Author: seacat
NRG1 fusionIt is a rare but widespread gene variant that occurs in different types of solid tumors, and the incidence of NRG1 fusion in lung cancer is about 03%, the immune** effect is not good, and there is also a lack of targeted drugs. NRG1 fusions are usually solitary drivers, but may also be EGFR-TKI and ALK-TKI resistance genes.
Lung cancer Afatinib has a certain efficacy on NRG1 fusion, and in recent years, some progress has been made through the fusion of NRG1, a monoclonal antibody against HER3 HER2There are already two types of monoclonal antibodies: Seribantumab and Zenocutuzumab (MCLA-128) have been granted Fast Track Designation by the US Food and Drug Administration (FDA) for treatment-experienced NRG1 fusion solid tumors, both of which have objective response rates of more than 30% for NRG1 fusion non-small cell lung cancer. DNA sequencing alone for NRG1 fusions is easy to miss, while RNA sequencing is relatively more reliable.
NRG1 fusion in non-small cell lung cancer
The incidence of NRG1 fusions in lung cancer is about 03%, of which the incidence of lung adenocarcinoma was 026%, and the incidence of lung squamous cell carcinoma was 021%, compared with a rare type of adenocarcinoma, mucinous adenocarcinoma, where the incidence of NRG1 fusions is higher at 7%.
Figure 1 Incidence of NRG1 fusion in different solid tumor types, with lung cancer in green.
Due to the rarity of NRG1 fusion lung cancer, data collection is needed worldwide for research. The Global ENRGY1 Registry, a consortium of 22 centers in 9 countries in Europe, Asia, and the United States, enrolled data from patients with pathologically confirmed, NRG1 fusion-positive lung cancer from June 2018 to February 2020, using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) to analyze DNA and/or RNA-based data.
The results showed that 110 patients with NRG1 fusion-positive lung cancer were enrolled, of whom 57% were never-smokers, 57% were mucinous adenocarcinomas, 43% were non-mucinous carcinomas, 6% were non-adenocarcinomas, and 71% were non-metastatic phenotype-predominant. The detection rate of NRG1 fusion in RNA detection was 74%.
Chemotherapy with platinum-doublet and taxane-based (platinum-doublet**) chemotherapy was associated with lower objective response rates of 13% and 14%, respectively, and median progression-free survival of 5., respectively8 months and 40 months.
withLow PD-L1 expression (28%) and low tumor mutational burden in NRG1 fusion lung cancer(Median: 0.)9 mut MB) immunophenotypic consistencyThe antitumor activity of chemotherapy combined with immunization** and single-agent immunization** was poor, with objective response rates of 0 and 20%, respectivelyand median progression-free survival of 33 months and 36 months. The objective response rate of afatinib is:(regardless of fusion type), median progression-free survival was2.8 months
NRG1 is fused with HER2 and HER3
The gene that is fused with NRG1 is called a partner gene, CD74 is the most common partner gene for NRG1 fusion, and there are many rare partner genes in addition to CD74, which will not be repeated here.
When the NRG1 gene is fused, an excess of NRG1 protein, which is an EGF-like growth factor, is produced, so who receives these NRG1 proteins? It is the HER3 protein on the cell surface, and the HER3 protein will be phosphorylated when it receives the NRG1 protein, which is activated, so the HER3 protein is activated and cannot work alone, it also has to pull its good brother HER2 protein, and the two brothers are hand in hand, shoulder to shoulder, which is to form a dimer of HER2 and HER3. Once the dimer is formed, it can give orders to the downstream signaling pathway, allowing the tumor cells to survive and proliferate.
By understanding the process of NRG1 evil, we know that to deal with NRG1 fusion, it is not necessary to directly target the NRG1 gene, but to deal with HER3 or HER2 to destroy the cancer-promoting effect of NRG1 protein.
It is not difficult to understand why afatinib has a certain efficacy, becauseAfatinib is a pan-EGFR inhibitor, EGFR (HER1) and HER2 can be inhibited, and wild-type HER2 can also be inhibited (the disadvantage is that the adverse effects are larger). At present, some drugs that have made rapid progress in research to deal with NRG1 fusion are also some HER3 HER2 monoclonal antibodies.
