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| Gene | FGFR3 |
| Variant | Y373C |
| Impact List | missense |
| Protein Effect | gain of function |
| Gene Variant Descriptions | FGFR3 Y373C lies within the extracellular domain of the Fgfr3 protein (UniProt.org). Y373C confers a gain of function to the Fgfr3 protein resulting in increased proliferation relative to wild-type Fgfr3 in a competition assay (PMID: 34272467), constitutive activation, downstream signaling (PMID: 11429702, PMID: 11157491), and transformation of cultured cells (PMID: 11429702, PMID: 11157491, PMID: 34272467). |
| Associated Drug Resistance | |
| Category Variants Paths |
FGFR3 mutant FGFR3 act mut FGFR3 Y373C |
| Transcript | NM_000142.5 |
| gDNA | chr4:g.1804372A>G |
| cDNA | c.1118A>G |
| Protein | p.Y373C |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_000142 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_000142.4 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_000142.5 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_001354809.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_001354809.2 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_001354810.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| NM_001354810.2 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_006713872 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_006713873 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_006713873.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_006713873.2 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513420 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513420.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513420.2 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513422 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513422.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_011513422.2 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_047449822.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_047449823.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| XM_047449824.1 | chr4:g.1804372A>G | c.1118A>G | p.Y373C | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| FGFR3 mutant | transitional cell carcinoma | sensitive | Erdafitinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase II trial (BCL2001) that supported FDA approval, Balversa (erdafitinib) treatment resulted in an objective response rate of 40% (40/99, 3 complete response, 37 partial response) and a disease control rate of 80% in patients with metastatic or unresectable urothelial carcinoma harboring FGFR alterations (PMID: 31340094; NCT02365597). | detail... 31340094 detail... |
| FGFR3 mutant | bladder urothelial carcinoma | sensitive | Erdafitinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase II trial (BCL2001) that supported FDA approval, Balversa (erdafitinib) treatment resulted in an objective response rate of 40% (40/99, 3 complete response, 37 partial response) and a disease control rate of 80% in patients with metastatic or unresectable urothelial carcinoma harboring FGFR alterations (PMID: 31340094; NCT02365597). | detail... 31340094 detail... |
| FGFR3 act mut | bladder urothelial carcinoma | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as second-line or subsequent-line therapy for patients with advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 alterations (NCCN.org). | detail... |
| FGFR3 act mut | maxillary sinus cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with maxillary sinus cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | lung non-small cell carcinoma | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines for patients with metastatic non-small cell lung cancer harboring oncogenic or likely oncogenic FGFR alterations (NCCN.org). | detail... |
| FGFR3 act mut | ethmoid sinus cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with ethmoid sinus cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | oral cavity cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with oral cavity cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | oropharynx cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with oropharynx cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | supraglottis cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with supraglottic larynx cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | transitional cell carcinoma | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as second-line or subsequent-line therapy for patients with advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 alterations (NCCN.org). | detail... |
