NRG1 Fusions Research Articles

Beamion LUNG-1, a Phase Ia/Ib trial of the HER2-specific tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with HER2-driven tumors: outcomes according to HER2 aberration type

Abstract Introduction/Objective Beamion LUNG-1 (NCT04886804) is an ongoing, Phase Ia/Ib trial evaluating the novel HER2- specific tyrosine kinase inhibitor, zongertinib, in patients with HER2 aberration-positive solid tumors (Phase Ia) and HER2 mutation-positive NSCLC (Phase Ib). Here, we report data from Phase Ia according to HER2 aberration type. Methods/Case Report Phase Ia enrolled patients with HER2 aberration-positive (by local assessment: gene mutations, rearrangements, amplification, or overexpression) advanced/metastatic solid tumors. Patients received escalating doses of zongertinib BID (≥15 mg) or QD (≥60 mg), guided by a Bayesian model with overdose control. The primary endpoint of Phase Ia was maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Results (if a Case Study enter NA) At data cut-off (January 29, 2024), 83 patients received zongertinib (BID n=17; QD n=66). Three patients had DLTs during the MTD evaluation period (G3 decreased platelets, G3 diarrhea, G4 neutropenia); the MTD was not reached. Treatment-related adverse events (TRAEs; all/G3/G4/G5) were reported in 76%/8%/1%/0% of patients. Confirmed investigator-assessed ORR/DCR rates in evaluable patients/patients with NSCLC (n=74/n=41) were 35%/85% and 44%/93%; median duration of response was 12.7/15.8 months, respectively. Based on preliminary data, 43 patients were HER2 mutation-positive (TKD/non-TKD/unknown n=36/n=6/n=1; A775_G776insYVMA n=16; G778dupGSP insertions n=3; S310F n=2); 23 patients overexpressed HER2 (2+/3+); 17 had HER2 amplification; 3 patients had NRG1 fusions. ORR/DCR rates (regardless of confirmation) in patients with TKD mutation-positive, A775_G776insYVMA-positive, non-TKD mutation-positive, G778dupGSP-positive and S310F- positive tumors were 64%/97%, 69%/94%, 20%/100%, 33%/100% and 50%/100%, respectively. ORR/DCR rates (regardless of confirmation) in patients with HER2 overexpressing tumors (+/- amplification) were 39%/83%. Of the 3 patients with NRG1 fusions, one had a partial response and two had stable disease. Conclusion In this preliminary analysis, zongertinib showed promising activity across a broad range of tumor types with different HER2 aberrations, including aberrations that have historically been difficult to treat. Updated data will be presented.

NRG1 Gene Fusions-What Promise Remains Behind These Rare Genetic Alterations? A Comprehensive Review of Biology, Diagnostic Approaches, and Clinical Implications.

Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials.

