Biomarker Consortium

GI Cancer

Gastric Cancer

T-cell immunoreceptor with Ig and ITIM domains (TIGIT)

 gene, located on chromosome 3q13.33. It functions as an inhibitory immune checkpoint receptor and is prominently expressed on exhausted CD8⁺ T cells, regulatory T cells (Tregs), and natural killer (NK) cells within the tumor microenvironment.

TIGIT binds to CD155 (PVR) expressed on tumor and antigen-presenting cells, resulting in downregulation of T-cell activation, cytokine production, and NK cell cytotoxicity—thereby promoting immune escape and tumor progression.

TIGIT expression is significantly elevated in gastric adenocarcinoma compared with normal gastric mucosa, with increased expression observed on tumor-infiltrating lymphocytes and peripheral CD8⁺ T cells from gastric cancer patients.

In a pooled analysis of immunohistochemistry (IHC) studies, 77.8% of gastric cancer cases showed high TIGIT expression in tumor cells (defined as > 5% of cells staining positive).

Co-expression with PD-1 is common in tumor-infiltrating lymphocytes, particularly in patients with high-grade, microsatellite-stable tumors.

In gastric cancer, TIGIT upregulation correlates with poor prognosis and a suppressive immune landscape.

TIGIT expression increases with cancer stage and is associated with lymph node metastasis.

Dual inhibition of TIGIT and PD-1/PD-L1 has shown synergistic potential in preclinical models by restoring T-cell function and enhancing antitumor immunity. TIGIT is therefore an emerging immunotherapeutic target, and combination strategies are actively being explored in early-phase clinical trials in gastric and other solid tumors.

While TIGIT testing is not yet part of standard clinical biomarker panels, its relevance is growing in the context of advanced or metastatic gastric cancer, particularly for patients being evaluated for immune checkpoint inhibitor therapy or enrollment in early-phase clinical trials.²

IHC is the most commonly used method for TIGIT detection in tumor-infiltrating lymphocytes.

primarily used in translational research settings, allows for simultaneous detection of TIGIT alongside multiple immune markers, providing insights into the functional immune context and cell–cell interactions.¹

Flow cytometry is often applied in research and clinical trials for functional profiling of TIGIT⁺ immune cell subsets, including circulating and tumor-infiltrating T cells and NK cells. Flow cytometry enables evaluation of co-expression patterns, immune exhaustion markers, and cytokine profiles.

Although TIGIT is not currently part of standard biomarker testing panels, it remains an active focus of investigation in combination immunotherapy trials, with ongoing studies expected to inform its potential integration into future clinical practice.

NCCN Gastric Cancer Guidelines (v7.2025) recommend that patients with progressive disease after standard therapies should be considered for clinical trials of novel immune checkpoints, including antiTIGIT agents.

There are no FDA-approved TIGIT-targeted agents as of 2025.

Domvanalimab is a humanized, Fc-silent IgG1 monoclonal antibody that targets TIGIT, an inhibitory immune checkpoint receptor expressed on CD8⁺ T cells, Tregs, and NK cells.

Domvanalimab is being developed as part of combination immunotherapy strategies in multiple solid tumors, including non–small cell lung cancer and gastroesophageal adenocarcinoma.

Domvanalimab selectively binds to TIGIT and prevents its interaction with CD155 (PVR), a ligand expressed on tumor and antigen-presenting cells.

This blockade relieves TIGIT-mediated suppression of effector immune responses, thereby enhancing T-cell activation, cytokine production, and NK cell cytotoxicity.

Importantly, its Fc-silent design reduces the potential for antibody-dependent cellular cytotoxicity (ADCC), preserving regulatory immune cell populations and potentially improving tolerability.

A phase 1b/2 trial evaluating domvanalimab + zimberelimab + chemotherapy in first-line upper GI cancers, including gastric adenocarcinoma.

Domvanalimab (anti-TIGIT) + zimberelimab (anti–PD-1) with chemotherapy showed over 12 months median progression-free survival in first-line upper GI cancers (gastric, GEJ, esophageal) in the phase II ARC-21 trial.