| FGFR3 act mut | hypopharynx cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with hypopharynx cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | salivary gland cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines for patients with unresectable locally advanced, recurrent, or metastatic salivary gland tumors harboring FGFR mutations or fusions (category 2B) who received prior systemic therapy and have no alternative systemic therapy available (NCCN.org). | detail... |
| FGFR3 act mut | breast cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines for patients with stage IV (M1) breast cancer harboring FGFR fusion or mutations (NCCN.org). | detail... |
| FGFR3 act mut | glottis cancer | sensitive | Erdafitinib | Guideline | Actionable | Balversa (erdafitinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with glottic larynx cancer harboring FGFR mutations or fusions and with no alternative options (NCCN.org). | detail... |
| FGFR3 act mut | Advanced Solid Tumor | predicted - sensitive | Fexagratinib | Phase II | Actionable | In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, with a partial response in 1 and stable disease in 2 of 7 patients with FGFR3 activating mutations (PMID: 32463741; NCT02465060). | 32463741 |
| FGFR3 act mut | transitional cell carcinoma | sensitive | Pemigatinib | Phase II | Actionable | In a Phase II trial (FIGHT-201), Pemazyre (pemigatinib) treatment resulted in an objective response rate (ORR) of 17.8%, median duration of response (mDOR) of 6.2 mo, median progression-free survival (mPFS) of 4.0 mo, and median overall survival (mOS) of 6.8 mo with continuous dosing, and an ORR of 23.3%, mDOR of 6.2 mo, mPFS of 4.3 mo, and mOS of 8.9 mo with intermittent dosing in patients with urothelial carcinoma harboring FGFR3 mutations or fusions/rearrangements (PMID: 37956738; NCT02872714). | 37956738 |
| FGFR3 act mut | Advanced Solid Tumor | predicted - sensitive | Erdafitinib | Phase II | Actionable | In a Phase II trial (RAGNAR), Balversa (erdafitinib) treatment resulted in an objective response rate of 29.5% (64/217, 6 complete and 58 partial responses), a disease control rate of 74%, clinical benefit rate of 46%, a median duration of response of 6.9 months, median progression-free survival of 4.2 months, and median overall survival of 10.7 months in patients with advanced solid tumors harboring FGFR1, FGFR2, or FGFR3 mutations or fusions (PMID: 37541273; NCT04083976). | 37541273 |
| FGFR3 mutant | transitional cell carcinoma | no benefit | Nivolumab | Phase II | Actionable | In a Phase II trial (CheckMate 275), Opdivo (nivolumab) (n=270) treatment resulted in similar response rate (20% vs 21%, p=0.2) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). | 31272788 |
| FGFR3 mutant | transitional cell carcinoma | predicted - sensitive | Cetrelimab + Erdafitinib | Phase II | Actionable | In a Phase II trial, the combination of Balversa (erdafitinib) and Cetrelimab (JNJ-63723283) treatment resulted in an overall response rate of 54.5% (6 complete responses), disease control rate of 79.5%, median duration of response of 11.10 months, median progression-free survival of 10.97 months, and a 12-month overall survival of 68% in patients with metastatic urothelial carcinoma harboring FGFR mutations (J Clin Oncol 41, 2023 (suppl 16; abstr 4504); NCT03473743). | detail... |
| FGFR3 mutant | transitional cell carcinoma | no benefit | Atezolizumab | Phase II | Actionable | In a Phase II trial (IMVigor 210, CheckMate 275), Tecentriq (atezolizumab) (n=119) treatment resulted in similar response rate (24% vs 21%, p=0.8) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). | 31272788 |
| FGFR3 mutant | bladder urothelial carcinoma | sensitive | Dovitinib | Phase II | Actionable | In a Phase II trial, Dovitinib (TKI258) treatment resulted in complete response in 33% (1/3) of patients with BCG-unresponsive, non-muscle-invasive, urothelial carcinoma of the bladder harboring FGFR3 mutations (PMID: 27932416). | 27932416 |
| FGFR3 act mut | transitional cell carcinoma | no benefit | Derazantinib | Phase Ib/II | Actionable | In a Phase I/II trial (FIDES-02), Derazantinib (ARQ 087) treatment was well tolerated but demonstrated limited efficacy in patients with urothelial carcinoma harboring FGFR1 (n=4), FGFR2 (n=7), or FGFR3 (n=35) mutations or FGFR3 fusions (n=6), with an objective response rate of 8.2% (4/49, all partial responses) and disease control rate of 30.6% (15/49) by independent central review (PMID: 38627238; NCT04045613). | 38627238 |
| FGFR3 act mut | transitional cell carcinoma | no benefit | Atezolizumab + Derazantinib | Phase Ib/II | Actionable | In a Phase I/II trial (FIDES-02), combination treatment with Derazantinib (ARQ 087) and Tecentriq (atezolizumab) was well tolerated but demonstrated limited efficacy in patients with urothelial carcinoma harboring FGFR3 mutations (n=8) or FGFR3 fusions (n=2), with an objective response rate (ORR) of 0% (0/10) and disease control rate of 20.0% (2/10) by independent central review (PMID: 38627238; NCT04045613). | 38627238 |
| FGFR3 mutant | transitional cell carcinoma | predicted - sensitive | Docetaxel + Vofatamab | Phase Ib/II | Actionable | In a Phase I/II trial, Vofatamab (B-701) in combination with Taxotere (docetaxel) demonstrated safety and preliminary efficacy, resulted in enhanced activity in patients with locally advanced or metastatic urothelial carcinoma harboring FGFR3 mutations or fusions comparing to wild-type patients (Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 4534-4534; NCT02401542). | detail... |
| FGFR3 act mut | Advanced Solid Tumor | predicted - sensitive | Erdafitinib | Phase I | Actionable | In a Phase I trial, Balversa (erdafitinib) treatment resulted in stable disease in 70% (16/23) and partial response in 22% (5/23) of patients with advanced solid tumors harboring FGFR 1-4 activating mutations (including amplifications, mutations and translocations), while no antitumor activity was observed in patients with unknown or no known changes in FGFR (PMID: 26324363; NCT01703481). | 26324363 |
| FGFR3 act mut | Advanced Solid Tumor | predicted - sensitive | KIN-3248 | Phase I | Actionable | In a Phase I trial, KIN-3248 treatment demonstrated safety and preliminary activity in patients with advanced solid tumors harboring alterations in FGFR2 or FGFR3, resulting in an objective response rate of 9.25% (5/54, 5 partial responses) and disease control rate of 46% (25/54), with stable disease in 20 patients (PMID: 38602417; NCT05242822). | 38602417 |
| FGFR3 act mut | Advanced Solid Tumor | sensitive | Zoligratinib | Phase I | Actionable | In a Phase I trial, Debio 1347 (CH5183284) dosing regimen has been determined in solid tumor patients with activating FGFR3 alterations (JCO, Vol 33, No 15_suppl (May 20 Supplement), 2015: 2540). | detail... |
| FGFR3 mutant | Advanced Solid Tumor | predicted - sensitive | Zoligratinib | Phase I | Actionable | In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297). | 30745300 |
| FGFR3 mutant | transitional cell carcinoma | sensitive | Infigratinib | Phase I | Actionable | In a Phase I trial, Truseltiq (infigratinib) treatment resulted in complete response in 4% (1/25) and partial response in 32% (8/25) of urothelial carcinoma patients harboring FGFR3 mutations or fusions (J Clin Oncol 34, 2016 (suppl; abstr 4517); NCT01004224). | detail... |
| FGFR3 mutant | transitional cell carcinoma | sensitive | Erdafitinib | Phase I | Actionable | In a Phase I trial, Balversa (erdafitinib) treatment resulted in an objective response rate of 46% (12/26) in patients with urothelial carcinoma harboring FGFR genomic alterations, including 17 with FGFR3 mutations, and 11 with FGFR2 and/or FGFR3 fusions (PMID: 31088831; NCT01703481). | 31088831 |
| FGFR3 mutant | cholangiocarcinoma | predicted - sensitive | Erdafitinib | Phase I | Actionable | In a Phase I trial, Balversa (erdafitinib) treatment resulted in an objective response rate of 27% (3/11) in patients with cholangiocarcinoma harboring FGFR genomic alterations, including 1 with FGFR2 mutation, 2 with FGFR3 mutations, and 8 with FGFR2 fusions (PMID: 31088831; NCT01703481). | 31088831 |
