HER3 Alpha Play Starts With Imaging While Efficacy and Precedent Are Absent

Actinium Begins Patient Enrolment in RADIANZ Imaging Trial for Solid Tumors

Actinium Pharmaceuticals has initiated patient enrolment in its Radiolabeled Antibody Distribution In Advanced Neoplasms with Zirconium-89 (RADIANZ) trial, an imaging study designed to support the pan-cancer therapeutic development of its antibody radioconjugate (ARC), ATNM-400. The study will enroll patients with advanced solid tumours, including breast, colorectal, non-small cell lung, ovarian, and pancreatic cancers, who have progressed after standard-of-care treatments. RADIANZ aims to assess tumour uptake, retention, biodistribution, pharmacokinetics, and radiation dosimetry over periods up to two weeks. This data is crucial for ATNM-400, which combines the monoclonal antibody barecetamab with Actinium-225 to target HER3, a protein involved in cancer cell proliferation and treatment resistance. The trial builds upon an ongoing first-in-human Phase I study in metastatic castration-resistant prostate cancer, where initial patients demonstrated tumour uptake without dose-limiting toxicities.

• RADIANZ Trial Objectives and Patient Population: Actinium's RADIANZ trial is an imaging study focused on understanding the biodistribution and pharmacokinetics of ATNM-400 in advanced solid tumours. It will enroll patients with progressive breast, colorectal, NSCLC, ovarian, and pancreatic cancers, who have failed prior standard treatments. The study's primary goal is to assess tumour uptake, retention, and radiation dosimetry over two weeks, providing critical data to guide the broader therapeutic development of ATNM-400 across multiple cancer types.
• ATNM-400: A HER3-Targeting Antibody Radioconjugate: ATNM-400 (²²⁵Ac-barecetamab-DOTA) is an innovative antibody radioconjugate that pairs the monoclonal antibody barecetamab with the alpha-emitting isotope Actinium-225. This construct specifically targets human epidermal growth factor receptor 3 (HER3), a key protein known to drive cancer cell proliferation, survival, and contribute to treatment resistance. The imaging data from RADIANZ, utilizing Zirconium-89, will help confirm the optimal delivery and retention of this targeted radiotherapy.
• Strategic Expansion and Clinical Foundation: The initiation of RADIANZ marks a significant step in Actinium's pan-cancer strategy for ATNM-400, extending its clinical investigation beyond prostate cancer. This imaging study builds upon promising initial results from an ongoing first-in-human Phase I trial in metastatic castration-resistant prostate cancer, where patients showed tumour uptake and no dose-limiting toxicities at initial doses. Preclinical evidence supports HER3 targeting potential in lung, breast, colorectal, and ovarian cancers, paving the way for ATNM-400 to address large, treatment-resistant patient populations.

HER3: A Novel Target for Advanced Solid Tumors

Recent research highlights DNA damage response pathways as a rich source of synthetic lethality targets beyond PARP inhibitors employed for treating tumors with BRCA1/2 deficiencies. DDR-associated targets summarized include WRN, USP1, PARP, ATR, DNA-PK, PRMT5, POLQ, and WEE1, which allow for development of targeted modulators like inhibitors and degraders. PARP inhibitors selectively kill cancer cells compromised by mutations in DDR genes like BRCA1/2, while sparing normal cells with functional homologous recombination repair, and beyond PARP inhibition, drugs inhibiting key DDR components such as ATR, ATM and DNA-PK have progressed to clinical trials alone or in combination with chemotherapy, radiotherapy, immunotherapy or other targeted therapy. An increasing trend in the preclinical and clinical setting is focused on inhibiting non-DDR pathways such as PRMT5 and SMARCA4/2, alongside Checkpoint Kinase 1 inhibition and cGAS-cGAMP-STING pathway activation.

