P2, N=184, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Mar 2026

P1/2, N=40, Active, not recruiting, Criterium, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Aug 2024 --> Mar 2026

The updated analysis of the phase 3 PHILA trial confirmed the superiority of pyrotinib in combination with trastuzumab and docetaxel over placebo in combination with trastuzumab and docetaxel in sustaining longer progression-free survival and improving overall survival for initial treatment of HER2 positive metastatic breast cancer. The safety profile remained consistent with interim findings, with no new safety signals identified during extended follow-up. This analysis reinforces the efficacy of this dual anti-HER2 (pyrotinib plus trastuzumab) regimen as an effective treatment strategy for this patient population.

Copy number-based oncogene dominance may suggest tumor dependence and response to HER2-targeted therapy, highlighting a potential novel biomarker in HER2-positive gastric cancer.

In the past few years, targeted therapeutic modalities such as antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

P1, N=128, Recruiting, D3 Bio (Wuxi) Co., Ltd | Trial completion date: Mar 2026 --> Dec 2028 | Trial primary completion date: Mar 2026 --> Dec 2028

P=N/A, N=42, Not yet recruiting, Peking University Cancer Hospital & Institute

Importance of clinical vigilance: Although this patient had no family history of gastric cancer, her nonspecific gastrointestinal symptoms ultimately led to the diagnosis of dual primary SRCC. This highlights the need for high suspicion of malignancy in elderly patients presenting with nonspecific symptoms.Diagnostic value of multidisciplinary collaboration: The integration of endoscopic, pathological, imaging (computed tomography/magnetic resonance imaging), and immunohistochemical findings enabled accurate diagnosis of this rare case of dual primary gastric malignancy and identification of HER2 expression heterogeneity. The heterogeneity in HER2 expression (1+ vs 3+) demonstrates potential molecular differences between lesions in the same patient, emphasizing the necessity for comprehensive biopsy sampling.

Tucatinib significantly decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2 + breast cancer, which can be longitudinally quantified with PET imaging. Our data suggests molecular imaging may improve understanding and prediction of tucatinib response.

Two metastatic SDC patients with HER2 amplification responded to HER2 tyrosine kinase inhibitor (TKI) pyrotinib and the combination of trastuzumab and pertuzumab, respectively. Our work underscores the potential of genomic profiling to guide precision therapy in SDC, with HER2-targeted treatments offering promising therapeutic avenues.

P2, N=30, Recruiting, Ruth O'Regan | Trial completion date: Jan 2026 --> Jul 2027 | Trial primary completion date: Dec 2025 --> Jun 2026

P2, N=84, Not yet recruiting, Xijing Hospital