NRG1 fusion

Multiple strategies are employed to achieve ever-increasing efficacy of the newly proposed therapies, including combination therapies with other targeted approaches, small compounds, and monoclonal antibodies. This narrative review summarizes the available data on the spectrum of all available drugs targeting NRG1/HER deregulation in cancers with NRG1 fusions, their chemistry, pharmacodynamics, pharmacokinetics, and metabolism, as well as the clinical efficacy in NRG1-positive patients.

NRG1 fusions were identified in 0.8% of NSCLC, exceeding historical estimates and underscoring the importance of RNA-based NGS for fusion detection. The clinical and molecular profile mirrored prior reports, with predominant female patients, IMA histology, PD-L1 negativity, and low TMB. Outcomes were poor in metastatic patients lacking access to targeted therapy, supporting the need for broader implementation of RNA sequencing and access to anti-HER3 agents.

This study revealed the distinct clinicogenomic landscapes of NRG1 fusions and SNVs in NSCLC. These findings emphasize the important role of molecular profiling for precision diagnosis and individualized treatment of NSCLC.

P=N/A, N=500, Not yet recruiting, The University of Sydney

P3, N=94, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

Critical challenges persist, such as intrinsic resistance mediated by the heterogeneity of NRG1 fusion isoforms and compensatory activation of the epidermal growth factor receptor (EGFR) pathway. This comprehensive analysis underscores the unmet need for novel therapeutics and provides a framework for optimizing precision oncology strategies in this molecularly defined NSCLC subset, highlighting the necessity for standardized diagnostic protocols and globally collaborative clinical trials.

P1, N=100, Recruiting, Cogent Biosciences, Inc.

NRG1 fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), with therapeutic relevance highlighted by the FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases...No significant difference in progression-free survival was seen following first-line EGFR TKI therapy between uncommon and wild-type groups. Our findings highlight the heterogeneity of NRG1 fusions in NSCLC, revealing novel fusions, unique pathway enrichments, and expression profiles that may inform future personalized treatment strategies.

A higher rate of CDx SV detection-most significantly for NRG1 and NTRK fusions-was observed using concurrent DNA-CGP and RNA-CGP compared to DNA-CGP alone. Our results highlight the complementary nature of these methods. Given the substantial clinical benefit of SV targeted therapies, an integrated DNA/RNA profiling strategy should be part of routine clinical care.

These results support the antitumor activity and safety of seribantumab in patients with advanced solid tumors harboring NRG1 fusions.

NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology.