Pemigatinib for Previously Treated Locally Advanced or Metastatic Cholangiocarcinoma

Background: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in cholangiocarcinoma pathogenesis. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.Methods: In this phase 2 study, we evaluated the antitumour activity and safety of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma. Eligible adults (disease progression following at least one prior treatment) were assigned to cohorts A (FGFR2 fusions or rearrangements), B (other FGF/FGFR alterations), or C (no FGF/FGFR alterations), and received pemigatinib 13·5 mg once daily (21-day cycle; 2-weeks-on/1-week-off) until disease progression/unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (cohort A).Findings: One-hundred-forty-six patients were enrolled (median age, 59 years; Eastern Cooperative Oncology Group performance score 0 or 1, 92%; metastatic disease, 86%; at least two and three prior therapies, 39% and 13%, respectively). Objective response rate in cohort A (n = 107) was 35·5% (95% confidence interval [CI] 26·5%─45·4%; three complete responses); disease control rate was 82%; median duration of response was 7·5 (95% CI 5·7─14·5) months; median progression-free survival was 6·9 (95% CI 6·2–9·6) months. Cohorts B/C had no responders. Overall, the most frequent adverse events were hyperphosphatemia (60%), alopecia (49%), diarrhoea (47%), nail toxicities (42%), fatigue (42%), and dysgeusia (40%). Adverse events resulted in dose interruptions in 42%, dose reductions in 14%, and treatment discontinuation in 9% of patients.Interpretation: Patients with FGFR2 fusions or rearrangements receiving pemigatinib achieved an objective response rate of 35·5% with durable responses. Hyperphosphataemia was the most common adverse event, managed with a low phosphate diet, phosphate-lowering therapy, or dose modifications. These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma harbouring FGFR2 fusions or rearrangements.Trial Registration: ClinicalTrials.gov identifier, NCT02924376.Funding Statement: Funded by Incyte Corporation; FIGHT-202.Declaration of Interests: Dr. Abou-Alfa reports grants and personal fees from Incyte, during the conduct of the study; grants and personal fees from Agios, grants from Array, grants and personal fees from Astra Zeneca, grants and personal fees from Bayer, grants and personal fees from Beigene, grants and personal fees from BMS, grants and personal fees from Casi, grants and personal fees from Celgene, grants and personal fees from Exelixis, grants from Genentech, grants and personal fees from Halozyme, grants and personal fees from Incyte, grants and personal fees from Lilly, grants from Mabvax, grants from Novartis, grants from OncoQuest, grants from Polaris Puma, grants and personal fees from QED, grants from Roche, personal fees from 3DMedcare, personal fees from Alignmed, personal fees from Amgen, personal fees from Antengene, personal fees from Aptus, personal fees from Aslan, personal fees from Astellas, personal fees from Bioline, personal fees from Boston Scientific, personal fees from Bridgebio, personal fees from Carsgen, personal fees from Cipla, personal fees from CytomX, personal fees from Daiichi, personal fees from Debio, personal fees from Delcath, personal fees from Eisai, personal fees from Flatiron, personal fees from Genoscience, personal fees from Hengrui, personal fees from Inovio, personal fees from Ipsen, personal fees from Jazz, personal fees from Jansen, personal fees from Klus, personal fees from Kyowa Kirin, personal fees from LAM, personal fees from Loxo, personal fees from Merck, personal fees from Mina, personal fees from Novella, personal fees from Onxeo, personal fees from PCI Biotech, personal fees from Pfizer, personal fees from Pieris, personal feesfrom Redhill, personal fees from Sanofi, personal fees from Servier, personal fees from Silenseed, personal fees from Sillajen, personal fees from Sobi, personal fees from Targovax, personal fees from Tekmira, personal fees from Twoxar, personal fees from Vicus, personal fees from Yakult, personal fees from Yiviva, outside the submitted work. Dr. Sahai reports institutional grants from Incyte, during the conduct of the study; institutional grants from Agios, Bristol-Myers Squibb, Celgene, Clovis, Debiopharm, Fibrogen, Medimmune, Merck, NCI, Rafael; institutional grants and personal fees from Halozyme, Incyte, Ipsen; and personal fees from QED, Klus, NewLink Genetics outside the submitted work. Dr. Hollebecque reports grants from Incyte, during the conduct of the study; personal fees from Amgen, personal fees from Spectrum Pharmaceuticals, personal fees from Lilly, personal fees from Debiopharm, personal fees from Servier, personal fees from Incyte, personal fees from Bayer, personal fees from EISAI, other from Drug Development Department (DITEP), grants from Astra Zeneca, grants from BMS, grants from Boehringer Ingelheim, grants from Janssen Cilag, grants from Merck, grants from Novartis, grants from Pfizer, grants from Sanofi, grants from Roche, outside the submitted work. Dr. Vaccaro reports personal fees from Bayer Healthcare, personal fees from Genentech, personal fees from Excelixis, personal fees from Incyte, personal fees