patritumab deruxtecan (U3-1402)

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.

Patritumab deruxtecan has clinical efficacy in previously treated EGFR-mutant non-small cell lung cancer.

P1, N=271, Active, not recruiting, Daiichi Sankyo, Inc. | Trial completion date: Dec 2023 --> Dec 2024

No abstract available

P2, N=120, Active, not recruiting, SOLTI Breast Cancer Research Group | Recruiting --> Active, not recruiting

P2, N=420, Active, not recruiting, Daiichi Sankyo, Inc. | Trial completion date: Jul 2024 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Jun 2024

P2, N=121, Recruiting, SCRI Development Innovations, LLC | Trial completion date: Nov 2023 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2025

After tumor progression with EGFR TKI therapy and PBC in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Pharmacokinetics and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402-insensitive tumors.

HERTHENA-Lung01 is a global, registrational, phase II trial further evaluating HER3-DXd in previously treated advanced EGFR-mutated NSCLC. Clinical Trial Registration: NCT04619004 (ClinicalTrials.gov); 2020-000730-17 (EudraCT).

a CR + PR. b 11 pts with CR only had nontarget lesions

These observations in patients with EGFRm NSCLC after osimertinib and PBC indicate that currently available therapies provide limited clinical benefit, highlighting a significant clinical unmet need. Moreover, these data provide important context for interpreting the results of patritumab deruxtecan as assessed in study HL-01 in this patient population.

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

As more effective strategies are needed for patients with refractory non-oncogene-addicted NSCLC, the design of novel clinical trials with ADCs targeting TROP-2 is encouraged as both a monotherapy or combination strategy with existing agents (e.g., monoclonal antibodies targeting immune checkpoint inhibitors or chemotherapy).

P1; Recruiting --> Active, not recruiting | Trial completion date: Apr 2023 --> Sep 2023

When the tumor of the cohort reached an average volume of 250mm3, mice were treated or not with cetuximab...HER3 targeting (by means of the novel antibody drug conjugate patritumab deruxtecan) and AREG/EREG silencing strongly affected cell viability, suggesting that sensitive models rely on these pathways for their growth.ConclusionWe identified a subset of GEA sensitive to EGFR targeting drugs and propose HER3 and AREG/EREG expression as markers for patients' selection. Further validation on GEA samples derived from clinical trials evaluating effectiveness of EGFR targeting is needed. We believe that, despite the negative results of clinical trials so far, EGFR can represent a suitable target in molecularly selected GEA patients.

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Exact Sciences Corporation, Lilly, Merck, Natera Inc, Puma Biotechnology Inc, Seagen Inc, Stemline Therapeutics Inc, and TerSera Therapeutics LLC. Efficacy and safety findings with pembrolizumab/chemotherapy for previously untreated, PD-L1-positive mTNBC; optimal integration into practicePublished data evaluating the utility of ctDNA testing to assess immunotherapy response in patients with mTNBC; potential role of this strategyKey clinical research findings guiding the use of PARP inhibitors for mTNBCAvailable findings with and current role of PARP inhibitor monotherapy for patients with mBC harboring germline or somatic mutations in DNA damage response pathway genes beyond germline BRCA1/2Outcomes reported with T-DXd among patients with ER-negative, HER2-low mBC in the DESTINY-Breast04 study; optimal sequencing of T-DXd opposite other available treatment optionsKey efficacy and safety findings from the Phase III ASCENT trial comparing sacituzumab govitecan to physician’s choice of chemotherapy for relapsed/refractory mTNBC; integration into current clinical practiceAvailable efficacy and safety findings with and ongoing investigation of other antibody-drug conjugates, including datopotamab deruxtecan and patritumab deruxtecan, for mTNBCOther novel agents and strategies under investigation for advanced TNBC

P1, N=280, Recruiting, Daiichi Sankyo, Inc. | Trial completion date: Jan 2024 --> Feb 2026 | Trial primary completion date: Jan 2024 --> Jun 2025

A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in HR-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.