Emerging immunomodulatory targets span co-inhibitory and co-stimulatory markers of innate and adaptive immunity. T lymphocyte markers include Lymphocyte Activation Gene 3 [LAG-3], T-cell Immunoglobulin- and Mucin-domain-containing molecule 3 [TIM-3], V-domain containing Ig Suppressor of T cell Activation [VISTA], T cell ImmunoGlobulin and ITIM domain [TIGIT], B7-H3, Inducible T-cell Co-stimulator [ICOS/ICOS-L], CD27/CD70, and Glucocorticoid-Induced TNF Receptor [GITR], with additional mechanisms including TIM-3, CD47, and OX-40L mediating tumor metastasis. Macrophage markers include CD47/Signal-Regulatory Protein alpha [SIRPα] and Indoleamine-2,3-Dioxygenase [IDO], and natural killer cell markers include CD94/NKG2A and the Killer Immunoglobulin-like receptor [KIR] family. IMSA101, a small molecule analog of cGAMP and potent STING agonist, was evaluated as monotherapy and in combination with a programmed death ligand 1 (PD-(L)1)-ICI in advanced solid tumors with at least one lesion suitable for injection.

Antibody-drug conjugates, cell therapies and tumor-agnostic biomarkers are expanding options for advanced solid tumours. SHR-A2102 is a new antibody-drug conjugate consisting of a fully human nectin-4-directed monoclonal antibody bound to a topoisomerase I inhibitor payload via a cleavable linker, evaluated in unresectable, locally advanced or metastatic solid tumours. Glypican-3 (GPC3) and trophoblast cell-surface antigen 2 (TROP2) are highly expressed antigens in lung squamous cell carcinoma, with GPC3 overexpressed in 70% of LUSC tissues while negatively expressed in all normal tissues, supporting GPC3-targeted CAR-T cells secreting TROP2-directed bispecific T cell engagers. B7 family protein H3 (B7-H3)-targeted CAR-T cells coexpressing interleukin-7 (IL-7), interleukin-15 (IL-15), and C-C motif chemokine ligand 19 (CCL19) showed infiltration and antitumor efficacy in pancreatic cancer- and non-small cell lung cancer-derived xenograft tumor models. Tumor-agnostic targets with regulatory drug approvals include NTRK fusion, RET fusion, BRAF V600E mutation, FGFR1 rearrangement, HER2 overexpression, microsatellite instability or mismatch repair deficiency (MSI-H/dMMR), and high tumor mutational burden (TMB-H), with emerging alterations including NRG1 fusion, ALK fusion, MTAP loss, KRAS G12C, TP53 Y220C and homologous repair deficiency (HRD).

Addressing Critical Unmet Needs in Advanced Solid Tumors

Recent literature frames advanced solid tumors around heavily pretreated disease that has progressed on current standard treatment and rare molecular subsets with limited options. The landscape has shifted from histology-specific to tissue-agnostic approaches, targeting molecular alterations regardless of tumor origin, while integration requires overcoming challenges related to tumor heterogeneity and lineage-specific molecular dependencies.

• Refractory locally advanced or metastatic solid tumours after standard therapy: a first-in-human phase 1 trial of BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, enrolled 195 patients with histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma, with 60 (34%; 95% CI 27-42) of 174 patients evaluated for activity having an objective response.

• Tissue-agnostic biomarker-defined populations with unmet need in rare/ultra-rare malignancies: six pan-cancer biomarkers — NTRK, BRAF V600E, RET, HER2-positive, MSI-high, and TMB-high — along with nine molecularly targeted therapies, including larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAF mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers).

• Emerging candidates for expansion of precision oncology: FGFR, ALK, MET, ROS1, NRG1, PIK3CA, AKT, KRAS G12C, HER2 mutations, HER2-low/ultralow, B7-H3, and tumor-infiltrating lymphocytes (TILs), with further investigation into TILs as a predictive biomarker for immunotherapy warranted, given their distinct immunophenotypic features and prognostic significance in shaping treatment responses across cancer types.

• Central nervous system spread and metastatic persistence: CNS metastases include brain parenchymal, spinal cord, and leptomeningeal metastases, with leptomeningeal disease occurring when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS); effective treatment for metastatic cancer has remained elusive due to the persistence of drug-resistant metastasis stem cells (MetSCs) that drive relapse and express the L1 cell adhesion molecule (L1CAM).