patritumab deruxtecan (U3-1402)

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

P2, N=277, Active, not recruiting, Daiichi Sankyo | Trial completion date: Nov 2024 --> Jan 2026

This prioritization by the FDA is grounded in compelling results from the global Phase II HERTHENA-Lung01 trial, wherein HER3-DXd exhibited clinically meaningful efficacy, achieving a median progression-free survival (mPFS) of 5.5 months in patients with heavily treated EGFR-mutated NSCLC. A pivotal question remains: Is a mPFS of 5.5 months sufficient in the context of the evolving first-line landscape observed in the FLAURA-2 and MARIPOSA trials?

Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

In this review, we discuss the HER3 role in the pathogenesis of breast cancer and its relevance across all subtypes. We also explore the new anti-HER3 treatment strategies, calling into question the significance of HER3 detection as crucial information in breast cancer treatment.

P2, N=400, Recruiting, Daiichi Sankyo | N=120 --> 400

P2, N=60, Recruiting, MedSIR | Trial primary completion date: Apr 2024 --> Dec 2025

P1, N=309, Recruiting, Daiichi Sankyo | Active, not recruiting --> Recruiting | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Jan 2022 --> Mar 2026

P2, N=30, Not yet recruiting, Samsung Medical Center

In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 (datopotamab deruxtecan and sacituzumab govitecan [SG]) and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing...The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.

P2, N=277, Active, not recruiting, Daiichi Sankyo | N=420 --> 277

P1/2, N=152, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting

P2, N=120, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P1/2, N=152, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris

In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

P2, N=16, Not yet recruiting, The Netherlands Cancer Institute

Preliminary results indicate combining HER3-specific treatments with EGFR TKIs enhances antitumor effects, leading to an increased objective response rate (ORR) and prolonged overall survival (OS) in resistant cases. Embracing HER3-targeting therapies represents a transformative approach against EGFR TKI resistance and emphasizes the importance of further research to optimize patient stratification and understand resistance mechanisms.

Monoclonal antibodies such as lumretuzumab, seribantumab, and patritumab have shown potential in targeting HER3 to overcome resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Additionally, antibody-drug conjugates (ADCs) like HER3-DXd (patritumab deruxtecan) are new drug candidates that have demonstrated selective delivery of cytotoxic chemicals to NSCLC cells by exploiting HER3's widespread expression, minimizing cytotoxicity. This review aims to evaluate the efficacy of current HER3 therapeutics in development and their therapeutic potential in NSCLC, incorporating evidence from clinical trials.

P2, N=60, Recruiting, MedSIR | Not yet recruiting --> Recruiting

P2, N=420, Active, not recruiting, Daiichi Sankyo, Inc.

P1/2, N=184, Completed, Daiichi Sankyo Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Sep 2023

P2, N=120, Not yet recruiting, Daiichi Sankyo, Inc.

HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).

P3, N=560, Active, not recruiting, Daiichi Sankyo, Inc. | Recruiting --> Active, not recruiting

P1, N=15, Not yet recruiting, Mustafa Khasraw, MBChB, MD, FRCP, FRACP | Initiation date: Aug 2023 --> Jan 2024

P=N/A, Available, Daiichi Sankyo, Inc.

HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.