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

Abstract

Background: 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.

Patients and methods: 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.

Results: 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%)].

Conclusions: 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.

Keywords: FGFR; advanced malignancies; genomic profiling; pemigatinib; phase I/II clinical trial.

Conflict of interest statement

Disclosure VS reports a consulting or advisory role with Incyte Corporation; grants from Eli Lilly/Loxo Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics, Boston Pharmaceuticals; research funding from Helsinn Pharmaceuticals, during the conduct of the study; research funding and consulting or advisory role with Eli Lilly/Loxo Oncology, during the conduct of the study; research funding from Roche/Genentech, Bayer, GlaxoSmithKline, NanoCarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte Corporation, Fujifilm, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum Pharmaceuticals, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, MedImmune; an advisory board/consultant position with Helsinn, Incyte Corporation, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Janssen, Relay Therapeutics, Roche, MedImmune; travel funds from Pharmamar, Incyte Corporation, ASCO, ESMO; other support from Medscape. MG reports stock in and has other ownership of COTA; has a consulting or advisory role with Bayer, Eli Lilly & Company, and Karyopharm Therapeutics; participates in the speakers’ bureau for Bristol Myers Squibb, Eli Lilly & Company, FoundationOne Inc., and Merck; received research funding (institutional) from AbbVie, Acceleron Pharma, Bayer, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Eli Lilly & Company, EMD Serono, Esanex, Genentech/Roche, Gilead Sciences, Incyte Corporation, Karyopharm Therapeutics, Loxo Oncology, MedImmune, Merck, Mirati Therapeutics, Moderna Therapeutics, Novartis, Regeneron, Rexahn Pharmaceuticals, Sanofi, Seattle Genetics, Tesaro, and TG Therapeutics. DCS reports research funding (institutional) from Agensys, Astellas Pharma, Bayer, Bristol Myers Squibb/Medarex, Eli Lilly & Company, ESSA, Exelixis, Genentech, Incyte Corporation, MedImmune, Medivation/Astellas, Merck, Millendo, Novartis, OncoMed, and Seattle Genetics. IMS reports employment and stock ownership with Repare Therapeutics. LF, CFL, CT, and TJ report employment and stock ownership with Incyte Corporation. MS reports participating in the speakers’ bureau for Novartis. NOI has declared no conflicts of interest.

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