The combination was well tolerated, with durable disease control and early signs of synergy in PD-L1–positive patients.

Randomized, open-label, multicenter phase 3 trial of domvanalimab + zimberelimab + chemotherapy versus nivolumab + chemotherapy in participants with previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

Zhang P, Liu X, Gu Z, et al. Targeting TIGIT for cancer immunotherapy: recent advances and future directions. 

. 2024;12(1):7. doi:10.1186/s40364-023-00543-z

He W, Zhang H, Han F, et al. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. 

. 2017;77(22):6375-6388. doi:10.1158/0008-5472.CAN-17-0381

Xiao K, Xiao K, Li K, Xue P, Zhu S. Prognostic role of TIGIT expression in patients with solid tumors: a meta-analysis. 

 2021;2021:5440572. doi:10.1155/2021/5440572.

Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. 

. 2024;14. doi:https://doi.org/10.3389/fonc.2024.1382183

Wainberg ZA. Dr Wainberg on phase 2 domvanalimab/zimberelimab/chemo data in gastric cancer. OncLive. 2025;1. 

https://www.onclive.com/view/dr-wainberg-on-phase-2-domvanalimab-zimberelimab-chemo-data-in-gastric-cancer

Xu D, Zhao E, Zhu C, et al. TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer. 

. 2020;225(3):151915. doi:10.1016/j.imbio.2020.151915

‌‌National Comprehensive Cancer Network. Clinical practice guidelines in oncology: gastric cancer. Version 2.2025

https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf

Anti-TIGIT – Domvanalimab. Arcus Biosciences, Inc, 2025. 

https://arcusbio.com/our-science/clinical-candidates/domvanalimab/?utm_source=chatgpt.com

A safety and efficacy study of treatment combinations with and without chemotherapy in adult participants with advanced upper gastrointestinal tract malignancies (EDGE-Gastric). ClinicalTrials.gov. Updated June 27, 2025. Accessed July 10, 2025. 

https://www.clinicaltrials.gov/study/NCT05329766

A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed July 14, 2025. 

https://clinicaltrials.gov/study/NCT05568095

TIGIT

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)

The v-Raf murine sarcoma viral oncogene homolog B1 (

) gene was discovered in 1988, and it encodes a kinase protein in the RAS-RAF-MEK-ERK signal transduction pathway.

BRAF is located on chromosome 7 and belongs to the RAF family of serine/threonine-specific protein kinases but is the only one known to be a proto-oncogene in humans.

Under normal circumstances, RAF proteins participate in the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation and differentiation.

Activated BRAF phosphorylates MEK proteins, which subsequently activate ERK proteins, which activate cellular transcription factors.

BRAF contains 3 conserved regions: CR1, CR2, and CR3. CR1 and CR3 produce autoinhibitory interaction for BRAF, with CR2 functioning as a hinge of the other conserved regions.

 mutation is V600E, resulting in constitutively activated BRAF kinases that stimulate tumor growth.

 mutations occur within 2 different protein locations, exons 11 and 15, resulting in the loss of the autoinhibitory region combined with targeting BRAF to the plasma membrane.

The prevalence of BRAF V600E mutations in gastric cancer is relatively low, ranging from

 mutations in gastric cancer, the role of mutation status and clinicopathological variables is unclear.

BRAF is a known predictor of poor prognosis in colorectal cancer (CRC) to EGFR-targeted agents, but the predictive value in gastric cancer is unknown.

Gastric cancer is characterized by high tumor heterogeneity, so biomarker testing has a high impact on appropriate treatment selection.

Patients with gastric cancer should undergo testing for BRAF mutations and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.

BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).

Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample.

In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include 

 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, 

Gastric cancer accounts for only about 1.5% of new cancer cases in the United States each year.

The relative rarity means that targeted treatments are limited, and most treatments include traditional chemotherapy.

Currently, the only FDA-approved treatment for gastric cancer with a BRAF V600E mutation is dabrafenib plus trametinib.

