V Subbiah1, N O Iannotti2, M Gutierrez3, D C Smith4, L Féliz5, C F Lihou6, C Tian6, I M Silverman6, T Ji6, M Saleh7. 1. Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, USA. Electronic address: VSubbiah@mdanderson.org. 2. Hematology Oncology Associates of the Treasure Coast, Stuart, USA. 3. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, USA. 4. University of Michigan Health System, Ann Arbor, USA. 5. Incyte Biosciences International Sàrl, Morges, Switzerland. 6. Incyte Corporation, Wilmington, USA. 7. O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, USA; Department of Hematology and Oncology, Aga Khan University, Nairobi, Kenya.
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.
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.
Authors: Daniel Zingg; Jinhyuk Bhin; Julia Yemelyanenko; Sjors M Kas; Frank Rolfs; Catrin Lutz; Jessica K Lee; Sjoerd Klarenbeek; Ian M Silverman; Stefano Annunziato; Chang S Chan; Sander R Piersma; Timo Eijkman; Madelon Badoux; Ewa Gogola; Bjørn Siteur; Justin Sprengers; Bim de Klein; Richard R de Goeij-de Haas; Gregory M Riedlinger; Hua Ke; Russell Madison; Anne Paulien Drenth; Eline van der Burg; Eva Schut; Linda Henneman; Martine H van Miltenburg; Natalie Proost; Huiling Zhen; Ellen Wientjens; Roebi de Bruijn; Julian R de Ruiter; Ute Boon; Renske de Korte-Grimmerink; Bastiaan van Gerwen; Luis Féliz; Ghassan K Abou-Alfa; Jeffrey S Ross; Marieke van de Ven; Sven Rottenberg; Edwin Cuppen; Anne Vaslin Chessex; Siraj M Ali; Timothy C Burn; Connie R Jimenez; Shridar Ganesan; Lodewyk F A Wessels; Jos Jonkers Journal: Nature Date: 2022-08-10 Impact factor: 69.504