Afatinib in patients (pts) with solid tumors with neuregulin 1 (NRG1) fusions: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3131 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a small cohort of pts with advanced solid tumors with NRG1 fusions treated with afatinib are reported. Methods: Eligible pts had measurable, advanced disease, NRG1fusion, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Pts with non-small cell lung cancer (NSCLC) were eligible if they had no pathogenic mutations in ALK, BRAF, EGFR or ROS1. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 40 mg of afatinib daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response, duration of SD, and safety. This cohort was closed after 2 years before completing stage 1 enrollment (n = 10) of the Simon’s 2-stage design used in TAPUR according to a prespecified cohort closure rule. Results: 4 pts with 3 tumor types with NRG1 fusion were enrolled between February 2020 and July 2021. 1 pt had NSCLC with a CD74- NRG1 fusion and achieved a PR that lasted 24 weeks (wks). This pt was a 58-year-old White, non-Hispanic female with ECOG PS 0, 2 prior systemic therapies and progressed after 32 wks on study tx. Co-alterations included CCNE1 amplification (amp), GATA amp, TP53 R65fs*58, and an ALK G1121D variant of unknown significance. 2 pts achieved SD16+: 1 was a 47-year-old White, Hispanic female with colorectal cancer (CRC) with a MATN2- NRG1 fusion, ECOG PS 1, 3 prior systemic therapies and co-alterations in APC, DDX11, FBXW7, FGFR1 and TP53; the other pt was a 49-year-old Black, non-Hispanic male with pancreatic cancer with a NRG1 exon 2 fusion, ECOG PS 1, 5 prior systemic therapies, a comutation in ARID1A. The durations of SD for these 2 pts were 136 and 64 wks, respectively. The pt with CRC underwent resection of a remaining target lesion and is still alive off study drug at 198 wks after the baseline visit as of Dec 2023. 1 pt was a 70-year-old White, non-Hispanic female with CRC with a CD74- NRG1 fusion, ECOG PS 0, 1 prior systemic therapy, and a best response of progressive disease. This pt had comutations in ARID1A, PBRM1 and TP53and progressed at 8 wks. Median OS was 81 wks. No grade 3-5 tx-related adverse events (AE) or serious AEs were reported. Conclusions: Though a small sample size, afatinib demonstrated promising activity in pts with advanced solid tumors with NRG1 fusion, including very durable DC. Additional study in a larger group of pts is warranted to confirm the efficacy of afatinib in pts with NRG1 fusion. Clinical trial information: NCT02693535 .

Abstract 1903: Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective in cancer models with high NRG1 expression

Abstract Neuregulin 1 (NRG1) is a ligand that binds to HER3, promotes HER2/HER3 dimerization and PI3K/AKT/mTOR signaling, and causes malignant transformation. Zenocutuzumab (Zeno, MCLA-128) is a humanized IgG1 bispecific antibody that docks on HER2, preventing heterodimerization with HER3, while also blocking NRG1 interaction with HER3, and potently inhibiting NRG1-induced HER2:HER3 proliferation and survival signaling of cancer cells. High NRG1 expression arising from autocrine signaling or gene amplification is associated with poor prognosis in certain cancers, and resistance to standard therapies. The clinical efficacy and safety of Zeno in patients with NRG1 fusion-driven cancer who were enrolled in the ongoing global multicenter eNRGy study and Early Access Program were recently presented. Treatment with Zeno led to durable responses across multiple different previously treated NRG1 fusion tumor types. Zeno utilizes the Merus Dock & Block® mechanism to inhibit HER2/HER3 dimerization and the NRG1/HER3 tumor-signaling pathway and is effective at high NRG1 concentrations. Here, we examined the efficacy of Zeno in preclinical models representing different tumor types expressing high NRG1 levels. Zeno treatment of the lung cancer cell line HCC95, which harbors an NRG1 gene amplification, effectively inhibited signaling pathways involved in the regulation of proliferation and survival, including the PI3K/AKT/mTOR pathway and inhibited cell proliferation. The anti-tumor efficacy of Zeno in vivo against a panel of 28 patient-derived xenograft (PDX) models representing different tumor types was examined. Zeno significantly inhibited tumor growth in seven high-NRG1-expressing PDX models. These results show that Zeno is effective in tumor cell killing in vitro and in vivo in high NRG1-expressing cancer models representing multiple different tumor types. Citation Format: Marie N. O'Connor, Ron C. Schackmann, Igor Odintsov, Szabolcs Fatrai, Arie B. Brinkman, Sidney Walker, Jeroen J. Lammerts van Bueren, Cecile A. Geuijen. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective in cancer models with high NRG1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1903.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . 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.

Pulmonary invasive mucinous adenocarcinoma.

Invasive mucinous adenocarcinoma (IMA) is a relatively rare subtype of lung adenocarcinoma, composed of goblet and/or columnar tumour cells containing abundant intracytoplasmic mucin vacuoles. While a majority of IMAs are driven by KRAS mutations, recent studies have identified distinct genomic alterations, such as NRG1 and ERBB2 fusions. IMAs also more frequently present as a pneumonic-like pattern with multifocal and multilobar involvement, and comparative genomic profiling predominantly shows a clonal relationship, suggesting intrapulmonary metastases rather than synchronous primary tumours. 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.