from Alexion, personal fees from Amgen, personal fees from Novartis, personal fees from Celgene, personal fees from Astellas, outside the submitted work; and Research funds paid directly to institution: Astellas, Eli Lilly, Merck, Incyte, EMD Serono, Celgene, E.R. Squibb and Sons, Eli Lilly, Boston Scientific. Dr. Melisi reports grants from Incyte, during the conduct of the study; grants and personal fees from Shire, grants and personal fees from Incyte, grants and personal fees from Evotec, grants from Celgene, grants and personal fees from iOnctura, personal fees from Eli Lilly, personal fees from Baxter, outside the submitted work. Dr. Al-Rajabi reports grants from Incyte, during the conduct of the study; other from Seattle Genetic, other from Actinium Pharmaceutical , personal fees from Sirtex, outside the submitted work. Dr. Paulson reports grants from Incyte, during the conduct of the study; personal fees from AAA, grants and personal fees from Taiho, personal fees from Ipsen, grants and personal fees from BMS, personal fees from Eisai, personal fees from Amgen, other from Aptose, other from Seattle Genetics, other from Immunomedics, grants from Incyte, grants from Exelixis, other from Actinium, other from Alexion, outside the submitted work. Dr. Borad reports grants from Incyte, during the conduct of the study; grants from Senhwa Pharmaceuticals, grants from Adaptimmune, grants from Agios Pharmaceuticals, grants from Halozyme Pharmaceuticals, grants from Celgene Pharmaceuticals, grants from EMD Merck Serono, grants from Toray, grants from Dicerna, grants from Taiho Pharmaceuticals, grants from Sun Biopharma, grants from Isis Pharmaceuticals, grants from Redhill Pharmaceuticals, grants from Boston Biomed, grants from Basilea, grants from Incyte, grants from Mirna Pharmaceuticals, grants from Medimmune, grants from Bioline, grants from Sillajen, grants from ARIAD, grants from PUMA, grants from Novartis Pharmaceuticals, grants from QED Pharmaceuticals, other from Pieris, personal fees from Exelixis, personal fees from G1 Therapeutics, personal fees from Immunovative Therapies, other from OncBioMune Pharmaceuticals, personal fees from Western Oncolytics, personal fees from Lynx Group, personal fees from Astra Zeneca, personal fees from Inspyr Therapeutics, personal fees from ADC Therapeuctics, other from Intercept, other from AVEO, personal fees from Merck, outside the submitted work. Dr. Gallinson has no financial disclosures to declare. Dr. Murphy reports grants from BMS, outside the submitted work. Dr. Oh reports personal fees from Genentech/Roche, grants and personal fees from AstraZeneca, personal fees from Novartis, personal fees from Merck Serono, personal fees from Bayer, personal fees from Taiho, personal fees from ASLAN, personal fees from Halozyme, personal fees from Zymeworks, grants from Novartis, grants from Array, grants from Eli Lilly, grants from Green Cross, outside the submitted work. Dr. Dotan reports grants from Incyte, during the conduct of the study; grants and personal fees from Boston Medical, personal fees from ARMO, grants and personal fees from Pfizer, grants from Merck, grants from Astra Zeneca, grants from GSK, grants from Medimmune, grants from Incyte, grants from Oncomed, outside the submitted work. Dr. Catenacci reports grants from Incyte, during the conduct of the study; personal fees from Merck, personal fees from BMS, personal fees from Five Prime, personal fees from Astellas, personal fees from Taiho, personal fees from Lilly, personal fees from Genentech/Roche, personal fees from Gritstone, personal fees from Foundation Medicine, personal fees from Tempus, personal fees from Guardant Health, outside the submitted work. Dr. Van Cutsem reports personal fees from Incyte, during the conduct of the study; personal fees from Astellas, personal fees from AstraZeneca, grants and personal fees from Bayer, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Celgene, personal fees from Incyte, grants and personal fees from Lilly, grants and personal fees from Merck Sharp & Dohme, grants and personal fees from Merck KGaA, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Servier, grants from Amgen, grants from Boehringer Ingelheim, grants from Ipsen, outside the submitted work. Drs. Ji, Zhen, Féliz, and Ms. Lihou, are employees and hold stock with Incyte Corporation. Dr. Vogel reports personal fees from Incyte, during the conduct of the study; personal fees from Amgen, personal fees from Incyte, personal fees from AstraZeneca, personal fees from Roche, personal fees from Lilly, personal fees from Bayer, personal fees from Medac, personal fees from Delcath, personal fees from Shire, personal fees from Beigene, personal fees from BMS, personal fees from Celgene, personal fees from Eisai, personal fees from Hengrui, personal fees from Ipsen, personal fees from Merck, personal fees from Pieris, personal fees from QED, personal fees from Roche, personal fees from Sanofi, personal fees from Servier, outside the submitted work.Ethics Approval Statement: The protocol was approved by each institutional review board/ independent ethics committee; patients provided informed, written consent. The trial was performed in accordance with the Declaration of Helsinki.