Bring the potential of ROZLYTREK® to life

To help patients with
NTRK fusion+ or ROS1+
NSCLC, you must first
identify them

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To help patients with NTRK fusion+ or ROS1+ NSCLC, you must first identify them

Both neurotrophic tyrosine kinase (NTRK) and c-ros oncogene 1 (ROS1) have emerged as key targets in many different cancer types1–12

Introduction to clinically actionable fusions

Clinically actionable fusions

Oncogenic genomic alterations can involve chromosomal rearrangements, most commonly gene fusions, that result in the formation of chimeric fusion kinases.1

Gene fusions have been reported in approximately 20% of all cancers, accounting for a significant proportion of cancer morbidity and mortality.1

Gene fusions can lead to oncogenic fusion proteins13

  • Oncogenic gene rearrangements can lead to the expression of oncogenic fusion proteins when a 5' partner forms an in-frame gene fusion with a 3' proto-oncogene13
Diagram of oncogenic fusion protein with 5’ partner, transmembrane domain and 3’ proto-oncogene
  • When a fusion gene maintains the reading frame, an in-frame fusions results and there is expression of an active fusion protein, whereas an out-of-frame fusion results in a frameshift and a protein that is not functional13,14
  • The discovery of actionable gene fusions enables cancer patients to try targeted therapies13

NTRK

NTRK (neurotrophic tyrosine receptor kinase) gene fusions are most common in rare tumours, but have also been detected less frequently in more common cancers9

5%1,9,15,16
  • Colorectal cancer (0.2% to < 5%) 
  • Melanoma (0.3% to < 5%)
  • Thyroid (1.5% to 25%)
  • Glioblastoma (1.1% to < 5%)
  • Non-small cell lung cancer (0.23%)
  • Head and neck squamous cell cancer  (0.2% to < 5%)
  • Cholangiocarcinoma (3.6% to < 5%)
  

No filter results

5% to 25%1,9
  • Gastrointestinal stromal tumour (5% to 25%)
  • Spitzoid melanoma (16.4% to 25%)
  • Papillary thyroid cancer (12.3% to 25%)
  

No filter results

>80%1,9,17,18
  • Secretory breast carcinoma (~92%)
  • Congenital mesoblastic nephroma (83% to > 90%)
  • Infantile fibrosarcoma (> 86%)
  • Secretory carcinoma (93% to 100%)

No filter results

The TRK receptor family is encoded by the three NTRK genes that code for three proteins1

  • In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival3,10
  • TRK receptors are normally triggered by growth factors for the normal functioning of the nervous system3
Diagram of NTRK1, NTRK2 and NTRK3 genes, and TRKA, TRKB and TRKC proteins

NTRK gene fusions create oncogenic proteins3

  • Each of the three NTRK genes can combine with a 5’ fusion partner to create oncogenic proteins1–3,11
  • So far, 25 distinct fusions have been identified1
Diagram of oncogenic fusion protein with 5’ partner, transmembrane domain and NTRK gene

The oncogenic proteins drive cancer through aberrant signalling1,3–6

  • The oncogenic chimera proteins activate a ligand-independent signalling cascade implicated in cell proliferation, survival and angiogenesis1,3–6
Diagram of TRK and oncogenic proteins that drive cancer through aberrant signalling

Watch a video about NTRKs and how fusion proteins can result

ROS1

ROS1 is a therapeutic target in NSCLC, with gene fusions occurring in 1–2% of patients:19,20

  • Patients require an effective treatment with both systemic and central nervous system (CNS) activity, as: 21-25
    • In ROS1+ advanced NSCLC, up to 40% of patients have CNS metastases at diagnosis
    • A retrospective analysis found that approximately half of lung cancer patients with CNS metastases were asymptomatic for CNS disease
    • For 47% of patients with ROS1+ advanced NSCLC receiving crizotinib, the CNS is the first and only site of progression

ROS1 gene fusions create oncogenic proteins12,26,27

  • The genetic rearrangements leading to constitutive expression of ROS1 have been identified in a number of tumour types, including non-small cell lung cancer (NSCLC)12,26,27
  • In ROS1+ NSCLC, the ROS1 gene chromosomal rearrangement results in the fusion of the tyrosine kinase domain of ROS1 with one of several partner proteins27
Diagram of oncogenic fusion protein with 5’ partner, transmembrane domain and ROS1 gene