1618P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC)

1618P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC)

HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers: Implications for HER2-HER3-specific Versus Pan-HER Targeting Strategies

IntroductionNRG1 gene fusions are clinically actionable alterations identified in NSCLC and other tumors. Previous studies have reported that NRG1 fusions signal through HER2 and HER3 but, thus far, strategies targeting HER3 specifically or HER2-HER3 signaling have exhibited modest activity in patients with NSCLC bearing NRG1 fusions. Although NRG1 fusion proteins can bind HER4 in addition to HER3, the contribution of HER4 and other HER family members in NRG1 fusion-positive cancers is not fully understood. MethodsWe investigated the role of HER4 and EGFR-HER3 signaling in NRG1 fusion-positive cancers using Ba/F3 models engineered to express various HER family members in combination with NRG1 fusions and in vitro and in vivo models of NRG1 fusion-positive cancer. ResultsWe determined that NRG1 fusions can stimulate downstream signaling and tumor cell growth through HER4, independent of other HER family members. Moreover, EGFR-HER3 signaling is also activated in cells expressing NRG1 fusions, and inhibition of these receptors is also necessary to effectively inhibit tumor cell growth. 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 were more effective than tyrosine kinase inhibitors 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. ConclusionsOur 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.

Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer.

Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older). We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values (Q) < .05. Patients with YOPC had higher proportions of mismatch repair-deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC-KRASWT] v 10.6 [AOPC-KRASWT] months; P = .008) but not KRAS-mutant tumors (P = .084). 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.

Durable response to afatinib in advanced lung adenocarcinoma harboring a novel NPTN-NRG1 fusion: a case report

BackgroundNRG1 fusions are rare oncogenic drivers in solid tumors, and the incidence of NRG1 fusions in non-small cell lung cancer (NSCLC) was 0.26%. It is essential to explore potential therapeutic strategies and efficacy predictors for NRG1 fusion-positive cancers.Case presentationWe report an advanced lung adenocarcinoma patient harboring a novel NPTN-NRG1 fusion identified by RNA-based next-generation sequencing (NGS), which was not detected by DNA-based NGS at initial diagnosis. Transcriptomics data of the tissue biopsy showed NRG1α isoform accounted for 30% of total NRG1 reads, and NRG1β isoform was undetectable. The patient received afatinib as fourth-line treatment and received a progression-free survival (PFS) of 14 months.ConclusionsThis 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.

NRG1 fusions in solid tumors.

3132 Background: NRG1 fusions are rare but actionable genomic drivers that occur across a growing number of tumor types. NRG1 has an EGF-like domain that serves as a ligand for ErbB (HER3) receptors, thereby inducing heterodimerization, usually with HER2, and subsequent activation of relevant downstream signaling pathways. 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. Here, we update the incidence and characterization of NRG1 fusions across tumor types. Methods: Samples were submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by next-generation sequencing. Results: In an analysis of 169,273 tumor specimens, 261 unique tumors with an NRG1 fusion were identified for an overall incidence of 0.154% across tumors. NRG1 fusions were most frequently detected in NSCLC, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma, colorectal cancer, cholangiocarcinoma, prostate cancer, bladder and urothelial cancers, esophagogastric cancers and less commonly, prostate cancer, soft tissue sarcoma, anal cancer, salivary gland cancers, head and neck cancer, small intestine cancer, small cell lung cancer, endometrial cancer, thyroid cancer, neuroendocrine cancer, high grade glioma, and melanoma. The highest incidence was in breast cancer (0.301%), followed by cholangiocarcinoma (0.263%), NSCLC (0.232%), carcinoma of unknown primary (0.215%), pancreatic ductal adenocarcinoma (0.190%), ovarian cancer (0.174%), bladder cancer (0.148%), esophageal cancer (0.145%) and vulvar cancers (0.145%). There were 153 unique NRG1 fusion partners. The most common fusion partner was CD74 (12.37%), followed by SLC3A2 (8.13%), ATP1B1 (4.59%), and RBPMS (4.24%). Conclusions: NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.

