NRG1 fusion

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

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.

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.

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.

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

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

HMBD-001 will next be evaluated in Part B in biomarker selected mCRPC with Enzalutamide. Trials of HMBD-001 in squamous NSCLC and NRG1 fusions are also planned for Q3/4 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.

We are currently investigating the pathological relevance of identified genetic variants by increasing the cohort size.

Stage IV NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically heterogeneous. Forty-one percent of NRG1 fusion-positive cancers was non-mucinous adenocarcinoma. In addition, although classified as mucinous type, they frequently showed 'atypical' mucinous features.

The overall lack of co-occurring drivers highlights the importance of identifying NRG1 gene fusions, as these patients are unlikely to harbor other targetable alterations. In addition, RNA sequencing is important to identify NRG1 gene fusions given the variety of fusion partners and large genomic areas where breakpoints can occur.

Various clinical responses were observed in patients with NRG1 fusions. Despite the rarity of NRG1 fusions in Korean patients with solid tumors, identification through next-generation sequencing enables the possibility of new targeted therapies.

Among ALK-rearranged NSCLC patients treated with crizotinib, alectinib, brigatinib, or ensartinib, the Asian population exhibited a slightly better effect than the non-Asian population in first-line therapy. It was revealed that ceritinib may have a slightly better effect in the non-Asian ALK-rearranged population as first-line therapy...The non-Asian population were shown to be more likely to be treated with selpercatinib and pralsetinib for RET-rearranged NSCLC than the Asian population. The present report summarizes the current state of fusion gene research and the associated therapeutic methods to improve understanding for clinicians, but how to better overcome drug resistance remains a problem that needs to be explored.

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.

"This study revealed the comprehensive mutational landscape of advanced NSCLC through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies."

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.

Appropriate test selection is paramount as novel NRG1 fusions are more robustly detected by RNA over DNA NGS and are more routinely detected in tissue over liquid biopsies. Clinical trials investigating therapies to target NRG1 fusions are ongoing [CRESTONE (NCT04383210); eNRGy (NCT02912949)].

fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: both zenocutuzumab and seribantumab have FDA Fast Track Designation for tumors with NRG1-fusions. CONCLUSION NRG1 fusions are rare but actionable genomic events in NSCLC but there is striking heterogeneity within this family of alterations. The clinical impact of this heterogeneity on response to targeted agents warrants close attention.

In this study, we systemically analyzed the actionable landscape of melanoma in the largest Asian cohort. In addition, we first demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more patients with melanoma.

CME Provider and Supporter(s): This event is organized and accredited by Research to Practice and supported through educational grants provided by AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Eisai Inc, Exelixis Inc, Genentech, a member of the Roche Group, Incyte Corporation, and Merck. Spectrum and frequency of molecular alterations in cholangiocarcinoma and other BTCs; optimal timing and type of genomic analysis to identify actionable abnormalities Principal findings with pemigatinib, infigratinib and futibatinib for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements Published outcomes from the Phase III ClarIDHy study of ivosidenib for cholangiocarcinoma with an IDH1 mutation; FDA approval and optimal incorporation into clinical practice Ongoing research evaluating targeted therapies (eg, FGFR inhibitors, ivosidenib) for patients with newly diagnosed cholangiocarcinoma Efficacy and safety of trastuzumab deruxtecan among patients with HER2-positive and HER2-low BTCs in the Phase II HERB study Mechanism of action of seribantumab; design, eligibility criteria, key endpoints and early findings from the ongoing Phase II CRESTONE trial assessing seribantumab for advanced solid tumors with NRG1 fusions, including BTCs Other promising biomarker-based strategies for patients with advanced BTCs

No abstract available

We report a well-characterized cohort of BTC patients analyzed with three molecular assays. The 7% of BTC patients with DDR deficiency might be another subgroup suitable for targeted therapies, i.e. PARP inhibition.

Initial efficacy and safety data will be presented and was previously presented at ASCO 2022.Conclusions : Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions with a favorable safety profile. These data support the evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study.

However, recent breakthroughs have identified subgroups of patients who benefit from novel, biomarker-driven therapies. We review the data and role for PARP inhibitors and for other biomarker-directed therapies, including for patients with NTRK fusions, NRG1 fusions, mismatch repair deficiency, and KRAS p.G12C mutations.

We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.