Fig. 2 NRG1 fusion produces EGF-like growth factor, which binds to HER2 HER3 dimer and activates downstream signaling pathways. Various TKIs, monoclonal antibodies, and ADCs targeting HER2 and HER3 are all drugs with potential ** NRG1 fusion.
Seribantumab**NRG1 fusion non-small cell lung cancer with an objective response rate of 39%.
Seribantamab is a monoclonal antibody targeting HER3, which can block NRG1 from the door by preemptively combining with HER3, and cannot be in contact with HER3, so it naturally cannot play a role in promoting cancer.
Results from the Phase II study of seribantumab**nrg1 fusion solid tumors, called Crestone, were reported at the 2023 AACR CongressIncluded in the treatment, but not treated for ERBB(is the name of the HER family).Targeting**(Cohort 1) of patients with NRG1 fusions, while patients who have received ERBB-targeted** are included in exploratory cohort 2, and patients with genetic variants other than NRG1 are included in exploratory cohort 3.
Efficacy data were presented only in Cohort 1 in patients who received a once-weekly dose of 3 g, while safety data included all patients in all three cohorts.
A total of 51 patients were included, including non-small cell lung cancer (NSCLC, n = 30), pancreatic adenocarcinoma (PDAC, n = 6), biliary cholangiocarcinoma (CCA, n = 6), breast cancer (n = 4), and others (n = 5); Fifteen different NRG1 fusion chaperones were identified, with CD74 (22%) and SLC3A2 (16%) being the most common.
In Cohort 1, 30 patients received a 3 g weekly dose with an objective response rate (ORR) of 36%, a disease control rate (DCR) of 95%, and an overall duration of response (DOR) of 14 to 172 months. among themPatients with NSCLC had an ORR of 39% and a DCR of 94%.
Security aspectThe most common** related adverse events (20%) were diarrhoea (41%), fatigue (29%), rash (24%), and nausea (22%). 4 patients (8%) experienced 3 grade 4 trae; No grade 5 trae (i.e., death).
Solid tumors such as seribantumab**nrg1 fusion NSCLC have shown promising efficacy, but Elevation Oncology, the company that developed seribantumab in February 2023, announced that it would suspend the development of seribantumab alone to reduce company expenses.
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Dual-targeted zenocutuzumab**NRG1 fusion NSCLC, afatinib resistance is also effective
Zenocutuzumab (MCLA-128) is a dual-target monoclonal antibody targeting HER2 and HER3. The function of the double target is that if you fail to block the door of HER3 first, you can also block HER2 and prevent HER2 and HER3 from forming a dimer, of course, it would be better if HER2 and HER3 were blocked at the same time.
In addition, MCLA-128 acts as a monoclonal antibody, which also attracts immune cells to attack tumor cells to which it binds, which is known as antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is an indirect antitumor effect of monoclonal antibodies.
Figure 3 Schematic diagram of the effect of zenocutuzumab (MCLA-128).
The 2023 ESMO Congress reported the results of the Phase I clinical trial of MCLA-128**-treated NRG1 fusion NSCLC.
Efficacy analysis was available in 79 patients, including:51% are AsianPatient prior receiving** included: platinum-based chemotherapy (72%) and afatinib (11%). In addition, 15% of patients did not receive**. In terms of disease histology,% and 1% of patients had adenocarcinoma, invasive mucinous adenocarcinoma, squamous cell carcinoma, and poorly differentiated carcinoma, respectively
The most common NRG1 fusion partner genes are CD74 (57%), SLC3A2 (22%), SDC47 (9%), and CDH12 (3%). The majority of NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%).
As of data cut-off, 25% of patients are still on study**; Seventy-three percent of patients discontinued due to disease progression, and one patient discontinued for other reasons. The median drug exposure time was 74 months(Range: 0.)3-36.2）。
In terms of efficacy,The ORR is 372%, 29 patients achieved partial response (PR), 30 patients had stable disease (SD), 12 patients had disease progression (PD), and the disease control rate (DCR) was 615%。Among the 8 patients treated with afatinib, 3 were PR, 4 were SD, and 1 was PD.