NRG1 fusions in non-small cell lung cancer: a narrative review on biology, detection and therapy

NRG1 fusions in non-small cell lung cancer: a narrative review on biology, detection and therapy

The genomic landscape of adolescent and young adult (AYA) malignancies using DNA and RNA-based next generation sequencing.

e15091 Background: Survival for adolescents and young adult (AYA) cancer patients (defined as age 15-39 years by the NCI) has not improved compared to survival outcomes in pediatric and older adult patients. Several factors contribute to the outcomes disparity, including lack of access to novel treatments. Currently, only a fraction of AYA cancer patients receive advanced genomic testing. Herein, we aim to characterize the molecular landscape of AYA cancers. Methods: De-identified records of 2,706 AYA patients diagnosed with solid tumors and hematologic malignancies who received Tempus xT next-generation sequencing (NGS) were identified. The prevalence of pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs), insertions/deletions (indels), fusions, and copy number alterations were assessed to describe the somatic landscape. Tumor biomarkers, such as microsatellite instability (MSI) and tumor-mutational burden (TMB) were also analyzed. Results: The cohort consisted of 2,706 AYA patients diagnosed with: central nervous system (N = 779), breast cancer (N = 700), bone and soft tissue sarcomas (N = 226), hematologic (N = 198), and gastrointestinal (GI) (N = 803) malignancies. Among 407 high-grade gliomas (HGG WHO Grade 3 &amp; 4), variants in TP53 167 (41%), 136 (33%) IDH1, 125 (31%) ATRX, and 48 (12%) TERT were seen. Among the 82 patients with low-grade glioma (LGG, WHO Grade 1 &amp; 2), 42 (51%) had a variant in IDH1, 40 (49%) TP53, and 35 (43%) ATRX. Among 269 patients with HR+ HER2- breast cancer, 82 (30%) had variants in TP53, 66 (25%) PIK3CA, 46 (17%) GATA3, 43 (16%) FGFR1 and 34 (13%) in ESR1. In triple-negative breast cancers (TNBC), 95 (77%) had a variant in TP53, and 9 (7.3%) in BRCA1. In ewing sarcomas (N = 36), 28 (78%) patients had a fusion with EWSR1, with TP53, STAG2, FGFR2, and RET altered in 2 (5.6%) patients. Within osteosarcomas (N = 46), 12 (26%) patients had a variant in TP53 and 9 (20%) in RB1 . In the AML subgroup (N = 34), WT1 was altered in 5 (15%) and FLT3 in 4 (12%) cases. Finally, in the GI cohort (806), 22 (5%) cases were MSI-H. Within colorectal cancer patients (N = 446), 247 (55%) patients had a variant in TP53, 150 (34%) in KRAS, 64 (14%) in PIK3CA, and several with NRG1 (8, 1.8%) and NTRK (3, 0.7%) fusions. Conclusions: We describe the somatic landscape of common malignancies in one of the largest AYA datasets. Additional analyses will focus on how this landscape differs from non-AYA age groups.

The impact of single gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) success in community oncology practice for advanced non-small cell lung cancer (NSCLC): Results from a prospective observational reference laboratory testing program.

