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.

in Annals of oncology : official journal of the European Society for Medical Oncology by V Subbiah, N O Iannotti, M Gutierrez, D C Smith, L Féliz, C F Lihou, C Tian, I M Silverman, T Ji, M Saleh

TLDR

  • The FIGHT-101 study demonstrated the safety and efficacy of pemigatinib in patients with advanced malignancies, with a manageable safety profile and promising response rates.

Abstract

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.

Overview

  • The FIGHT-101 study evaluated the safety, pharmacokinetics, and efficacy of pemigatinib, a FGFR 1-3 inhibitor, in patients with advanced malignancies.
  • The study included 128 patients with advanced malignancies, with or without FGFR gene alterations, who received pemigatinib as monotherapy or in combination therapy.
  • The primary objective was to determine the maximum tolerated dose and preliminary efficacy of pemigatinib in patients with advanced malignancies.

Comparative Analysis & Findings

  • The study found no dose-limiting toxicities, with doses ≥4 mg being pharmacologically active and the recommended phase II dose being 13.5 mg once daily.
  • The most common treatment-emergent adverse events were hyperphosphatemia and fatigue, with 12 patients experiencing partial responses across various tumor types.
  • The overall response rate was highest in patients with FGFR fusions/rearrangements (25.0%) followed by those with FGFR mutations (23.1%).

Implications and Future Directions

  • The study demonstrated the manageable safety profile and pharmacodynamic and clinical activity of pemigatinib, making it a promising treatment option for patients with FGFR-positive tumors.
  • Future studies will focus on registrational trials in cholangiocarcinoma and phase II/III trials in multiple tumor types to further evaluate the benefit of precision therapy.
  • The study highlights the importance of targeting specific biomarkers, such as FGFR fusions/rearrangements and mutations, to improve treatment outcomes in patients with advanced malignancies.
Read Full Article