patritumab deruxtecan (U3-1402)

P2, N=277, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jul 2026 --> Jan 2027

Late-phase ADCs include trastuzumab deruxtecan (targeting HER2 [human epidermal growth factor receptor 2]), datopotamab deruxtecan and sacituzumab govitecan (targeting TROP2 [trophoblast cell-surface antigen 2]), patritumab deruxtecan (targeting HER3), telisotuzumab vedotin (targeting c-MET [cellular-mesenchymal epithelial transition factor]), and sigvotatug vedotin (targeting IB6 [integrin beta-6]). Ongoing, biomarker-driven trials and combination strategies with immunotherapy or tyrosine kinase inhibitors hold the potential to further enhance the efficacy of ADCs. In this review, the authors highlight the current landscape and future directions of ADCs in NSCLC, emphasizing available results for compounds in late-stage clinical development and different disease settings.

In HER3/c-Met dual-positive cell lines, SDP0505 demonstrated enhanced cell binding and internalization over the in-house synthesized U3-1402 analog...SDP0505 represents a novel HER3 × c-Met ADC with superior internalization and anti-tumor activity in preclinical models, especially in EGFR TKI-resistant PDX models. These results supported the initiation of a Phase I clinical trial in China.

P2, N=63, Completed, MedSIR | Trial completion date: Oct 2026 --> Apr 2026 | Active, not recruiting --> Completed

While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have long served as the frontline standard, the emergence of heterogeneous resistance mechanisms requires more robust therapeutic strategies. This review evaluates the clinical impact of the MARIPOSA trial, which demonstrated the superior efficacy of combining the bispecific antibody amivantamab with lazertinib...Furthermore, we explore the diversifying landscape of second-line interventions, including the rise of antibody-drug conjugates (ADCs) like Sac-TMT and patritumab-deruxtecan, dual PD-1/VEGF inhibitors, and novel fourth-generation TKIs. By integrating preclinical insights on drug-tolerant persister cells with late-phase clinical data, this article outlines a future for EGFR-mutant NSCLC management defined by precision sequencing and the proactive mitigation of molecular resistance.

P2, N=63, Active, not recruiting, MedSIR | Completed --> Active, not recruiting

P1/2, N=50, Recruiting, Merck Sharp & Dohme LLC | N=32 --> 50

Recent innovations include antibody-drug conjugates (ADCs) such as TROP-2-targeting agents and HER3-DXd, which show promising efficacy in refractory disease. Next-generation tyrosine kinase inhibitors (TKIs), including lorlatinib, tepotinib, and glecirasib, have shown improved outcomes for patients with oncogene-driven NSCLC...Future efforts must prioritize overcoming resistance through combination strategies and ADCs, validating biomarkers using AI and ctDNA, streamlining CGP implementation, and addressing the unique needs of special populations. Bridging these biological and systemic challenges is essential for improving survival outcomes and ensuring equitable benefits for all NSCLC patients.

Combining HER3-DXd with an ATR inhibitor could benefit HER3+/HR+ BC patients with both endocrine-sensitive and -resistant diseases.

P2, N=63, Completed, MedSIR | Active, not recruiting --> Completed

P2, N=277, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jan 2026 --> Jul 2026

Of 52 patients (55.8% female; mean age 64.5 years), 59.6% received chemotherapy and 40.4% received an EGFR TKI as first-line treatment; erlotinib constituted 71.2% of targeted therapies. These results suggest that HER3 expression may warrant further investigation as a candidate biomarker for treatment sequencing decisions and as a potential therapeutic target in EGFR-mutant NSCLC. Prospective studies evaluating chemotherapy-TKI sequencing and HER3-directed agents such as patritumab deruxtecan (HER3-DXd) in HER3-positive patients are needed to confirm these preliminary observations.