6506 Background: CGP concurrently tests tumor tissue for guideline-recommended predictive biomarkers for optimal therapy selection and identification of clinical trials in NSCLC patients. A common practice in the community oncology setting is to first order SGT, then consider CGP when SGT results are negative or after treatment failure. Given the limited tissue available and the scope of alterations not tested by SGT, we sought to characterize the effects of prior SGT on subsequent CGP testing success, and therapeutic opportunities identified by CGP beyond SGT for NSCLC patients in the community setting. Methods: Reference laboratory information systems were used to prospectively contact clinicians across 80 community practices who ordered at least 1 SGT for guideline-recommended genomic variants in NSCLC. CGP was offered for their patients prior to SGT or upon receipt of negative SGT results. SGT included individual assays for BRAF, EGFR, KRAS, MET exon 14 skipping mutations; ALK, RET, and ROS1 rearrangements; and PD-L1 IHC . CGP included DNA-seq for mutations, copy number variants in 523 genes including guideline-recommended genomic variants, MSI, and tumor mutational burden; RNA-seq for rearrangements/fusions/splice variants; and PD-L1 IHC. Results: Among a total of 580 NSCLC patients with CGP ordered (May 2021-December 2022), 168 (29%) had ≥1 SGT ordered prior to CGP (median=5). No patients had all SGT performed, with untested cases ranging from 10% for ALK to 90% for MET exon 14. The same FFPE tissue block was used for CGP in 150/168 (89%) of cases with prior negative SGT. Compared to CGP-only cases, CGP for cases with prior negative SGT was canceled twice as often at tissue review (16% vs 7%; p=.001), had higher DNA extraction failures (13% vs 8%; p=.09), and lower DNA sequencing success (70% vs 83%, p&lt;.001). CGP detected guideline-recommended variants in 51% of all cases. Among prior negative SGT cases, frequencies were higher in genes where SGT was performed less often and is less sensitive than CGP RNA-seq ( RET fusions , MET exon 14 skipping). CGP also identified guideline-recommended variants in genes with no SGT offered during the study period ( ERBB2 mutations , NTRK2/3 fusions), as well as variants with emerging evidence for FDA expedited program-designated clinical trial therapies in 28% of patients, including NRG1 fusions and BRAF non-V600E , KEAP1, KRAS non-G12C, NFE2L2, STK11, and TP53 Y220C mutations. Conclusions: Prior negative SGT doubled subsequent CGP test cancellations for NSCLC due to tissue insufficiency and increased CGP DNA extraction failures. SGT practice in the community oncology setting does not meet practice guideline recommendations and negatively impacts the potential benefit of subsequent CGP for NSCLC patients.

RNA Sequencing Identifies Novel NRG1 Fusions in Solid Tumors that Lack Co-Occurring Oncogenic Drivers

NRG1 gene fusions are rare, therapeutically relevant, oncogenic drivers that occur across solid tumor types. To understand the landscape of NRG1 gene fusions, 4397 solid tumor formalin-fixed, paraffin-embedded samples consecutively tested by comprehensive genomic and immune profiling during standard care were analyzed. Nineteen NRG1 fusions were found in 17 unique patients, across multiple tumor types, including non-small-cell lung (n=7), breast (n=2), colorectal (n=3), esophageal (n=2), ovarian (n=1), pancreatic (n=1), and unknown primary (n=1) carcinomas, with a cumulative incidence of 0.38%. Fusions were identified with breakpoints across four NRG1 introns spanning 1.4 megabases, with a mixture of known (n=8) and previously unreported (n=11) fusion partners. Co-occurring driver alterations in tumors with NRG1 fusions were uncommon, except colorectal carcinoma, where concurrent alterations in APC, BRAF, and ERBB2 were present in a subset of cases. 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.

Abstract 921: Identification of NRG1 fusions in patients with solid tumors: analysis from a real-world community oncology network

Abstract Neuregulin-1 (encoded by NRG1) serves as a ligand for ERBB3 and can lead to dysregulated cellular proliferation in cases of NRG1 fusions. The reported incidence of NRG1 fusions in solid tumors is ~0.1-0.3% with enrichment in invasive mucinous adenocarcinoma of the lung and KRAS wildtype pancreatic adenocarcinoma. However, the real-world incidence of NRG1 fusions across diverse tumor types continues to evolve with the clinical implementation of comprehensive next-generation sequencing (NGS) methods including RNA based NGS. The true diversity and prognostic significance of specific NRG1 fusion partners has yet to be elucidated. We report on NRG1 fusions from a large clinico-genomic database of patients (pts) in community-based oncology settings where NGS is ordered as standard clinical practice. We conducted a retrospective, records-based analysis of pts across Sarah Cannon’s network of over 299 partner community-based oncology clinics to identify pts with NRG1 fusions detected by commercial NGS testing ordered as a part of standard of care from 1/1/2017 - 7/7/2022. NRG1 fusions were reported in 0.05% (19 of 40,857) of pts with commercial NGS test results across a range of tumor types including lung (59%; n=11/19), pancreas (11%; n=2), breast (5%; n=1), colorectal (5%), esophageal (5%), endometrial (5%), soft tissue liposarcoma (5%), and carcinoma of unknown primary (5%). NGS identifying an NRG1 fusion was performed in 5 (26%) pts with early stage disease while 11 (58%) pts had NGS testing after initial diagnosis of or progression to advanced/metastatic disease. A majority of pts harboring NRG1 fusions were female (68%; n=13). NRG1 fusions were detected by DNA (58%; n=11) and RNA based (42%; n=8) NGS from liquid (5%; n=1) and tissue biopsies (95%; n=18). A total of 11 different fusion partners were reported. CD74 was the most prevalent fusion partner and was primarily detected by DNA NGS including in one pt from liquid biopsy. Five novel, as yet to be described, fusion partners (CDK13, IL1RL2, FUT10, PPP2R2A, PIM3) were detected - 3 by RNA sequencing and 2 by DNA sequencing of NRG1 (versus sequencing of the fusion partner). TP53 (42%; n=8), CDKN2A (32%; n=6), and MTAP (16%; n=3) were the most frequently co-altered genes. Other notable co-altered genes included mutations in PIK3CA (11%; n=2), BRAF (5%; n=1), EGFR (5%), ALK (5%), and NRAS (5%). Immune biomarkers were largely negative, with 16% (n=3) PD-L1 positive, 0% MSI-high, and 5% (n=1) TMB-high cases. These data highlight the importance of comprehensive molecular profiling for pts with solid tumors, as NRG1 fusions occur across tumor types and stage of disease. 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)]. Citation Format: Emma G. Sturgill, Jaya Srivastava, Jessica Correia, Cooper Schumacher, Daniel Luckett, Cesar A. Perez, Judy S. Wang, Stephen G. Divers, Babar Bashir, Jennifer Johnson, Valerie M. Jansen, Andrew J. McKenzie, David R. Spigel. Identification of NRG1 fusions in patients with solid tumors: analysis from a real-world community oncology network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 921.

Abstract 4042: Role of individual HER family members and pan-HER targeting treatment strategy in NRG1 fusion positive cancer

