Deruxtecan (T-DXd/DS-8201), the metastatic foci significantly shrank, and after surgical resection, a tumor-free state (NED) was achieved. Up to now, the patient's survival period has reached 56 months.

 This real-world analysis revealed that the efficacy, safety, and tolerability of T-DXd in the Portuguese population are consistent with the outcomes observed in the DESTINY-Breast02 clinical trial.

This review comprehensively examines the toxicities of ADCs employed in breast cancer treatment and explores their management strategies. Furthermore, we investigate novel ADCs beyond trastuzumab deruxtecan and sacituzumab govitecan, evaluating their potential efficacy and corresponding safety profiles.

P=N/A, N=135, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Trial completion date: Dec 2026 --> Mar 2027 | Trial primary completion date: Dec 2026 --> Mar 2027

This study suggested that two-thirds of HER2-negative unresectable/mBC patients in Taiwan were HER2-low. Reassessing the HER2 status of HER2-negative patients could improve treatment strategies with the evolving HER2 classification paradigm.

For patients with FIGO stage III-IVA locally advanced cervical cancer, irrespective of PD-L1 status, chemoradiation plus pembrolizumab followed by maintenance pembrolizumab also confers a survival benefit. For newly diagnosed advanced ovarian cancer responding to primary systemic chemotherapy, maintenance therapy using PARP inhibitors and/or bevacizumab according to germline and somatic mutational analysis have been demonstrated to improve progression-free survival...Adverse event mitigation strategies, biomarker discovery, and sequencing are paramount in successfully exploiting the therapeutic window provided by these novel compounds. This review discusses the application of ADCs in gynecologic cancers, including the current FDA-approved drugs mirvetuximab soravtansine, tisotumab vedotin, and trastuzumab deruxtecan, as well as relevant ongoing clinical trials, including TROP2 ADCs.

For instance, amivantamab has been approved as a treatment for epidermal growth factor receptor (EGFR)-mutant NSCLC, including those with EGFR exon 20 insertion mutations. Additionally, antibody-drug conjugates (ADCs), including HER2-targeting trastuzumab deruxtecan, TROP2-targeting ADCs, HER3-targeting patritumab deruxtecan, and MET-targeting telisotuzumab vedotin, have demonstrated promising outcomes in several clinical trials. This review summarizes the recent advancements and challenges associated with the evolving NSCLC therapeutic landscape.

P3, N=686, Not yet recruiting, Daiichi Sankyo

P1/2, N=490, Recruiting, AstraZeneca | Trial completion date: Aug 2026 --> Feb 2027 | Trial primary completion date: Aug 2026 --> Feb 2027

These data highlight the unmet clinical needs of patients with HER2-low mBC by characterizing the treatment patterns and poor outcomes in this population on the current standard of care.

P2, N=50, Recruiting, Yale University | Not yet recruiting --> Recruiting

P3, N=582, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

This overview of the 2025 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, treatment, and follow-up of MIBC patients and is designed for effective integration into clinical practice.

The antibody-drug conjugates (ADCs) tisotumab vedotin-tftv (TV) and trastuzumab deruxtecan (T-DXd) are approved for use in previously treated metastatic cervical cancer, the latter in HER2-expressing tumors. There is paucity of data regarding the efficacy and safety of TV and T-DXd in the management of metastatic GAS. We report outcomes of four patients with metastatic GAS who were treated with these ADCs in the second-line setting in Singapore.