ROS1 fusion proteins drive cancer through aberrant signalling12,26,27

  • The resulting ROS1-fusion kinases are constitutively activated to trigger growth and survival signalling pathways that drive cellular proliferation27,28
Diagram of ROS1 and oncogenic proteins that drive cancer through proliferation and survival

Testing

To help patients with NTRK fusion+ or ROS1+ NSCLC, patient identification is critical

IHC (Immunohistochemistry)30,31
  • Screening tool only
  • Can identify NTRK overexpression and ROS1 protein expression
  • Requires a confirmatory test
  • Quick and inexpensive

No filter results

FISH* (DNA fluorescence in situ hybridisation)30,32,33
  • For NTRK, can identify fusion events but not exact fusion breakpoints 
  • Cannot be multiplexed—3 separate tests need to be run for all 3 NTRK fusion genes
  • Approved technology for ROS1 fusion detection by guideline bodies, eg, CAP, IASLC, AMP

No filter results

RT-PCR (Reverse-transcriptase polymerase chain reaction)1,34–36
  • Can detect a limited number of fusion partners and fusion events that are targeted by PCR probes
  • Typically tests for known fusion partners at hotspot breakpoints 
  • NTRK gene fusions involve a high number of genetic partners, many of which are novel

No filter results

RNA-seq NGS (RNA sequencing next-generation sequencing)30,31,35,37
  • High multiplexing ability
  • High confidence fusion calls
  • Can identify fusion events with exact breakpoints across multiple genes and partners
  • Can identify novel fusion partners

No filter results

DNA-seq NGS (DNA sequencing next-generation sequencing)30,31,35
  • High multiplexing ability
  • Cannot detect expression
  • Can identify fusions as well as other actionable alterations
  • Can identify novel fusion partners

No filter results

*Detected rearrangements by DNA-based assays may not result in fusions, correlation with surgical pathology and predicted transcript (for sequencing) is needed.

Appropriate molecular testing can help uncover gene fusions1,37

NTRK fusion detection – European Society for Medical Oncology (ESMO) recommends using NGS38,39

ESMO algorithm to help detect NTRK fusions

ESMO Guidelines recommend testing all patients with metastatic NSCLC for ROS1 gene fusion40

  • Fluorescence in situ hybridisation (FISH) is standard for ROS1 testing in clinical trials
  • Immunohistochemistry (IHC) may be used to select patients for confirmatory FISH testing but currently lacks specificity
  • Next-generation sequencing (NGS) clinical use is expanding
  • External quality assurance is essential

"Testing for epidermal growth factor receptor (EGFR) mutations and rearrangements involving the anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) genes are now considered mandatory in most European countries"40

CAP-IASLC-AMP* Guideline strongly recommends ROS1 testing in advanced lung adenocarcinoma33

  • IHC may be used as a screening test in lung adenocarcinoma patients
  • However, positive ROS1 IHC results should be confirmed by a molecular or cytogenetic method

*College of American Pathologists-International Association for the Study of Lung Cancer-Association for Molecular Pathology

"ROS1 testing must be performed on all lung advanced-stage adenocarcinoma patients, irrespective of clinical characteristics"33

ROZLYTREK as monotherapy is indicated for the treatment of patients 12 years of age and older, with NTRK fusion+ solid tumours:29

  • Who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and
  • Who have not received a prior NTRK inhibitor
  • Who have no satisfactory treatment options.

ROZLYTREK is also indicated for the treatment of adult patients with ROS1+ NSCLC not previously treated with ROS1 inhibitors.29

Read more about ROZLYTREK efficacy in:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for details on how to report adverse reactions.

Footnotes

AKT, protein kinase B; ALK, anaplastic lymphoma kinase; College of American Pathologists-International Association for the Study of Lung Cancer-Association for Molecular Pathology; CNS, central nervous system; DAG, diacylglycerols; EGFR, epidermal growth factor receptor; ERK, Extracellular signal-regulated kinase; ESMO, European Society for Medical Oncology; FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; JAK, janus kinase; MEK, mitogen-activated protein kinase kinase; MTOR, the mammalian (mechanistic) target of rapamycin; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PI3K, phosphoinositide 3-kinases; PCR, polymerase chain reaction; PKC, protein kinase C; PLC, phospholipase C; RAF, rapidly accelerated fibrosarcoma; ROS1, c-ros oncogene 1; RT-PCR, reverse transcriptase polymerase chain reaction; SHP2, SH2 containing protein tyrosine phosphatase-2; TRK, tropomyosin receptor kinase.

 

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