The treatment of adult and pediatric patients ≥ 1 year who have unresectable or metastatic solid tumors that harbor a 

V600E mutation, whose disease has progressed following prior treatment, and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Dabrafenib is an inhibitor of mutated BRAF proteins, which are constitutively active; they stimulate tumor cell proliferation via the MAPK pathway.

Trametinib is a reversible inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2.

MEK proteins are upstream regulators of the MAPK pathway.

Tumor cells that initially respond to dabrafenib can develop resistance via the MEK protein, providing the rationale for combination therapy.

Learn more about Dabrafenib and Trametinib >

https://us.tafinlarmekinist.com/metastatic-nsclc/patient-support/patient-resources

Wan PTC, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. 

. 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6

TAFINLAR (dabrafenib). Prescribing information. GSK; 2024. Accessed May 5, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf

MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed May 5, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf

Hewitt LC, Hutchins GG, Melotte V, Saito Y, Grabsch HI. KRAS, BRAF and gastric cancer. 

. 2015;4(6). doi:10.3978/j.issn.2224-4778.2015.09.08

Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. 

. 2019;11(8):1197. doi:10.3390/cancers11081197

Choi YY, Noh SH, Cheong JH. Molecular dimensions of gastric cancer: translational and clinical perspectives. 

. 2016;50(1):1-9. doi:10.4132/jptm.2015.09.10

Van Grieken NCT, Aoyma T, Chambers PA, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. 

. 2013;108(7):1495-1501. doi:10.1038/bjc.2013.109

NCCN guidelines version 1.2024: gastric cancer

Zhu X, Pigazzi A, Zell J, Lu Y. Changing disparity of gastric cancer incidence by histological types in US race-specific populations. 

 2020;27(1):1073274820977152. doi:10.1177/1073274820977152

National Comprehensive Cancer Network. NCCN guidelines version 1.2024: pancreatic adenocarcinoma. 2024. Accessed May 5, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf

Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: results of the NCI-MATCH trial subprotocol H. 

. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. 

. 2023;29(5):1103-1112. doi:10.1038/s41591-023-02321-8

BRAF V600E

Fibroblast Growth Receptor Factor 2b (FGFR2b)

The family of fibroblast growth factor receptors (FGFRs) consists of four receptor tyrosine kinases (RTKs): FGFR1 to FGFR4. These cell surface proteins possess 3 immunoglobulin (Ig)-like extracellular domains, a single-pass transmembrane domain, and an intracellular tyrosine kinase domain.

The ligands for FGFRs are Fibroblast Growth Factors (FGFs), a family of 22 small proteins with diverse expression patterns.

The binding of FGFs drives the dimerization of FGFRs triggering downstream signaling pathways, including PI3K, ATK, MAPK, STAT, and PLC, which regulate various cell processes such as proliferation, differentiation, cell migration and survival.

FGFR2b (also known as fibroblast growth factor receptor 2 isoform IIIb) is one of the proteins resulting from the transcription and subsequent translation of the alternatively spliced 

The FGFR2b protein receptor is primarily localized on epithelial cell membranes.

Due to the FGFR2b unique extracellular domain, only a specific subset of FGF ligands will bind to the receptor – FGF ligands 7, 10, and 22 specifically bind to FGFR2b.

Aberrant activation of FGFR2b can drive the transformation and proliferation of tumor cells as well as angiogenesis.

FGFR2b protein overexpression is an emerging biomarker prevalent in 

 of patients with advanced G/GEJC with 2+ or 3+ staining in any percentage of tumor cells (any %, 2+/3+ TC–positive) and in ~17% with 2+ or 3+ staining in ≥10% of tumor cells (≥10%, 2+/3+ TC positive).

FGFR2b protein overexpression in gastric cancer may be associated with poorly differentiated diffuse-type histology and poor outcomes, including lower overall survival, and warrants further investigation.

 gene amplification is observed in approximately 3% to 9% of GC cases.

FGFR2b protein overexpression can be independent of FGFR2 gene amplification in advanced G/GEJC and further studies are warranted to definitively demonstrate a correlation.

Biomarker testing should be performed at diagnosis for patients with newly diagnosed, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma to evaluate for currently targetable biomarkers.

Current guidelines do not include specific recommendations for FGFR2b testing, as no agents targeting the protein FGFR2b are FDA approved as of March 2025.

 genomic alterations can be detected using next-generation sequencing (NGS), fluorescence in-situ hybridization (FISH), or immunohistochemistry (IHC), although NGS and FISH are less favored to establish FGFR2b protein overexpression due to the lack of definitive concordance data between 

 gene amplification and FGFR2b protein overexpression.

IHC is the preferred method for identifying FGFR2b protein overexpression, offering lower cost, faster turnaround.

Since FGFR2b protein overexpression can occur in the absence of 

 gene amplification, IHC detection of FGFR2b protein overexpression remains the appropriate testing methodology.

Current guidelines do not have recommendations regarding FGFR2b testing as of March 2025.

For currently actionable biomarkers, IHC/ISH/targeted PCR are the preferred approaches to assess biomarkers initially for patients with G/GEJC. However, NGS testing through a CLIA-approved laboratory may be considered later in the clinical course of patients who have sufficient tumor tissue available for testing.

There are currently no FDA-approved agents that target the protein FGFR2b within the setting of G/GEJC.

Bemarituzumab is a first-in-class humanized IgG1 monoclonal antibody that selectively binds to the cell surface protein receptor FGFR2b and is presently under investigation for the treatment of FGFR2b-positive/HER-negative previously untreated advanced GC and gastroesophageal junction cancer.

Bemarituzumab’s mechanism of action is twofold: (1) it directly inhibits FGFR2b ligand binding and downstream signaling, and (2) it enhances antibody-dependent cell-mediated cytotoxicity (ADCC).

Study design: A phase 1/2, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of bemarituzumab-mFOLFOX6 in patients with advanced HER-2 non-positive gastric cancer prescreened for FGFR2b overexpression (via IHC) and/or 

 gene amplification (via circulating tumor DNA [ctDNA] assay).

Study design: A double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy.

Study design: A phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety.

Xiang H, Chan AG, Ahene A, et al. Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer. 

. 13(1):1981202. doi:10.1080/19420862.2021.1981202

Sato Y, Okamoto K, Kawano Y, et al. Novel biomarkers of gastric cancer: current research and future perspectives. 

. 2023;12(14):4646. doi:10.3390/jcm12144646

Khosravi F, Ahmadvand N, Bellusci S, Sauer H. The multifunctional contribution of fgf signaling to cardiac development, homeostasis, disease and repair. 

Ahn S, Lee J, Hong M, et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. 

. 2016;29(9):1095-1103. doi:10.1038/modpathol.2016.96

Lian Y, Bodian D, Shehu A. Elucidating the role of wildtype and variant fgfr2 structural dynamics in (dys)function and disorder. 

2024;25(8):4523. doi:10.3390/ijms25084523.

Wainberg ZA, Kang YK, Lee KW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial. 

 2024 May;27(3):558-570. doi:10.1007/s10120-024-01466-w.

Rha SY, Zhang Y, Elme A, et al. Prevalence of FGFR2b protein overexpression in advanced gastric cancers during prescreening for the phase III FORTITUDE-101 trial. 

. 2025;(9):e2400710. doi:10.1200/PO-24-00710

Zhang J, Tang PMK, Zhou Y, et al. Targeting the oncogenic FGF-FGFR axis in gastric carcinogenesis. 

. 2019;8(6):637. doi:10.3390/cells8060637.

NCCN guidelines version 2.2025: gastric cancer

Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. 

. 2022;23(11):1430-1440. doi:10.1016/S1470-2045(22)00603-9

Smyth EC, Chao J, Muro K, et al. Trial in progress: phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101). 