| FGFR3 mutant | Advanced Solid Tumor | predicted - sensitive | ICP-192 | Phase I | Actionable | In a Phase I trial, ICP-192 (gunagratinib) was well-tolerated, and resulted in an overall response rate or 33.3% (4/12, 1 complete response, 3 partial response) and a disease control rate of 91.7% (11/12) in patients with advanced solid tumors harboring FGF/FGFR gene aberrations (J Clin Oncol 39, 2021 (suppl 15; abstr 4092); NCT03758664). | detail... |
| FGFR3 mutant | bladder urothelial carcinoma | sensitive | Infigratinib | Phase I | Actionable | In a Phase I trial, patients with bladder urothelial carcinoma harboring an FGFR3 mutation demonstrated a disease control rate of 75% (6/8) when treated with Truseltiq (infigratinib), including 3 patients with a partial response and 3 with stable disease (PMID: 27870574; NCT01004224). | 27870574 |
| FGFR3 mutant | transitional cell carcinoma | sensitive | Infigratinib | Clinical Study | Actionable | In a clinical study, Truseltiq (infigratinib) treatment in patients with FGFR3 alterations led to 25.4% (17/67) confirmed responses and a disease control rate of 64% (43/67), which included complete responses, partial responses, and stable disease, and resulted in a median progression-free survival of 3.75 months and a median overall survival of 7.75 months (PMID: 29848605). | 29848605 |
| FGFR3 mutant | Advanced Solid Tumor | predicted - sensitive | Erdafitinib | Case Reports/Case Series | Actionable | In a Phase II trial (MATCH), Balversa (erdafitinib) treatment resulted in an objective response rate of 16% (4/25), median progression-free survival of 3.6 months, and median overall survival of 11.0 months in patients with advanced solid tumors harboring FGFR1, FGFR2, or FGFR3 mutations or fusions (PMID: 38603650; NCT02465060). | 38603650 |
| FGFR3 mutant | transitional cell carcinoma | sensitive | Erdafitinib | Case Reports/Case Series | Actionable | In a Phase I trial, Balversa (erdafitinib) treatment resulted in 25% tumor shrinkage at week 8 in an urothelial cancer patient harboring FGFR3 mutations (PMID: 26324363; NCT01703481). | 26324363 |
| FGFR3 mutant | Advanced Solid Tumor | sensitive | Pemigatinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a variety of cancer cell lines harboring mutations in FGFR1, FGFR2, and/or FGFR3 demonstrated sensitivity to Pemazyre (pemigatinib) in culture and in cell line xenograft models, resulting in inhibition of tumor growth (Cancer Res 2015;75(15 Suppl):Abstract nr 771). | detail... |
| FGFR3 mutant | urinary bladder cancer | sensitive | Fexagratinib | Preclinical - Cell culture | Actionable | In a preclinical study, AZD4547 inhibited survival of bladder cancer cells harboring FGFR3 mutation in culture (PMID: 27550940). | 27550940 |
| FGFR3 act mut | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited receptor phosphorylation and cell growth in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). | 22238366 |
| FGFR3 act mut | urinary bladder cancer | predicted - sensitive | S-49076 | Preclinical | Actionable | In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells over expressing constitutively active FGFR3 in culture (PMID: 23804704). | 23804704 |
| FGFR3 act mut | Advanced Solid Tumor | decreased response | Nintedanib | Preclinical | Actionable | In a preclinical study, transformed cells expressing constitutively active FGFR3 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). | 22238366 |
| FGFR3 act mut | Advanced Solid Tumor | no benefit | Brivanib | Preclinical | Actionable | In a preclinical study, Brivanib (BMS-540215) did not inhibit receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). | 22238366 |
| FGFR3 act mut | Advanced Solid Tumor | decreased response | Cediranib | Preclinical | Actionable | In a preclinical study, transformed cells expressing constitutively active FGFR3 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Cediranib (AZD-2171) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). | 22238366 |
| FGFR3 act mut | Advanced Solid Tumor | sensitive | Dovitinib | Preclinical | Actionable | In a preclinical study, Dovitinib (TKI258) inhibited receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR3 in culture (PMID: 22238366). | 22238366 |
| FGFR3 mutant | Advanced Solid Tumor | sensitive | Infigratinib | Preclinical | Actionable | In a preclinical study, tumor cell lines with FGFR3 mutations demonstrated sensitivity to Truseltiq (infigratinib) in culture (PMID: 23002168). | 23002168 |