Enhertu (fam-trastuzumab deruxtecan-nxki)

P1/2, N=36, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Suspended --> Active, not recruiting

P2, N=116, Recruiting, Yonsei University | Not yet recruiting --> Recruiting

Gastric or gastroesophageal junction (GEJ) cancers are usually diagnosed at advanced stages with poor prognoses and 5-year survival rates. DESTINY-Gastric05 (NCT06731478) is a global, multicenter, open-label, randomized, phase III trial to evaluate the efficacy and safety of first-line T-DXd 5.4 mg/kg plus 5-fluorouracil or capecitabine and pembrolizumab versus platinum-based chemotherapy with trastuzumab and pembrolizumab in patients with unresectable, locally advanced or metastatic, centrally confirmed HER2-positive (immunohistochemistry 3+ or immunohistochemistry 2+/in situ hybridization positive) gastric or GEJ cancer with a PD-L1 CPS ≥1. An exploratory cohort is to evaluate T-DXd plus 5-fluorouracil or capecitabine in patients with PD-L1 CPS <1.

A key feature is the systematic integration of GA tools (Geriatric-8, Cancer and Aging Research Group toxicity score) and PMI analysis to explore efficacy and tolerability predictors. EN-COURAGE represents the first prospective study designed to elucidate real-world T-DXd outcomes in elderly patients with HER2-positive GC.

In the remaining HER2 cohort, CLDN18.2-positive patients had shorter PFS (3.2 versus 8.0 months, HR 3.40, 95% CI 1.38-8.40, P = 0.008) and OS (7.1 versus 12.9 months, HR 2.44, 95% CI 1.04-5.74, P = 0.041). CLDN18.2 positivity may attenuate the efficacy of T-DXd in HER2-positive mGC/GEJC, supporting the rationale for dual blockade of CLDN18.2 and HER2.

P2, N=25, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

We retrospectively evaluated the clinical outcomes of patients with HER2-positive AGC who received first-line fluoropyrimidine-containing chemotherapy between 2011 and 2023 according to the approval period of each agent in Japan: group A (pre-immunotherapy approval), 2011-2016; group B (nivolumab approval for third-line or later treatment), 2017-2019; and group C (trastuzumab deruxtecan approval for third-line treatment), 2020-2023...The most commonly administered third-line treatments were irinotecan (63%) in group A, immunotherapy (43%) in group B, and trastuzumab deruxtecan (70%) in group C. The proportion of patients receiving trastuzumab deruxtecan at any line gradually increased across the three groups (7.5%, 30.4%, 44.4%; p < 0.0001). The emergence of novel agents and treatment modalities may have contributed to improvements in the survival of patients with HER2-positive AGC. This highlights the benefits of effective treatment strategies, including efforts to identify biomarkers and develop new agents.

P2, N=28, Active, not recruiting, MedSIR | Recruiting --> Active, not recruiting

P1, N=25, Recruiting, Daiichi Sankyo

Trastuzumab deruxtecan demonstrated substantial real-world activity after prior T-DM1 exposure, but PFS was significantly shorter compared with T-DM1 naive patients, even after rigorous adjustment for measured confounding. These findings highlight the clinical relevance of antibody drug conjugate sequencing and support prospective studies to define the optimal positioning of T-DXd in HER2 positive mBC treatment algorithms.

P1/2, N=30, Completed, National Cancer Center Hospital East

P=N/A, N=50, Active, not recruiting, Nagoya City University | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026