P2, N=282, Recruiting, Salubris Biotherapeutics Inc

P2, N=105, Completed, Merus N.V. | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Jul 2023

P2, N=30, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

P2, N=30, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

P2, N=60, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

P1, N=60, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

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=250, Recruiting, Merus N.V. | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2026

Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy.

P2, N=69, Not yet recruiting, Shanghai Institute Of Biological Products

P2, N=90, Recruiting, Merus N.V.

P1, N=36, Completed, Shanghai Institute Of Biological Products | Recruiting --> Completed | N=68 --> 36

P1/2, N=160, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Aug 2025 --> Nov 2025 | Initiation date: Aug 2023 --> Oct 2023 | Trial primary completion date: Aug 2025 --> Nov 2025

Lysates were collected and prepared for western blot analysis to assess for activation of downstream signaling cascades, both with and without zenocutuzumab and enzalutamide treatment. Here, we show that NRG1 promotes prostate cancer cell survival and resistance to AR inhibition in PTEN wild-type prostate cancer cells. Activation of downstream PI3K-AKT signaling in a prostate cancer epithelial cell line was seen after both recombinant NRG1 stimulation and culturing with cancer associated fibroblast conditioned media. This supports a paracrine mediated action of NRG1 whereby it is secreted by stromal cells in the tumor microenvironment to promote resistance through PI3K signaling.

P1, N=60, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Aug 2023 --> Dec 2023 | Trial primary completion date: Aug 2023 --> Dec 2023

P2, N=30, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jul 2023 --> Dec 2023 | Trial primary completion date: Jul 2023 --> Dec 2023

P2, N=30, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jul 2023 --> Dec 2023 | Trial primary completion date: Jul 2023 --> Dec 2023

P2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Sep 2023 --> Dec 2023 | Trial primary completion date: Sep 2023 --> Dec 2023

No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.

In vitro assays in HER2 /HER3 SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

P3, N=584, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.

P2, N=75, Active, not recruiting, Elevation Oncology | Trial completion date: Jun 2023 --> Mar 2025 | Trial primary completion date: Jun 2023 --> Jan 2025

Pts had a median of 2 prior systemic therapies (range 0-5), 93% with FOLFIRINOX and/or gemcitabine-based therapy...No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno continues to demonstrate unprecedented efficacy in pts with previously treated advanced/metastatic NRG1+ PDAC with robust and durable responses and a well-tolerated safety profile.

MP was performed by using Next Generation sequencing by using Foundation one CDX/liquidCDX & it was based on 3 protocols: STING (NCT04932525), MCLA-128 (NCT03321981) & STARTRK (NCT02568267) which allowed liquid & tissue biopsies studies...Molecularly matched tx was administered to 15 pts: anti-MEK (n = 11) & imatinib (n = 2)...Conclusions Potentially actionable mutations can be found in more than 50% of pts with resistant melanoma. Tumor agnostic trials based on molecular alterations should be more broadly available to evaluate the potential benefit of innovative precision medicine in this population.

No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.

P1/2, N=160, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P3, N=584, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

P1, N=13, Active, not recruiting, Pediatric Brain Tumor Consortium | Recruiting --> Active, not recruiting | N=28 --> 13

P1, N=60, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Active, not recruiting --> Recruiting

P2/3, N=14, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Active, not recruiting --> Recruiting

SI-B001 plus docetaxel demonstrated antitumor activity in locally advanced or metastatic NSCLC EGFR/ALK wild-type pts who failed on prior first-line anti-PD-1/L1 antibody plus PBC, especially without AGA. The toxicity of SI-B001 + docetaxel was manageable. These findings support the continued investigation of SI-B001 and docetaxel as a treatment option in NSCLC.

Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: currently zenocutuzumab has FDA Fast Track Designation for tumors harboring NRG1-fusions... NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.

P2/3, N=14, Active, not recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | N=50 --> 14

P1, N=130, Recruiting, Bio-Thera Solutions | N=24 --> 130

In vitro, the inhibition of tumor cell growth by SI-B001 was stronger than cetuximab and duligotuzumab in FaDu (mRNA expression levels of EGFRhigh/HER3high/NRG1medium). Currently, 6 phase II clinical trials of SI-B001, either alone or in combination with chemotherapy, have been conducted in different epithelial carcinomas. These studies have shown a potential break-through activity in NSCLC and HNSCC with a very good safety profile.

In this study, both 225Ac-HER3 ARC and 177Lu-HER3 ARC demonstrated significant antitumor activity against HER3-expressing tumors in a dose-dependent manner. The HER3 targeted radiotherapy approach that we have undertaken could potentially overcome the limitations of current solid tumor therapies in resistance settings and warrants further evaluation in patients with HER3-expressing tumors.

Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option.