Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology			2022 Feb 14	522-533	Ann Oncol

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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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 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