Abstract NRG1 gene fusions are rare, clinically actionable somatic alterations identified in 0.1% of all tumors. Previous studies have demonstrated that NRG1 fusions signal through ERBB/HER family members and that HER2 inhibition has anti-tumor activity in NRG1 fusion-driven cancers. However, NRG1 can also bind to HER4 in addition to HER3, and the contribution of individual HER family members in tumor cells with NRG1 fusions has not been fully elucidated. To determine the role of individual HER family members in NRG1 fusion positive cancer cells, we engineered Ba/F3 cells to express various HER family members along with NRG1 fusions. Expression of NRG1 fusions in combination with EGFR/HER3, HER2/HER4 or HER4 induced cellular transformation as measured by IL-3 independent growth. These results indicated that in addition to HER2/HER3 signaling, EGFR/HER3, HER4, and to a greater extent, HER2/HER4 signaling, may activate key oncogenic signaling pathways in cells expressing NRG1 fusions. We next assessed whether targeted inhibition of HER family members could inhibit the growth of NRG1 fusion positive cancer cells using our panel of engineered Ba/F3 cells, human tumor cell lines, and xenograft models. Our data indicated that pan-HER tyrosine kinase inhibitors (TKIs), such as poziotinib, were more effective at blocking HER2/HER3, EGFR/HER3 and HER4 signaling in NRG1-fusion expressing cells as compared to TKIs with greater relative specificity for EGFR (erlotinib, lapatinib), HER2 (pyrotinib), EGFR/HER2 (afatinib, dacomitinib, neratinib) or HER2/HER4 (TAS0728,tucatinib). In NRG1 fusion-positive cancer cell lines, poziotinib showed potent anti-tumor cell activity with IC50 values of 0.2 - 0.4 nM. The IC50 values of EGFR/HER2 TKIs were 0.3 - 23 nM, and HER2/HER4 TKIs showed modest activity with IC50 values of 11 - 560 nM. Next, we assessed whether inhibition of HER family dimerization also had activity against tumor cells harboring NRG1 fusions. We observed that pertuzumab, a HER2 antibody which inhibits HER2 dimerization with other HER family members, had improved single agent activity as compared to trastuzumab, a HER2 antibody that inhibits HER2 activation, suggesting crosstalk between HER family members. Moreover, an additive effect was observed when tumor cells were treated with trastuzumab in combination with pertuzumab. Treatment with cetuximab, an antibody that targets EGFR, in combination with trastuzumab and pertuzumab yielded a synergistic effect on tumor cell killing. These data indicate that HER4 and EGFR can play a role in NRG1 fusion-driven signaling through crosstalk with HER2/HER3 and thus, pan-HER/EGFR inhibitors are more effective than EGFR/HER2 or HER2/HER4-selective inhibitors, highlighting the therapeutic potential of targeting multiple members of the HER family in NRG1 fusion driven cancers. Citation Format: Hibiki Udagawa, Monique Nilsson, Junqin He, Alissa Poteete, John Victor Heymach. Role of individual HER family members and pan-HER targeting treatment strategy in NRG1 fusion positive cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4042.

Clinical characteristics and targeted therapy of different gene fusions in non-small cell lung cancer: a narrative review.

Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy. Although the incidence rate of gene fusion is low in NSCLC, it is of great significance in advanced refractory patients. However, the clinical characteristics and the latest treatment progress of patients with gene fusions in lung cancer have not been thoroughly explored. The objective of this narrative review was to summarize the latest research progress of targeted therapy for gene fusion variants in NSCLC to improve understanding for clinicians. We conducted a search of PubMed database and American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) abstracts meeting proceedings from 1 January 2005 to 31 August 2022 with the following keywords "non-small cell lung cancer", "fusion", "rearrangement", "targeted therapy" and "tyrosine kinase inhibitor". We comprehensively listed the targeted therapy of various gene fusions in NSCLC. Fusions of ALK, ROS proto-oncogene 1 (ROS1), and rearranged during transfection proto-oncogene (RET) are relatively more common than others (NTRK fusions, NRG1 fusions, FGFR fusions, etc.). 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 effect of crizotinib might be similar in Asians and non-Asians with ROS1-fusion-positive NSCLC in 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.

&lt;i&gt;NRG1&lt;/i&gt; fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents

ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions. A review article published in Annals of Oncology discusses the biology, detection, and incidence of NRG1 fusions, and the therapeutic role of afatinib and other ErbB-targeted agents in patients with cancer harboring NRG1 fusions. This Publication Perspective video summarizes the review article on behalf of Dr Stephen Liu (Georgetown University Medical Center, Washington, D.C., USA) and his co-authors.

PP01.67 Decentralized, Real-World Study of Afatinib in Patients with Advanced/Metastatic Solid Tumors with NRG1 Fusions

PP01.67 Decentralized, Real-World Study of Afatinib in Patients with Advanced/Metastatic Solid Tumors with NRG1 Fusions