The median onset time of action was 18 monthsThe median duration of response (DOR) was 149 months（95% ci，7.4-20.4）。
Figure 4 Waterfall diagram of tumor changes in MCLA-128**, with triangles representing patients treated with afatinib and T-shaped indicating patients still receiving**.
Figure 5 MCLA-128** duration and DOR curve.
Security aspectThe most common** period-emergent adverse reactions associated with MCLA-128(TEAE) is diarrhea (any grade, 61%; 3 Grade 4, 6%), infusion-related reactions (17%; 0%), fatigue (19%; 0%), nausea (8%; 1%), vomiting (6%; 1%), anemia (4%; 1%), constipation (3%; 0%), elevated alanine aminotransferase (ALT; 3%;1%), elevated aspartate aminotransferase (AST; 3%;1%) decreased appetite (3%; 1%), abdominal pain (2%; 1%), dyspnea (1%; 0%), glutamyl transpeptidase (ggt; 1%;1%) and decreased platelet count (1%; 1%)), hyperuricemia (1%; 1%)), bacteremia (1%; 1%) and hyperaminotransferaseemia (1%; 1%)。
No grade 5 TEAEs (i.e., deaths) were observed, and no patients stopped due to TEAEs**.
Detection of NRG1 fusions
As can be seen from the above two studies, most of the enrolled patients were identified by RNA sequencing to identify NRG1 fusions, while DNA sequencing was relatively rare. This is due to the complexity and diversity of the fusion structure and the large intron region of NRG1Single-NGS DNA sequencing may miss some NRG1 fusions, meaning that RNA sequencing may be more reliable than DNA NGS for detecting NRG1 fusions
Due to the rarity of nrg1, the high cost of RNA sequencing**, and the high quality requirements for samples, it is not cost-effective to find nrg1 directly through RNA sequencing. The more economical methodProbablyImmunohistochemistry is passed first(IHC) to detect phosphorylated HER3, as phosphorylated HER3 has a good correspondence with NRG1 fusion. If HER3 phosphorylation is detectedand RNA sequencing to determine if there is an NRG1 fusion. However, the IHC primary screening method also has limitations, because the detection of HER3 phosphorylated protein requires relatively fresh tumor tissue samples, and it is difficult to take samples from patients with advanced disease.
In general, it is not bad for money, that is, NGS DNA, RNA together, if there is a fresh tissue sample, you can first IHC to detect phosphorylated HER3, no rabbit does not scatter eagles (RNA sequencing).
Summary
NRG1 fusion is rare, and there is currently no approved target**, and the immune ** effect is poorFor patients with NRG1 fusions, the most readily available targeted agents are various oral HER2-TKIs, such as afatinib, pyrotinib, and neratinib, these TKIs may have some effect. Monoclonal antibodies targeting HER3 HER2 have entered the clinical research stage with definite efficacy and are not affected by previous TKI**, but these monoclonal antibodies have not been studied in China and are not used by general patients.
For this we can also considerTargeted HER2 has been marketedPertuzumab and trastuzumab or HER2-targeting ADCs, such as T-DM1, T-DXD. NRG1 fusion is also not easy to detect, NGS DNA is easy to miss, RNA sequencing is more reliable, but ** is also higher; IHC is inexpensive, but requires a fresh sample of tumor tissue.
References
1、 lucia anna muscarella，nrg1 fusions in non-small cell lung cancer: a narrative review on biology, detection and therapy.
doi: 10.21037/pcm-23-2
2、 alexander drilon, et al. clinicopathologic features and response to therapy of nrg1 fusion-driven lung cancers: the enrgy1 global multicenter registry.
doi: 10.1200/jco.20.03307
3、 tejas patil et al. abstract ct229: crestone: a phase 2 study of seribantumab in adult patients with neuregulin-1 (nrg1) fusion positive locally advanced or metastatic solid tumors.
4、a. schram,et al. 1315mo durable efficacy of zenocutuzumab, a her2 x her3 bispecific antibody, in advanced nrg1 fusion-positive (nrg1+) non-small cell lung cancer (nsclc).
doi: