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Ref Type Journal Article
PMID (35176457)
Authors Subbiah V, Iannotti NO, Gutierrez M, Smith DC, Féliz L, Lihou CF, Tian C, Silverman IM, Ji T, Saleh M
Title FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies.
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol
Issue
Date 2022 Feb 14
URL
Abstract Text The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations.Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant.Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)].Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 CLIP1 FGFR2 - CLIP1 fusion gain of function FGFR2-CLIP1 results from the fusion of FGFR2 and CLIP1, leading to increased PI3K, MAPK, and FGFR2 signaling (PMID: 31371345), and transformation in culture (PMID: 35176488). FGFR2-CLIP1 has been identified in metastatic cholangiocarcinoma (PMID: 31371345, PMID: 35176457).
FGFR2 USP33 FGFR2 - USP33 fusion unknown FGFR2-USP33 results from the fusion of FGFR2 and USP33 (PMID: 35176457). FGFR2-USP33 has been identified in pancreatic cancer (PMID: 35176457), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Nov 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - CCDC6 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response lasting 11.3 months in a cholangiocarcinoma patient harboring FGFR2-CCDC6 (PMID: 35176457; NCT02393248). 35176457
FGFR2 C382R cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a cholangiocarcinoma patient harboring FGFR2 C382R (PMID: 35176457; NCT02393248). 35176457
FGFR2 - BICC1 gallbladder cancer predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a gallbladder cancer patient harboring FGFR2-BICC1 (PMID: 35176457; NCT02393248). 35176457
FGFR2 - CLIP1 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a cholangiocarcinoma patient harboring FGFR2-CLIP1 (PMID: 35176457; NCT02393248). 35176457
FGFR2 fusion Advanced Solid Tumor predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to an objective response rate of 25% (5/20, all partial responses) in patients harboring FGFR rearrangements, with all 5 partial responses in patients with FGFR2 fusions, stable disease in 50% (10/20) of patients, and a median progression-free survival of 5.7 months (PMID: 35176457; NCT02393248). 35176457
FGFR2 - CCDC6 FGFR2 N549D FGFR2 N549K FGFR2 V564I cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), a cholangiocarcinoma patient harboring FGFR2-CCDC6 experienced disease progression after initially responding to Pemazyre (pemigatinib), and was found to have acquired FGFR2 N549K, FGFR2 N549D, and FGFR2 V564I (PMID: 35176457; NCT02393248). 35176457
FGFR1 N546K pilocytic astrocytoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a pilocytic astrocytoma patient harboring FGFR1 N546K (PMID: 35176457; NCT02393248). 35176457
FGFR3 S249C transitional cell carcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a urothelial cancer patient harboring FGFR3 S249C (PMID: 35176457; NCT02393248). 35176457
FGFR2 - USP33 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-USP33 led to a partial response that was maintained for 10.7 months, followed by disease progression, however, patient continued on Pemazyre (pemigatinib) treatment for over 12 months further, due to lack of alternative treatment options (PMID: 35176457; NCT02393248). 35176457