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NRG1 fusions and the CRESTONE study

Inhibiting HER3 with seribantumab in any solid tumor with an NRG1 fusion may stop the tumor’s primary driver of growth.

NRG1 is a protein that plays an important role in healthy tissue

NRG1 is an abbreviation for neuregulin-1 (sometimes also called heregulin), and may refer to either the NRG1 gene or the NRG1 protein. Healthy cells throughout the body use the genomic information in the NRG1 gene to create NRG1 proteins, which perform a wide variety of functions and are essential for normal development of the nervous system and heart. [1, 2]

Rare genomic alterations can cause a cell to incorrectly produce NRG1 fusion proteins

Fusion proteins occur when two genes are accidentally combined by a cell. NRG1 fusion proteins contain components of both the NRG1 protein and another protein. As long as the NRG1 portion of the fusion protein retains its active component, known as the EGF-like domain, the fusion protein can act like a normal NRG1 protein. [2, 3]

NRG1 fusions can cause a normal cell to become a cancer cell through over-activation of the HER3 pathway

NRG1 proteins predominantly bind to the HER3 receptor on the surface of a cell. This signals the cell to perform certain actions important to its survival and proliferation.

Cells normally regulate the creation of normal NRG1 proteins to avoid unchecked growth. However, NRG1 fusion proteins may continue to act like NRG1 proteins and activate HER3 when they shouldn’t. This unregulated activation can cause transformation into a tumor cell, or “tumorigenesis”.
[1, 2]

“While these fusions are uncommon events, if we detect just one, it changes everything.”

DR. ROBERT DOEBELE, MD, PHD, Targeted Oncology, January 2020

NRG1 fusions are driver alterations and an important therapeutic target

“While these fusions are uncommon events, if we detect just one, it changes everything.”

DR. ROBERT DOEBELE, MD, PHD, Targeted Oncology, January 2020

Tumor cells often carry many different genomic alterations at once, but only some of these genomic changes drive its tumorigenesis and survival. These critical alterations are called oncogenic “driver alterations”.

The identification of driver alterations has changed the way that cancer can be treated. As each new driver is found, new therapies can be developed to specifically target them and precisely inhibit a tumor’s growth and survival.

When NRG1 fusions are found in a tumor, other known oncogenic drivers such as KRAS, EGFR, ALK, ROS1, and RET mutations are often absent. Because of this, NRG1 fusions are considered unique oncogenic driver alterations when detected in patients with cancer, and an important new therapeutic target. [2, 3, 4, 5, 6]

Additional treatment options are needed for tumors driven by an NRG1 fusion

Multiple targeted therapies have now been approved to inhibit known driver alterations such as KRAS, EGFR, ALK, ROS1, RET, and BRAF mutations. Recently, two drugs have been approved for tumors driven by a different kind of gene fusion involving the NTRK gene. These approvals are based on clinical trials showing that treatment with a targeted therapy matched to a driver mutation improves patient outcomes over traditional standard of care.

NRG1 fusions have now been identified as a driver alteration for which new targeted treatment options are needed.

Patients with NRG1 fusions do not normally respond well to treatment with standard chemotherapy, chemoimmunotherapy or novel checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 therapies.[7] NRG1 fusions have also been correlated with worse overall and disease-free-survival.[8] For patients with an NRG1 fusion, treatment with a HER3 inhibitor in clinical trials may represent the most direct path to stopping the growth of the tumor.

NRG1 fusions can also emerge at the time of progression in cancer patients whose original tumor carried other oncogenic driver mutations and may be the driving cause of resistance to their targeted therapy. [2, 3, 6] For patients with an emerging NRG1 fusion, treatment with a HER3 inhibitor in clinical trials may also re-sensitize a tumor to targeted therapy.

Seribantumab is a promising investigational therapy for tumors with an NRG1 gene fusion

Seribantumab is a fully human monoclonal antibody that binds to HER3 so that the NRG1 fusion protein cannot, preventing activation of the HER3 signaling that sustains the tumor. Because NRG1 gene fusions are oncogenic driver events, they are important biomarkers that should guide treatment decisions. We believe that seribantumab may offer a precise treatment path forward for patients whose tumor’s growth is driven by an NRG1 gene fusion.

Seribantumab is being tested in a tumor-agnostic way for any advanced solid tumor with a confirmed NRG1 fusion

NRG1 fusions have been identified in over 10 unique solid tumor types, including many that become resistant to standard treatment approaches such as breast, ovarian, colorectal, kidney and bladder cancers as well as sarcomas. Today, NRG1 gene fusions are believed to be found in 0.2% of all solid tumors. [4, 9]

Emerging research suggests that certain cancer subtypes may have higher rates of NRG1 gene fusions, such as in invasive mucinous adenocarcinomas (IMA) of the lung where it may be found in 27-31% of cases, and in the pancreatic ductal adenocarcinomas (PDAC) subtype of pancreatic cancer where it may be found in up to 6% of cases. [3, 5] As testing methodologies improve and more patients are tested, the identification of NRG1 fusions is expected to increase.

