HER-2 amplification

P2, N=18, Recruiting, Peking Union Medical College Hospital | N=45 --> 18 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P2, N=33, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=185 --> 33 | Trial completion date: Feb 2026 --> Dec 2024 | Recruiting --> Terminated; Abandon of the partner, ROCHE

P2, N=51, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Dec 2027 --> Feb 2025 | Suspended --> Terminated; Abandon of the partner, GSK

ERBB2 focal amplification is associated with improved outcomes in trastuzumab-treated patients with HER2-positive gastric cancer, whereas NOTCH3 alterations predict a poor prognosis. These genomic features may support risk stratification and therapeutic decisions.

Temporal analysis showed conversion rates of 50.0% for synchronous metastases, 30.8% within 12 months, and 63.6% beyond 12 months. We identified a high prevalence of HER2-low and HER2-ultralow subtypes, suggesting potential eligibility for ADC therapies.

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

P2, N=90, Active, not recruiting, Centre Leon Berard | Recruiting --> Active, not recruiting

P2, N=88, Active, not recruiting, Fudan University | Recruiting --> Active, not recruiting

Our data support the development of DTC-Flow as a sensitive and specific platform to identify breast cancer patients harboring DTCbm and better understand the biology of minimal residual disease. Ultimately, this platform could enable the selection of personalized therapeutic approaches based on molecular features of DTCbm, monitoring of DTCbm to assess the efficacy of such therapies, and the development of novel therapeutic approaches targeting unique biological vulnerabilities of DTCs in order to eradicate these cells before they can give rise to lethal recurrent cancers.

This review also investigates ongoing challenges in expanding HER2-targeted therapies, including addressing intrinsic and acquired resistance, and tailoring strategies to low HER2-expressing or HER2-mutant tumors. Lastly, we provide insights into future directions, emphasizing the importance of precision oncology to broaden the therapeutic opportunities of HER2-targeted therapies across diverse HER2-driven malignancies.

In HER2-positive breast cancer, T-DXd significantly outperformed trastuzumab emtansine (T-DM1), with substantial improvements in progression-free and overall survival, while also showing benefit in HER2-low disease. The recent tumor-agnostic FDA approval highlights its broad clinical potential across solid tumors. This review summarizes the mechanism of action, pivotal clinical evidence, and emerging applications of T-DXd, underscoring its transformative role in modern oncology and outlining future prospects for combination strategies, biomarker-driven patient selection, and expanded global access.

P2, N=90, Recruiting, Centre Leon Berard | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Jan 2025 --> Jan 2027