. 2022;40(suppl 16):TPS4164-TPS4164. doi:10.1200/JCO.2022.40.16_suppl.TPS4164

Bemarituzumab or placebo plus chemotherapy in gastric cancers with fibroblast growth factor receptor 2b (FGFR2b) overexpression (FORTITUDE-101). ClinicalTrials.gov. Updated February 7, 2025. Accessed April 8, 2025. 

https://clinicaltrials.gov/study/NCT05052801

Bemarituzumab plus chemotherapy and nivolumab versus chemotherapy and nivolumab for FGFR2b overexpressed untreated advanced gastric and gastroesophageal junction cancer. (FORTITUDE-102). ClinicalTrials.gov. Updated November 22, 2024. Accessed April 8, 2025. 

https://clinicaltrials.gov/study/NCT05111626

FGFR2b

Neurotrophic tropomyosin kinase receptors (NTRK)

Neurotrophic tropomyosin kinase receptors (NTRK) are transmembrane kinases involved in neural cells’ development, proliferation, and survival.

After localization to cell membranes, the protein family is activated by nerve growth factor (NGF) ligands, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4, and NT-5.

The TRK family consists of 3 members, including TKRA, TKRB, and TRKC and activation of these proteins leads to downstream activation of the signal pathways RAS-RAF-MEK-ERK, phosphatidylinositol-3 (PI3) kinase, and phospholipase C gamma (PLC-γ).

NTRK genes are proto-oncogenes that activate into oncogenic driver mutations via gene fusions that lead to chimeric TRK proteins.

in solid tumors, but there is a lack of data regarding the prevalence in gastroesophageal cancer.

gene fusions occur through chromosome rearrangements, point mutations, deletions, or gene fusions and cause spontaneous ligand-independent dimerization.

These chimeric proteins have constitutive TRK protein activity or overexpression of the kinase function.

Current research suggests that oncogenic mutations cause a change exclusively in the extracellular domain of chimeric proteins, suggesting a common regulatory domain.

Patients with gastric cancer should undergo testing for 

 gene fusions and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.

Feasible testing methods include immunohistochemistry (ICH), fluorescence in situ hybridization (FISH), DNA-based next-generation sequencing, and RNA-based NGS.

The ideal approach appears to be RNA-based NGS because of the higher rates of false positives and lack of evidence of functional transcription present in other methods.

Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing.

If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised.

Key biomarkers for interrogation include 

Currently, 2 FDA-approved options exist for treating unresectable or metastatic NTRK gene fusion–positive solid tumors.

Larotrectinib and entrectinib are recommended as second- or subsequent-line treatments in NTRK+ patients. Their favorable safety profile and clinically meaningful response support regular screening for gene fusions.

Approval for larotrectinib was based on the data from 3 trials, LOCO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).

The overall response rate in 55 patients was 75% (95% CI, 61-85), 71% of responses remained ongoing at 1 year, and 55% remained progression-free at 1 year.

Entrectinib approval was based on data from the trials STARTRK-2 (NCT02568267) and STARTRK-1 (NCT02097810), and ALKA-372-001.

The study population comprised 54 adults with an overall response rate of 57% (95% CI, 43-71), progression-free survival 11.2 months (95% CI, 8.0-14.9), and overall survival 20.9 (95% CI, 14.9-NR).

The FDA has approved entrectinib for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment. 

This indication has received accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes 

 respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib also inhibits JAK2 and TNK2.

Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.

https://www.gene.com/patients/medicines/rozlytrek

The FDA has approved larotrectinib for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment.

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. TRKA, B, and C are encoded by the genes 

Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.

https://hcp.vitrakvi-us.com/support-and-resources/resources

Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. 

. 2022;79:103893. doi:10.1016/j.amsu.2022.103893

 fusions: merits and limitations of current diagnostic platforms. 

. 2019;79(13):3163-3168. doi:10.1158/0008-5472.CAN-19-0372

Lange A, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. 

. 2018;10(4):105. doi:10.3390/cancers10040105

Arnold A, Daum S, Von Winterfeld M, et al. Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry. 

. 2019;215(11):152662. doi:10.1016/j.prp.2019.152662

ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. 

https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf

VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. 

https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf

Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in 

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