FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target?
Abstract
:1. Introduction
2. The FGFR Signaling Pathway and Its Alterations in Gastric Cancer
3. A Pharmacological Overview on the Anti-FGFR Agents
4. FGFR-Targeted Therapies in Gastric Cancer
4.1. Preclinical Studies and Early Phase Clinical Trials
4.1.1. Multikinase Inhibitors
4.1.2. Pan-FGFR Inhibitors
4.1.3. FGFR1-3 Inhibitors
4.1.4. Selective FGFR Inhibitors
4.1.5. Antibody–Drug Conjugates
4.2. Clinical Trials for FGFR Inhibitors: State of the Art
5. Future Perspectives
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Name of Drug, Intervention | Tumor Type, Setting, Patient Inclusion/Stratification by Molecular Status | Phase | Study Name, Trial ID | Primary Endpoint |
---|---|---|---|---|
Multikinase Inhibitors | ||||
Anlotinib | Advanced stomach cancer patients, subsequent line of treatment, no molecular stratification | II/III | ALTER0503, NCT02461407 | OS |
Anlotinib | Advanced stomach cancer patients, subsequent line of treatment, no molecular stratification | II | THALIA, NCT05029102 | PFS |
TQB2450 /Anlotinib hydrochloride/ Oxaliplatin/Capecitabine | HER2/Neu negative, advanced or metastatic gastric, second-line treatment | N/A | NCT04891900 | ORR |
TISLELIZUMAB, Anlotinib plus XELOX | Metastatic gastric cancer, first-line, no molecular stratification | III | NCT04963088 | MTD, ORR |
Tislelizumab + anlotinib | Metastatic gastric cancer, first-line, no molecular stratification | II | NCT04777162 | ORR |
Anlotinib Plus Toripalimab | Metastatic gastric cancer, subsequent line, no molecular stratification | II | NCT04278222 | ORR |
Anlotinib | High grade (3), second-line | II | NCT03457844 | PFS |
Anlotinib Hydrochloride with Nivolumab | Metastatic gastric cancer, second-line, no molecular stratification | II | NCT04503967 | ORR |
Dovitinib | Advanced gastric cancer, FGFR2 amplification required, subsequent line | II | NCT01719549, GASDOVI-1 | RR |
Dovitinib Plus Docetaxel | Advanced gastric cancer, first-line, no molecular stratification | I/II | NCT01921673 | MTD, PFS |
TKI258 | Advanced gastric cancer, subsequent line, no molecular stratification | II | NCT01576380 | DCR |
Lenvatinib + Pembrolizumab | Non-metastatic, fist-line, no molecular classification | II | NCT04745988 | MPR rate |
Lenvatinib + Pembrolizumab | Advanced gastric cancer, subsequent line, no molecular stratification | II | NCT03321630 | ORR, OS |
Lenvatinib + Pembrolizumab | Female, advanced ovarian and gastric neoplasms, subsequent line | II | NCT04519151 | PFS |
Lenvatinib + Pembrolizumab | PD-L1 positive, subsequent line | II | NCT03797326 | ORR |
Lenvatinib | Advanced gastric cancer, subsequent to prior imatinib or sunitinib | II | NCT04193553 | PFS |
Pazopanib Hydrochloride | Low- or intermediate-grade neuroendocrine carcinoma, advanced, second-line | II | NCT01841736 | PFS |
Pan FGFR inhibitors | ||||
Erdafitinib | Advanced gastric cancer, Mandatory FGFR testing, beyond first-line | II | NCT02699606 | ORR |
Erdafitinib | Advanced Solid tumor, second-line or beyond, FGFR testing | II | NCT02465060 | ORR |
Futibatinib | Advanced gastric cancer, FGFR testing, beyond first-line | II | NCT04189445 | ORR |
FGFR1-3 inhibitors | ||||
AZD 4547 | Advanced, second line or third line, Mandatory confirmation of FGFR gene amplification | II | NCT01795768 | Molecular change as correlated with tumor size change |
AZD 4547 | Advanced solid tumor, second-line or beyond, based on molecular stratification | NCT02465060, MATCH | ORR | |
Debio1347 | Advanced solid tumor, second-line or beyond, based on molecular stratification | II | NCT03834220 | ORR |
Infigratinib | Advanced gastric cancer, second-line or beyond, based on FGFR status | II | NCT05019794 | ORR |
Derazantinib + paclitaxel-ramucirumab/ atezolizumab | Advanced gastric cancer, second-line or beyond, based on FGFR status | I/II | NCT04604132, FIDES-03 | ORR |
Selective FGFR2-inhibitor | ||||
mFOLFOX6 ± bemarituzumab | Advanced gastric cancer, first-line, based on FGFR status | III | NCT05052801, FORTITUDE-101 | OS |
Pan FGFR inhibitors | ||||
Erdafitinib | Advanced gastric cancer, Mandatory FGFR testing, beyond first-line | II | NCT02699606 | ORR |
Erdafitinib | Advanced Solid tumor, second line or beyond, FGFR testing | II | NCT02465060 | ORR |
Futibatinib | Advanced gastric cancer, FGFR testing, beyond first-line | II | NCT04189445 | ORR |
FGFR1-3 inhibitors | ||||
AZD 4547 | Advanced, second-line or third-line, Mandatory confirmation of FGFR gene amplification | II | NCT01795768 | Molecular change as correlated with tumor size change |
AZD 4547 | Advanced solid tumor, second-line or beyond, based on molecular stratification | NCT02465060, MATCH | ORR | |
Debio1347 | Advanced solid tumor, second-line or beyond, based on molecular stratification | II | NCT03834220 | ORR |
Infigratinib | Advanced gastric cancer, second-line or beyond, based on FGFR status | II | NCT05019794 | ORR |
Derazantinib + paclitaxel-ramucirumab/ atezolizumab | Advanced gastric cancer, second-line or beyond, based on FGFR status | I/II | NCT04604132, FIDES-03 | ORR |
Potential Target | Mechanism of Resistance |
---|---|
SHP2 | Downstream mediator of the FGFR-response |
MET | Overexpression is associated with anti-FGFR resistance |
Pyk2 | Overexpression is associated with anti-FGFR resistance |
MET | Secondary activation associated with resistance to anti-FGFR |
YAP1 | Downstream modulator of the FGFR2 signalling |
TAK1 | Regulator of the lysosome biogenesis and mediated resistance to anti-FGFR agents |
mTORC1 | Regulator of the lysosome biogenesis and mediated resistance to anti-FGFR agents |
FGF18 | Oncogenic stimulation of cancer cells |
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Lengyel, C.G.; Hussain, S.; Seeber, A.; Jamil Nidhamalddin, S.; Trapani, D.; Habeeb, B.S.; Elfaham, E.; Mazher, S.A.; Seid, F.; Khan, S.Z.; et al. FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target? Life 2022, 12, 81. https://doi.org/10.3390/life12010081
Lengyel CG, Hussain S, Seeber A, Jamil Nidhamalddin S, Trapani D, Habeeb BS, Elfaham E, Mazher SA, Seid F, Khan SZ, et al. FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target? Life. 2022; 12(1):81. https://doi.org/10.3390/life12010081
Chicago/Turabian StyleLengyel, Csongor G., Sadaqat Hussain, Andreas Seeber, Sara Jamil Nidhamalddin, Dario Trapani, Baker S. Habeeb, Essam Elfaham, Syed Ayub Mazher, Fahmi Seid, Shah Z. Khan, and et al. 2022. "FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target?" Life 12, no. 1: 81. https://doi.org/10.3390/life12010081
APA StyleLengyel, C. G., Hussain, S., Seeber, A., Jamil Nidhamalddin, S., Trapani, D., Habeeb, B. S., Elfaham, E., Mazher, S. A., Seid, F., Khan, S. Z., El Bairi, K., Odhiambo, A., Altuna, S. C., & Petrillo, A. (2022). FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target? Life, 12(1), 81. https://doi.org/10.3390/life12010081