Clinical development and management of adverse events associated with FGFR inhibitors

Subbiah, Vivek; Verstovsek, Srdan

doi:10.1016/j.xcrm.2023.101204

Cited by 18 publications

(2 citation statements)

References 43 publications

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“…Erdafitinib administration resulted in prolonged progression-free survival. Approved FGFR inhibitors include erdafitinib, pemigatinib, and futibatinib[ 9 ]. Erdafitinib is an ATP competitive inhibitor of FGFR1-4.…”

Section: Erdafitinibmentioning

confidence: 99%

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic, gastrointestinal, and urinary bladder carcinomas: Recent concept

Wishahi

2024

World J Hepatol

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Cancer immunotherapy is administered for first-line, second-line, neoadjuvant, or adjuvant treatment of advanced, metastatic, and recurrent cancer in the liver, gastrointestinal tract, and genitourinary tract, and other solid tumors. Erdafitinib is a fibroblast growth factor receptor (FGFR) inhibitor, and it is an adenosine triphosphate competitive inhibitor of FGFR1, FGFR2, FGFR3, and FGFR4. Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1 (PD-1) and its ligand that exert intrinsic antitumor mechanisms. The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents, indicate a new concept in the treatment of advanced, metastatic, and recurrent hepatic and gastrointestinal carcinomas. Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life. Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas, or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy. The literature in the field is not definite, and so far, there has been no consensus on the best approach in this situation. At present, as it is described in this editorial, the decision is applied on a case-by-case basis.

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Section: Erdafitinibmentioning

confidence: 99%

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic, gastrointestinal, and urinary bladder carcinomas: Recent concept

Wishahi

2024

World J Hepatol

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“…The most common adverse effect of pan-FGFRi is hyperphosphatemia ( 12 – 15 ) caused by the inhibition of FGFR1, which is required for phosphate reabsorption in the kidney ( 16 ), and diarrhea caused by FGFR4 inhibition ( 16 ). Elevated serum phosphate levels are reported in 55% to 81% of patients with iCCA in Phase 2 clinical trials ( 13 – 15 ) and require active management (such as dietary modification, phosphate binders, and dose reductions) or treatment interruptions ( 17 , 18 ). Hyperphosphatemia has been observed with pan-FGFRi in both preclinical testing and in patients ( 19 ) and should be avoided to achieve maximum efficacy of an FGFR2 inhibitor ( 7 ).…”

mentioning

confidence: 99%

Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2

Schönherr,

Ayaz,

Taylor

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2 -altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

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FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

Noeraparast,

Krajina,

Pichler

et al. 2024

Cancer Communications

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In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well‐established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial‐mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3‐mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3‐mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co‐targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population‐specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3‐mutated BLCA.

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Clinical development and management of adverse events associated with FGFR inhibitors

Cited by 18 publications

References 43 publications

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic, gastrointestinal, and urinary bladder carcinomas: Recent concept

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic, gastrointestinal, and urinary bladder carcinomas: Recent concept

Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2

FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

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