Recently, the FDA has begun to recognize that some precision therapies that target oncogenic driver alterations may be “tumor-agnostic”, meaning they are likely to be effective no matter which organ the tumor is in.

Because NRG1 fusions are found in multiple solid tumors and are likely to be a unique oncogenic driver alteration whenever it is found, we are now testing seribantumab in a tumor-agnostic way. As long as your solid tumor has a confirmed NRG1 fusion, you may be eligible for a clinical trial with seribantumab.

Genomic testing of your tumor is the only way to confirm if it has an NRG1 fusion

We are still learning about NRG1 fusions and why they appear in some patients. Today, the only way to know for sure if your tumor has an NRG1 fusion is to have your tumor tested.

There are multiple types of tests available today for detecting gene fusions, but some are more sensitive than others. The most sensitive method of detecting an NRG1 gene fusion today is by getting an RNA-based Next Generation Sequencing (NGS) test that looks at your tumor’s RNA instead of its DNA.

There are multiple RNA-based NGS tests available today. If you are considering a test that uses a panel instead of a comprehensive review of your tumor’s RNA, be sure to confirm with the test provider that their panel includes NRG1 gene fusions to make sure that you are receiving the most comprehensive information about your tumor.

METHODS OF DETECTING NRG1 FUSIONS

Method [10, 11, 12, 13, 14]Sensitivity/
Specificity for known NRG1 gene fusions
Detection of novel NRG1 fusionsIdentification of NRG1 fusion partnerDetection of RNA transcription
RNA-seq NGS
(RNA sequencing next-generation sequencing)
High/High*YesYesYes
DNA-seq NGS
(DNA sequencing next-generation sequencing)
Moderate/HighLimitedYesNo
RT-PCR
(Reverse-transcriptase polymerase chain reaction)
High/High**NoLimitedLimited
FISH
(Fluorescence in-situ hybridization)
High/High**NoNoNo
RNA-seq NGS
(RNA sequencing next-generation sequencing)
Sensitivity/Specificity: High/High
Detection of fusion gene: Yes
Detection of fusion partner: Yes
Detection of expression: Yes
DNA-seq NGS
(DNA sequencing next-generation sequencing)
Sensitivity/Specificity: Moderate/High
Detection of fusion gene: Yes
Detection of fusion partner: Yes
Detection of expression: No
RT-PCR
(Reverse-transcriptase polymerase chain reaction)
Sensitivity/Specificity: High/High
Detection of fusion gene: Limited
Detection of fusion partner: Yes
Detection of expression: Yes

For more information, download our guide to detection of NRG1 fusions:

FISH
(Fluorescence in-situ hybridization)
Sensitivity/Specificity: High/High
Detection of fusion gene: No
Detection of fusion partner: No
Detection of expression: No

* Due to the extremely high sensitivity of RNA-based sequencing, test results should be reviewed by a trained professional to avoid a false positive. A high-quality test sample is important to maintain high sensitivity and avoid a false negative reading.

** Dependent on the quality and accuracy of the probes and primers used in the assay

Genomic testing is the key

Talk to your doctor about getting tested today

We believe that genomic testing is critical to ensuring that patients receive their best chance at improved outcomes. Knowing whether your tumor has a driver mutation can help your doctor best guide your treatment plans.

Ask your doctor today about your options for genomic testing, and whether you may be eligible for an approved targeted therapy or a clinical trial. Below are a few downloadable resources to help you start the discussion:

 

REFERENCES:

[1] Mota JM et al., A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer. Oncotarget. 2017

[2] Fernandez-Cuesta, L. and Thomas RK, Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer. Clin Cancer Res 2014

[3] Drilon A et al., Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. Cancer Discovery. 2018

[4] Jonna et al., Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res 2019

[5] Jones MR et al., NRG1 Gene Fusions are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clinical Cancer Research. 2019

[6] Dimou A and Camidge DR, Detection of NRG1 Fusions in Solid Tumors: Rare Gold?. Clinical Cancer Research. 2019

[7] Duruisseaux M et al., NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry. ASCO 2019



[8] Shin DH et al., Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Oncotarget. 2016

[9] Jonna et al., Characterization of NRG1 gene fusion events in solid tumors., ASCO 2020, abstract #3113

[10] Schram AM et al., Fusions in solid tumors: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol. 2017

[11] Heyer EE et al., Diagnosis of fusion genes using targeted sequencing. Nat Commun. 2019

[12] Mertens F et al., The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015 >

[13] Sussman RT et al., Validation of a Next-Generation Sequencing Assay Targeting RNA for the Multiplexed Detection of Fusion Transcripts and Oncogenic Isoforms. Arch Pathol Lab Med. 2020

[14] Teixidó C et al., RNA Analysis as a Tool to Determine Clinically Relevant Gene Fusions and Splice Variants. Arch Pathol Lab Med. 2018