Ghassan K Abou-Alfa1, Vaibhav Sahai2, Antoine Hollebecque3, Gina Vaccaro4, Davide Melisi5, Raed Al-Rajabi6, Andrew S Paulson7, Mitesh J Borad8, David Gallinson9, Adrian G Murphy10, Do-Youn Oh11, Efrat Dotan12, Daniel V Catenacci13, Eric Van Cutsem14, Tao Ji15, Christine F Lihou15, Huiling Zhen15, Luis Féliz15, Arndt Vogel16. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College, Cornell University, New York, NY, USA. Electronic address: abou-alg@mskcc.org. 2. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. 3. Gustave Roussy, Villejuif, France. 4. Providence Cancer Center Oncology and Hematology Care Clinic, Portland, OR, USA. 5. Digestive Molecular Clinical Oncology Unit, University of Verona, Verona, Italy. 6. University of Kansas Cancer Center, Kansas City, KS, USA. 7. Baylor Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. 8. Mayo Clinic Cancer Center, Phoenix, AZ, USA. 9. Morristown Memorial Hospital, Carol Cancer Center, Morristown, NJ, USA. 10. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 11. Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea. 12. Fox Chase Cancer Center, Philadelphia, PA, USA. 13. University of Chicago Medicine, Chicago, IL, USA. 14. University Hospitals Gasthuisberg, Leuven, Belgium; Clinical Digestive Oncology, KU Leuven, Leuven, Belgium. 15. Incyte Corporation, Wilmington, DE, USA. 16. Hannover Medical School, Hannover, Germany.
Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.
BACKGROUND:Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.
Authors: Miguel Garcia-Pardo; Laura Ortega; María Jesús Fernández-Aceñero; Pilar García Alfonso; Miguel Martín; Andrés J Muñoz Journal: J Gastrointest Cancer Date: 2021-03-08
Authors: Michael J Fusco; Daryoush Saeed-Vafa; Estrella M Carballido; Theresa A Boyle; Mokenge Malafa; Kirsten L Blue; Jamie K Teer; Christine M Walko; Howard L McLeod; J Kevin Hicks; Martine Extermann; Jason B Fleming; Todd C Knepper; Dae Won Kim Journal: JCO Precis Oncol Date: 2021-01-11
Authors: Anna M Varghese; Juber Patel; Yelena Y Janjigian; Fanli Meng; S Duygu Selcuklu; Gopakumar Iyer; Brian Houck-Loomis; James J Harding; Eileen M O'Reilly; Ghassan K Abou-Alfa; Maeve A Lowery; Michael F Berger Journal: JCO Precis Oncol Date: 2021-01-08
Authors: Misty M Attwood; Doriano Fabbro; Aleksandr V Sokolov; Stefan Knapp; Helgi B Schiöth Journal: Nat Rev Drug Discov Date: 2021-08-05 Impact factor: 84.694