patritumab deruxtecan (U3-1402)

P3, N=1000, Not yet recruiting, Merck Sharp & Dohme LLC

P1, N=246, Active, not recruiting, Daiichi Sankyo | Trial completion date: Feb 2026 --> Apr 2027 | Trial primary completion date: Jun 2025 --> Jan 2025

The previously reported efficacy and safety of HER3-DXd in heavily pretreated patients with EGFR-mutated NSCLC are also observed in those with other NSCLC subtypes and warrant further clinical evaluation.

P2, N=0, Withdrawn, Mustafa Khasraw, MBChB, MD, FRCP, FRACP | N=15 --> 0 | Recruiting --> Withdrawn

P1/2, N=50, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

Tumor-free mice developed immune memory that led to the rejection of syngeneic tumors after rechallenge. In conclusion, patritumab deruxtecan is equipped with a cytotoxic payload that induces hallmarks of ICD in vitro and elicits antitumor immunity in vivo.

TUXEDO-3 showed clinically relevant HER3-DXd activity in patients with LMD. ClinicalTrials.gov identifier: NCT05865990 .

Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd)...Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel...While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations.

P2, N=15, Recruiting, Mustafa Khasraw, MBChB, MD, FRCP, FRACP | Not yet recruiting --> Recruiting

The final integrated population PK model characterized the PK of both anti-HER3-ac-DXd and DXd in patients with solid tumors treated with HER3-DXd and supported the selected 5.6 mg/kg Q3W dosing regimen. Consistent with current data, dose adjustment based on the covariates investigated is not warranted.

Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.

P2, N=121, Completed, SCRI Development Innovations, LLC | Active, not recruiting --> Completed | Trial completion date: Nov 2025 --> Apr 2025 | Trial primary completion date: Nov 2025 --> Apr 2025

Efforts to extend disease control have led to various upfront intensification strategies, including combining EGFR TKIs with antiangiogenics or chemotherapy (e.g., the FLAURA-2 trial), and pairing novel bispecific antibodies such as amivantamab with third-generation TKIs...Emerging therapies targeting MET amplification (e.g., savolitinib plus osimertinib), leveraging antibody-drug conjugates (e.g., patritumab deruxtecan), or adding immunotherapy and antiangiogenics have shown preliminary promise in overcoming resistance...Ultimately, the evolving landscape of EGFR-mutant NSCLC underscores the need for refined biomarker-driven approaches and personalized regimens to achieve further gains in survival. In this review, we discuss these strategies in detail, highlighting current evidence and future directions for EGFR-mutant NSCLC treatment.

P1/2, N=450, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Feb 2039 --> Feb 2032 | Trial primary completion date: Feb 2039 --> Feb 2032

Among the many ADCs being developed, several can cause ILD of varying grades and intensity. Knowledge of their risks, diagnostic and therapeutic modalities is required in order to quickly detect and treat ADC-induced ILD.

P1/2, N=50, Not yet recruiting, Merck Sharp & Dohme LLC

This observation was supported by low predicted rates of adjudicated drug-related ILD and adverse events leading to treatment discontinuation with the 5.6 mg/kg Q3W regimen. Overall, these results support the selection of HER3-DXd 5.6 mg/kg Q3W as the recommended dosing regimen for patients with NSCLC, and these data inform the optimal dosing regimen for other tumor types.

The combination of TKI/chemotherapy (osimertinib/carboplatine-pemetrexed) and TKI/bispecific antibodies (e.g., amivantamab/lazertinib) are alternatives under evaluation, with benefits in PFS but increased toxicity. Other emerging approaches include conjugated antibodies (patritumab deruxtecan, datopotamab deruxtecan) and next-generation TKIs. In the future, personalized treatment based on the molecular profile and early response to TKIs could optimize management, particularly by integrating predictive markers such as EGFR clearance under treatment.

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.

P2, N=372, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

HER2-targeting antibody-drug conjugates (ADCs), trastuzumab deruxtecan (T-DXd), and patritumab deruxtecan (P-DXd) effectively suppressed the viability of the tumoroids. Therefore, the establishment of esophageal tumoroids with long-term cultivability makes it possible to obtain reproducible basic data, including drug sensitivity studies, which are important for the development of personalized therapies and treatment strategies.

P1/2, N=81, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=16, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

P2, N=90, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

This review summarizes recent advances and future potentials, aiming to provide insights into targeted therapy. We hope that this review will provide useful information to physicians in the field.

P2, N=372, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=121, Active, not recruiting, SCRI Development Innovations, LLC | Recruiting --> Active, not recruiting

P2, N=15, Not yet recruiting, Mustafa Khasraw, MBChB, MD, FRCP, FRACP | Phase classification: P1 --> P2

P2, N=90, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=30, Recruiting, Samsung Medical Center | Not yet recruiting --> Recruiting

P1, N=15, Not yet recruiting, Mustafa Khasraw, MBChB, MD, FRCP, FRACP | Trial completion date: Jan 2027 --> Apr 2027 | Trial primary completion date: Jan 2025 --> Apr 2026

P1/2, N=81, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=99, Active, not recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Active, not recruiting | N=170 --> 99 | Trial completion date: Jun 2026 --> Apr 2028 | Trial primary completion date: Jan 2024 --> Apr 2025

P3, N=586, Active, not recruiting, Daiichi Sankyo | Trial primary completion date: Aug 2024 --> May 2024

The antitumor activity of HER3-DXd (10 mg/kg or 3 mg/kg dosed once weekly, 4 doses in total; Q1W x 4) was assessed in 30 BC PDX models (21 ER+/HER2- and 9 triple negative [TNBC]) and compared to the antitumor activity of the clinically approved TOP1 inhibitor irinotecan (50 mg/kg dosed once weekly; Q1W). HER3-DXd exerts a potent antitumor response in BC PDXs across baseline levels of HER3/ERBB3 expression in ER+/HER2- and TNBC models. Based on our data, basal-like PDX models were more likely to show long-term responses to HER3-DXd than luminal B PDX models. Results also suggest that BRCA1/2-altered PARPi-resistant tumors will show high benefit with HER3-DXd treatment.

Pts were randomized 2:2:1 to: (A) HER3-DXd 5.6 mg/kg every (Q) 21 days (D) for 6 cycles; (B) HER3-DXd plus QD LET (+/- LHRH agonist); (C) CT with 4 cycles of EC/AC (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 Q14 or 21 D) followed by weekly paclitaxel 80mg/m2 for 12 weeks. In SOLTI VALENTINE, treatment with HER3-DXd, with or without LET, resulted in similar pCR rates to CT, while exhibiting a lower incidence of grade ≥3 TEAEs. CelTIL score at C2D1 correlated with response to HER3-DXd, but not to CT. The ongoing translational analysis, as well as the survival outcomes of VALENTINE, will provide further insights into the activity of HER3-DXd in EBC and clarify its potential role as a treatment strategy for high-risk HR+/HER2-neg breast cancer.

P1/2, N=130, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P1/2, N=450, Recruiting, Merck Sharp & Dohme LLC | Active, not recruiting --> Recruiting

P1/2, N=450, Active, not recruiting, Merck Sharp & Dohme LLC | Phase classification: P2 --> P1/2

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

P1/2, N=130, Not yet recruiting, Merck Sharp & Dohme LLC

P1, N=280, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting