Some of these targeted therapies have already been approved by the Food and Drug Administration (FDA), and many others are currently undergoing clinical trials. This review summarizes recent advances in NSCLC treatment with molecular targets, highlighting progress, challenges, and their impact on patient prognosis.

24 days ago

Review • Journal

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)

KRAS mutation • EGFR mutation • KRAS G12C • BRAF mutation • HER-2 mutation • RET fusion • ALK rearrangement • RET mutation • ROS1 fusion • ROS1 rearrangement • MET mutation • NRG1 fusion • KRAS G12 • NRG1 fusion • NTRK fusion

26d

Case report: High grade serous fallopian tube carcinoma with rare NRG1 gene fusion presenting as widespread peritoneal carcinomatosis. (PubMed, Front Oncol)

Twenty-five additional tumors were found to demonstrate NRG1 fusions, including 20 new genes partners that had not been previously identified in gynecologic carcinomas. Overall, NRG1 fusion events are rare in ovarian, fallopian tube, and primary peritoneal carcinomas, but they may carry diagnostic significance in the context of borderline/low grade serous tumors, which demonstrated exclusively CLU::NRG1 fusions, and could have important predictive implications for response to ERBB/ERBB2/ERBB3-directed therapies.

26 days ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

Redefining pancreatic cancer management with tumor-agnostic precision medicine. (PubMed, Carcinogenesis)

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

1 month ago

Journal • BRCA Biomarker • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Pan tumor

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • FGFR2 (Fibroblast growth factor receptor 2) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)

TP53 mutation • KRAS mutation • BRCA2 mutation • BRCA1 mutation • MSI-H/dMMR • KRAS G12C • HER-2 overexpression • BRAF mutation • BRAF V600 • RET fusion • FGFR2 mutation • FGFR2 fusion • ALK fusion • NRG1 fusion • KRAS G12 • NTRK positive • NTRK fusion

Keytruda (pembrolizumab) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Jemperli (dostarlimab-gxly) • Augtyro (repotrectinib)

Prevalence, Treatment, and Outcomes of Real-World Fusion/Isoform-Positive Non-small-Cell Lung Cancer in Southern Alberta (AMP 2024)

Archer FusionPlex testing is a sensitive method of identifying recurrent and novel alterations in lung adenocarcinomas that are therapeutically actionable. Assessment of fusion/isoform-driven tumors demonstrates these alterations are acted upon. Public funding for all level 1 targeted therapies should be considered if the maximum benefit is to be derived from biomarker testing.

1 month ago

Clinical • Real-world evidence • Real-world

ALK (Anaplastic lymphoma kinase) • NRG1 (Neuregulin 1) • NKX2-1 (NK2 Homeobox 1)

ALK fusion • NRG1 fusion

FusionPlex® Dx

A Phase I Clinical Study Evaluating the Safety, Tolerability, Pharmacokinetic Profiles, and Preliminary Efficacy of SYS6023 in Patients with Advanced Solid Tumors (ChiCTR2400089836)

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

1 month ago

New P1 trial • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • PGR (Progesterone receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)

KRAS mutation • EGFR mutation • KRAS G12C • BRAF mutation • HER-2 amplification • HER-2 negative • BRAF V600 • HER-2 expression • ALK positive • MET amplification • ALK fusion • ERBB3 expression • RET mutation • ROS1 fusion • MET mutation • NRG1 fusion • RET rearrangement • KRAS G12 • KRAS amplification • ER expression • PGR expression • ALK-ROS1 fusion • NRG1 fusion • NTRK fusion

2ms

CRUKD/22/002: A Phase I/IIa Trial of HMBD-001 in Advanced HER3 Positive Solid Tumours (clinicaltrials.gov)

P1/2, N=81, Recruiting, Cancer Research UK | N=135 --> 81

2 months ago

Enrollment change • Metastases

ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

ERBB3 expression • RAS wild-type • NRG1 fusion • ERBB3 overexpression

Xtandi (enzalutamide) • HMBD-001

2ms

NRG1 Fusions in NSCLC: Being eNRGy Conscious. (PubMed, Lung Cancer (Auckl))

Novel treatment approaches targeting the HER2/HER3 pathway are under investigation. Here, we discuss the biology and detection of NRG1 fusions in NSCLC and promising targeted treatment strategies for tumors harboring the mutation.

2 months ago

Review • Journal • IO biomarker

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

3ms

Study Evaluating Zenocutuzumab in Patients with or Without Molecularly Defined Cancers (clinicaltrials.gov)

P2, N=90, Active, not recruiting, Merus N.V. | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

NRG1 (Neuregulin 1)

NRG1 fusion

Gilotrif (afatinib) • Xtandi (enzalutamide) • abiraterone acetate • Bizengri (zenocutuzumab-zbco)

3ms

CRESTONE: Study of Seribantumab in Adult Patients with NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov)

P2, N=54, Terminated, Elevation Oncology | Trial completion date: Mar 2025 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Feb 2024; Business decision

3 months ago

Trial completion date • Trial termination • Trial primary completion date • Metastases

NRG1 (Neuregulin 1)

NRG1 fusion

seribantumab (MM-121)

3ms

Emerging Tumor-Agnostic Molecular Targets. (PubMed, Mol Cancer Ther)

Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK, mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (Class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.

3 months ago

Journal • Pan tumor

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1) • NRG1 (Neuregulin 1)

TP53 mutation • KRAS mutation • KRAS G12C • BRAF mutation • FGFR2 mutation • FGFR2 fusion • ALK fusion • ALK mutation • NRG1 fusion • KRAS G12 • FGFR1 fusion • TP53 Y220C

3ms

Clinical relevance and druggability of sole reciprocal kinase fusions: A large-scale study. (PubMed, Cancer Med)

This inaugural multicenter study introduces a novel algorithm for detecting and treating sole reciprocal fusions in advanced cancers, expanding the patient population potentially amenable to KIs.

3 months ago

Clinical • Journal

EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • NTRK2 fusion • ALK fusion • ROS1 positive • NRG1 fusion

3ms

Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers. (PubMed, Cancer Discov)

Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.

3 months ago

Preclinical • Journal

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • NRG1 (Neuregulin 1) • SDC4 (Syndecan 4)

HER-2 mutation • NRG1 fusion • HER-2 V777L • NRG1 fusion • SDC4-NRG1 fusion

Enhertu (fam-trastuzumab deruxtecan-nxki) • zongertinib (BI 1810631)

5ms

Concurrent DNA and RNA NGS Testing to Characterize Rare Fusions in Advanced NSCLC Patients (IASLC-WCLC 2024)

Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

5 months ago

Clinical • Next-generation sequencing • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NRG1 (Neuregulin 1)

BRAF V600E • KRAS G12C • BRAF V600 • NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • EGFR exon 19 deletion • EGFR T790M • MET exon 14 mutation • ALK fusion • ROS1 fusion • NRG1 fusion • KRAS G12 • BRAF fusion • EGFR fusion • KRAS deletion

Tempus xT Assay

5ms

RRAS and RRAS2 Mutations Are Oncogenic Drivers in Lung Cancer and are Sensitive to the Pan-RAS Inhibitor RMC-6236 (IASLC-WCLC 2024)

ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and PI3K (pictilisib) inhibitors inhibited growth of RRAS Q87L or RRAS2 Q72L cells more potently than cells expressing wildtype proteins. Oncogenic R RAS/RRAS2 mutations were detected in LUAD at a rate similar to some other well-characterized lung cancer drivers, such as HRAS/NRAS hotspot mutations or NRG1 fusions. Our study supports the inclusion of RRAS /RRAS2 into routine molecular diagnostic protocols for precision oncology and clinical development of pan-RAS inhibitors, such as RMC-6236, for patients with these driver mutations in order to fully realize the potential benefit of RAS-targeted therapies.

5 months ago

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NRG1 (Neuregulin 1) • SPRY2 (Sprouty RTK Signaling Antagonist 2)

KRAS mutation • NRAS mutation • RAS mutation • HRAS mutation • NRG1 fusion • NRG1 mutation • NRG1 fusion

MSK-IMPACT

Mektovi (binimetinib) • pictilisib (GDC-0941) • ulixertinib (BVD-523) • SCH772984 • RMC-6236

9ms

Afatinib in Advanced NRG1-Rearranged Malignancies (clinicaltrials.gov)

P2, N=3, Completed, German Cancer Research Center | Active, not recruiting --> Completed | N=60 --> 3 | Trial completion date: Dec 2024 --> Oct 2023 | Trial primary completion date: Dec 2024 --> Oct 2023

9 months ago

Trial completion • Enrollment change • Trial completion date • Trial primary completion date • Metastases

NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 rearrangement • NRG1 fusion

Gilotrif (afatinib)

9ms

Pancreatic cancer biomarkers: A pathway to advance in personalized treatment selection. (PubMed, Cancer Treat Rev)

Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.

9 months ago

Review • Journal • Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • PARP Biomarker • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • NRG1 (Neuregulin 1) • PALB2 (Partner and localizer of BRCA2) • NTRK (Neurotrophic receptor tyrosine kinase)

KRAS mutation • MSI-H/dMMR • KRAS G12C • PALB2 mutation • NRG1 fusion • KRAS G12

10ms

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors. (PubMed, Glob Med Genet)

Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

10 months ago

Review • Journal

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • CD74 (CD74 Molecule) • SLC3A2 (Solute Carrier Family 3 Member 2) • EGF (Epidermal growth factor) • NRG2 (Neuregulin 2)

NRG1 fusion • NRG1 fusion

10ms

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer. (PubMed, BMC Med)

Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

10 months ago

Review • Journal

EGFR (Epidermal growth factor receptor) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • ERBB4 (erb-b2 receptor tyrosine kinase 4)

NRG1 fusion • NRG1 fusion

10ms

Fusion genes in pancreatic tumors. (PubMed, Trends Cancer)

Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.

10 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FGFR2 (Fibroblast growth factor receptor 2) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)

KRAS wild-type • FGFR2 fusion • ALK fusion • RAS wild-type • NRG1 fusion • BRAF fusion

10ms

Clinicopathologic and Genomic Characterization of High-Grade Invasive Solid Papillary Carcinoma of the Breast (USCAP 2024)

High-grade SPC are occasionally encountered and not well-characterized. Similar to their lower-grade counterparts, approximately half show NE differentiation. However, in contrast, these cases frequently have more aggressive features such as necrosis, LVI/nodal metastases and alterations in cellular proliferation pathways and tumor suppressor transcription factors.

10 months ago

Clinical • Tumor mutational burden

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • NRG1 (Neuregulin 1) • MLH1 (MutL homolog 1) • KMT2C (Lysine Methyltransferase 2C) • GATA3 (GATA binding protein 3) • SYP (Synaptophysin) • INSM1 (INSM Transcriptional Repressor 1)

PIK3CA mutation • NRG1 fusion • NRG1 mutation • NRG1 fusion

Tempus xT Assay • Oncotype DX Breast Recurrence Score®Test

10ms

Clinicopathologic and Genomic Characterization of High-Grade Invasive Solid Papillary Carcinoma of the Breast (USCAP 2024)

10 months ago

Clinical • Tumor mutational burden

PIK3CA mutation • NRG1 fusion • NRG1 mutation • NRG1 fusion

Tempus xT Assay • Oncotype DX Breast Recurrence Score®Test

10ms

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. (PubMed, Future Oncol)

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.

10 months ago

P1/2 data • Review • Journal

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

Bizengri (zenocutuzumab-zbco)

11ms

Clinical findings and genomic characterization of NRG-1 alterations with a comprehensive genome profiling (CGP) in advanced non-small cell lung cancer (ANSCLC) (ELCC 2024)

Conclusions In our cohort, NRG-1 alterations resulted frequently associated with poor prognosis and main oncogene alterations and/or loss of function of oncosuppressor genes. Further investigations are needed.

11 months ago

Clinical • BRCA Biomarker • Metastases

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • NRG1 (Neuregulin 1) • BRCA (Breast cancer early onset)

TP53 mutation • NRG1 fusion

TruSight Oncology 500 Assay

11ms

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov)

P2, N=250, Recruiting, Merus N.V. | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2026

11 months ago

Trial completion date • Trial primary completion date

NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

Bizengri (zenocutuzumab-zbco)

11ms

Real-world outcomes associated with afatinib use in patients with solid tumors harboring NRG1 gene fusions. (PubMed, Lung Cancer)

This study provides real-world data on the characteristics of patients with NRG1 fusion-positive solid tumors treated with afatinib or other therapies; durable responses were observed in both groups. However, there were imbalances between the cohorts, and the study was not designed to compare outcomes. Further prospective/retrospective trials are required.

11 months ago

Journal • Real-world evidence • Real-world

NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

Gilotrif (afatinib)

12ms

Fluorescent in situ hybridization has limitations in screening NRG1 gene rearrangements. (PubMed, Diagn Pathol)

Considering the high cost of NGS, FISH remains a useful method for screening NRG1 fusions in various types of tumors. This study provides valuable insights into the molecular mechanisms of NRG1 fusion and identifies potential treatment targets for patients suffering from this disease.

12 months ago

Journal

ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

ERBB3 expression • NRG1 fusion • ERBB3 positive • NRG1 rearrangement • NRG1 fusion

12ms

Study Evaluating Zenocutuzumab in Patients With or Without Molecularly Defined Cancers (clinicaltrials.gov)

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

12 months ago

Trial completion date • Trial primary completion date

NRG1 (Neuregulin 1)

NRG1 fusion

Gilotrif (afatinib) • Xtandi (enzalutamide) • abiraterone acetate • Bizengri (zenocutuzumab-zbco)

1year

Study of an Anti-HER3 Antibody, HMBD-001, With or Without Chemotherapy in Patients With Solid Tumors Harboring an NRG1 Fusion or HER3 Mutation (clinicaltrials.gov)

P1, N=68, Recruiting, Hummingbird Bioscience | Phase classification: P1b --> P1

1 year ago

Phase classification • Metastases

ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • EGF (Epidermal growth factor)

NRG1 fusion • ERBB3 mutation

gemcitabine • docetaxel • albumin-bound paclitaxel • HMBD-001

1year

Analysis of CD74 Occurrence in Oncogenic Fusion Proteins. (PubMed, Int J Mol Sci)

Fusion proteins known to be oncogenic drivers, including those of CD74, are typically detected and targeted after standard chemotherapeutic plans fail and the disease relapses. The analysis reported herein provides insights into the early intervention of CD74 fusions and highlights the need for improved routine assessment methods so that targeted therapies can be applied while they are most effective.

1 year ago

Review • Journal

ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NRG1 (Neuregulin 1) • CD74 (CD74 Molecule) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • NRG2 (Neuregulin 2)

NTRK1 fusion • NRG1 fusion

1year

Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer. (PubMed, JCO Precis Oncol)

In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

1 year ago

Journal • BRCA Biomarker • MSi-H Biomarker

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NRG1 (Neuregulin 1) • CD8 (cluster of differentiation 8) • SF3B1 (Splicing Factor 3b Subunit 1) • PALB2 (Partner and localizer of BRCA2) • RNF43 (Ring Finger Protein 43) • SMAD4 (SMAD family member 4) • HLA-DPA1 (Major Histocompatibility Complex, Class II, DP Alpha 1)

TP53 mutation • BRCA2 mutation • MSI-H/dMMR • PALB2 mutation • KRAS wild-type • RAS wild-type • CDKN2A mutation • MET mutation • NRG1 fusion • BRAF fusion • RNF43 mutation • MET fusion

1year

Multi-omic Characterization and Molecular Profiling of NUT Carcinoma (AMP 2023)

NRG1 fusion events are infrequently observed in ovarian, fallopian tube, and primary peritoneal carcinomas, and include a diversity of previously unknown partner genes. However, they may carry diagnostic significance in the context of borderline/low-grade serous tumors and have important therapeutic implications with the emergence of new targeted treatments.

1 year ago

Tumor mutational burden • BRCA Biomarker

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • FGFR3 (Fibroblast growth factor receptor 3) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • ARID1A (AT-rich interaction domain 1A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NRG1 (Neuregulin 1) • KMT2D (Lysine Methyltransferase 2D) • CDK12 (Cyclin dependent kinase 12) • MUC16 (Mucin 16, Cell Surface Associated) • NOTCH2 (Notch 2) • CHEK2 (Checkpoint kinase 2) • ADAM9 (ADAM Metallopeptidase Domain 9) • EP300 (E1A binding protein p300) • RAD51D (RAD51 paralog D) • WRN (WRN RecQ Like Helicase) • IR (Insulin receptor) • FANCE (FA Complementation Group E) • JAG1 (Jagged Canonical Notch Ligand 1) • CXADR (CXADR Ig-Like Cell Adhesion Molecule) • FANCC (FA Complementation Group C) • TMEM65 (Transmembrane Protein 65) • TNFRSF12A (TNF Receptor Superfamily Member 12A)

NRG1 fusion • NRG1 fusion

MI Tumor Seek™

1year

Analytical Validation (Accuracy, Reproducibility, Limit of Detection) of Foundation One RNA Assay For Fusion Detection In 189 Clinical Tumor Specimens (AMP 2023)

F1R assay successfully detected oncogenic fusions with high concordance to orthogonal NGS-based tests. This study demonstrated the robustness of F1R and supports its use as a supplement to tissue DNA CGP in routine clinical practice. Additional work is required to clarify optimal clinical scenarios for fusion detection and enable GEP biomarkers for clinical use.

1 year ago

Clinical

BRAF (B-raf proto-oncogene) • FGFR3 (Fibroblast growth factor receptor 3) • NRG1 (Neuregulin 1)

NRG1 fusion • BRAF fusion • FGFR3 fusion • NRG1 fusion

FoundationOne®RNA

1year

Detection of NRG1 Fusion Events in Ovarian, Fallopian Tube, and Primary Peritoneal Carcinomas (AMP 2023)

This large patient cohort demonstrates that NC is characterized by NUTM1 gene fusions, low mutational burden, and general lack of additional oncogenic drivers. The prognosis of NCs remains dismal, and future work could focus on subpopulations of immune cell-rich tumors that might be responsive to immunotherapy.

1 year ago

Tumor mutational burden • IO biomarker

TMB (Tumor Mutational Burden) • NRG1 (Neuregulin 1) • KMT2D (Lysine Methyltransferase 2D) • KMT2C (Lysine Methyltransferase 2C) • KDM6A (Lysine Demethylase 6A) • NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • BRD4 (Bromodomain Containing 4) • NUTM1 (NUT Midline Carcinoma Family Member 1) • BRD3 (Bromodomain Containing 3)

TMB-L • NRG1 fusion • NRG1 fusion

MI Tumor Seek™

1year

Pulmonary invasive mucinous adenocarcinoma. (PubMed, Histopathology)

Accordingly, these unique features require different therapeutic approaches when compared to nonmucinous adenocarcinomas in general. In this article, we review recent updates on the histopathological, clinical, and molecular features of IMAs, and also highlight some unresolved issues for future studies.

1 year ago

Review • Journal

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • NRG1 (Neuregulin 1)

KRAS mutation • NRG1 fusion • HER-2 fusion

1year

Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC) (ESMO Asia 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.

1 year ago

Clinical • Metastases

NRG1 fusion • NRG1 fusion

Bizengri (zenocutuzumab-zbco)

1year

A phase Ib study of HMBD-001, a monoclonal antibody targeting HER3, with or without chemotherapy in patients with genetic aberrations in HER3 signaling (ESMO Asia 2023)

The study evaluates HMBD-001 in combination with standard of care chemotherapy in two cohorts: NRG1 fusions in PDAC (HMBD-001 + nab-paclitaxel + gemcitabine) and in NSCLC (HMBD-001 + docetaxel) and HMBD-001 monotherapy in two other cohorts: NRG1 fusions in other solid tumors and selected HER3 ECD mutations across solid tumors. The primary objectives are to determine the safety and tolerability of all combination regimens and to assess the preliminary anti-tumor activity in terms of objective response rate (ORR) by RECIST v1.1 for all regimens. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and pharmacokinetic (PK) and immunogenicity profile analysis.

1 year ago

Clinical • P1 data

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1)

NRG1 fusion • ERBB3 mutation • NRG1 fusion

gemcitabine • docetaxel • albumin-bound paclitaxel • HMBD-001

over1year

HER4 and EGFR activate cell signaling in NRG1 fusion-driven cancers: implications for HER2/HER3-specific vs. pan-HER targeting strategies. (PubMed, J Thorac Oncol)

We observed that cetuximab, an anti-EGFR antibody, in combination with anti-HER2 antibodies, trastuzumab and pertuzumab, yielded a synergistic effect. Furthermore, pan-HER tyrosine kinase inhibitors (TKIs) were more effective than TKIs with greater specificity for EGFR, EGFR/HER2 or HER2/HER4, although the relative degree of dependence on EGFR or HER4 signaling varied between different NRG1 fusion-positive cancers. Collectively, our findings indicate that pan-HER inhibition including HER4 and EGFR blockade is more effective than selectively targeting HER3 or HER2/HER3 in NRG1 fusion-positive cancers.

over 1 year ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • ERBB4 (erb-b2 receptor tyrosine kinase 4)

NRG1 fusion • NRG1 fusion

Herceptin (trastuzumab) • Erbitux (cetuximab) • Perjeta (pertuzumab)

over1year

Durable response to afatinib in advanced lung adenocarcinoma harboring a novel NPTN-NRG1 fusion: a case report. (PubMed, World J Surg Oncol)

This report supports afatinib can provide potential benefit for NRG1 fusion patients, and RNA-based NGS is an accurate and cost-effective strategy for fusion detection and isoform identification.

over 1 year ago

Journal • Metastases

NRG1 (Neuregulin 1)

NRG1 fusion • NRG1 fusion

Gilotrif (afatinib)

over1year

Study of an Anti-HER3 Antibody, HMBD-001, With or Without Chemotherapy in Patients With Solid Tumors Harboring an NRG1 Fusion or HER3 Mutation (clinicaltrials.gov)

P1b, N=54, Recruiting, Hummingbird Bioscience | Not yet recruiting --> Recruiting

over 1 year ago

Enrollment open • Metastases

ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • EGF (Epidermal growth factor)

NRG1 fusion • ERBB3 mutation

gemcitabine • docetaxel • albumin-bound paclitaxel • HMBD-001

over1year

CRESTONE: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (clinicaltrials.gov)

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

over 1 year ago

Trial completion date • Trial primary completion date • Metastases

NRG1 (Neuregulin 1)

NRG1 fusion

seribantumab (MM-121)

over1year

Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC) (ESMO 2023)

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.

over 1 year ago

Clinical • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NRG1 (Neuregulin 1) • ATP1B1 (ATPase Na+/K+ transporting subunit beta 1) • SLC4A4 (Solute carrier family 4 member 4)

NRG1 fusion • NRG1 fusion

gemcitabine • 5-fluorouracil • irinotecan • Bizengri (zenocutuzumab-zbco) • leucovorin calcium