TY - JOUR
T1 - Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy)
T2 - a multicentre, randomised, double-blind, placebo-controlled, phase 3 study
AU - Abou-Alfa, Ghassan K.
AU - Macarulla, Teresa
AU - Javle, Milind M.
AU - Kelley, Robin K.
AU - Lubner, Sam J.
AU - Adeva, Jorge
AU - Cleary, James M.
AU - Catenacci, Daniel V.
AU - Borad, Mitesh J.
AU - Bridgewater, John
AU - Harris, William P.
AU - Murphy, Adrian G.
AU - Oh, Do Youn
AU - Whisenant, Jonathan
AU - Lowery, Maeve A.
AU - Goyal, Lipika
AU - Shroff, Rachna T.
AU - El-Khoueiry, Anthony B.
AU - Fan, Bin
AU - Wu, Bin
AU - Chamberlain, Christina X.
AU - Jiang, Liewen
AU - Gliser, Camelia
AU - Pandya, Shuchi S.
AU - Valle, Juan W.
AU - Zhu, Andrew X.
N1 - Funding Information:
The funder had a role in study design, data collection, data analysis, and data interpretation. Medical writing support was provided by the funder. The first and last authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
Funding Information:
GKA-A is a consultant for 3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, Beigene, Bioline, Bristol-Myers Squibb, Boston Scientific, Bridgebio, Carsgen, Celgene, Casi, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Flatiron, Genoscience, Halozyme, Hengrui, Incyte, Inovio, Ipsen, Jazz, Jansen, Klus, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, Novella, Onxeo, PCI Biotech, Pfizer, Pieris, QED, Redhill, Sanofi, Servier, Silenseed, SillaJen, Sobi, Targovax, Tekmira, Twoxar, Vicus, Yakult, and Yiviva; has received research grants or funding from ActaBiologica, Agios, Array, AstraZeneca, Bayer, Beigene, Bristol-Myers Squibb, Casi, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis, OncoQuest, Polaris Puma, QED, and Roche. TM is on advisory boards for Baxalta, Celgene, H3B, QED, and Shire; has received honoraria from Genzyme, Roche, Sanofi, Shire, and Tesaro; has participated in speaker bureaus for Celgene, Sanofi, and Shire; has received research grants or funding (to institution) from Agios, ASLAN, AstraZeneca, Baxalta, Bayer, Genentech, Halozyme, Immunomedics, Lilly, Merrimack, Millennium, Novartis, Novocure, Pfizer, Pharmacyclics, and Roche; has received travel and accommodation funding from Bayer, H3B, Merck, and Sanofi. MMJ is on advisory boards for EDO, More Health, and OrigiMed; has received honoraria from Merck, Seattle Genetics, and Taiho; has received research grants or funding from ArQule (to institution), Lilly (to institution), Meclun (to individual), Novartis (to individual), and QED (to individual). RKK is on advisory boards for Agios (funding to institution), AstraZeneca (funding to institution), Bristol-Myers Squibb (funding to institution), Genentech–Roche (Independent Data Monitoring Committee; advisory board and funding to individual), and Ipsen (funding to individual); has received travel and accommodation funding from Ipsen; has received research grants or funding (to institution) from Agios, AstraZeneca, Bayer, Bristol-Myers Squibb, Exelixis, Lilly, MedImmune, Merck, Merck Serono, Novartis, Partner Therapeutics, QED, and Taiho. SJL is a consultant for Farcast Biosciences. JMC is on advisory boards for Agios and Bristol-Myers Squibb; has received honoraria from Agios; has received travel and accommodation funding from Agios, Bristol-Myers Squibb, and Roche; has received research grants or funding from Merck and Tesaro. DVC has received honoraria from Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Five Prime, Foundation Medicine, Genentech–Roche, Guardant, Lilly, Merck, Taiho, and Tempus. MJB holds stock in AVEO, Intercept, and OncBioMune; has received honoraria from ADC, Exelixis, G1, Immunovative, Inspyr, Lynx Group, Western Oncolytics; has received travel and accommodation funding from AstraZeneca; has received research grants or funding (to institution) from Adaptimmune, Agios, ARIAD, Basilea, Bioline, Boston Biomedical, Celgene, Dicerna, Halozyme, Incyte, Isis, MedImmune, Merck Serono, Mirna, Novartis, Pieris, PUMA, QED, Redhill, Senhwa, SillaJen, Sun, Taiho, and Toray. JB is on advisory boards for AstraZeneca, Basilea, Bayer, Incyte, Merck Serono, Roche, and Servier; has received honoraria from Merck Serono and Servier; has received travel or accommodation funding from Bristol-Myers Squibb, Bristol-Myers Squibb–Medarex, Merck, Sharp & Dohme, Merck Serono, and Servier; has participated in speaker bureaus for Amgen and Celgene; has received research grants and funding from Amgen. WPH is on advisory boards for Bayer, Bristol-Myers Squibb, Eisai, Exelixis, Neo Therma, QED, and Zymeworks; has received research grants or funding from Agios, ArQule, Bayer, Bristol-Myers Squibb, BTG, Eisai, Exelixis, Halozyme, MedImmune, and Merck. AGM has received research grants or funding from Bristol-Myers Squibb. D-YO is on advisory boards from ASLAN, AstraZeneca, Bayer, Celgene, Genentech–Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks; has research grants or funding (to institution) from Array, AstraZeneca, Lilly, and Novartis. MAL is on advisory boards for Agios, and Roche; has participated in speaker bureaus for Novartis; has received travel funding from Ipsen. LG is on advisory boards for Agios, Alentis, Debiopharm, Klus, Pieris, QED, Sirtex, and Taiho; is a consultant for Alentis, H3B, Incyte; has received travel funding from Taiho; is an Independent Data Monitoring Committee member for AstraZeneca. RTS is on advisory boards for Agios, Clovis, Debiopharm, Exelixis, Incyte, Merck, QED, and Seattle Genetics; has received research grants or funding from Agios, Exelixis, Halozyme, Merck, Pieris, and Taiho. ABE-K is on advisory boards for Agenus, Agios, Bayer, Bristol-Myers Squibb, CytomX, Eisai, Exelixis, Gilead, Merck, Merck Serono, Pieris, and Roche–Genentech (consultant and advisory board); has received research grants or funding from Astex (to institution), AstraZeneca (to institution), and Merck (to institution). BF, CXC, LJ, CG, and SSP are employees of and hold stock in Agios Pharmaceuticals. BW is an employee of, holds stock in, and holds patents, royalties, and other intellectual property with Agios Pharmaceuticals. JWV is on advisory boards for Agios, AstraZeneca, Debiopharm, Delcath, Genoscience, Imaging Equipment Limited, Incyte, Ipsen, Keocyt, Merck, Mundipharma, Novartis, NuCana, PCI, Pieris, Pfizer, QED, Servier, and Wren Laboratories; has received travel or accommodation funding from Ipsen, Novartis, and NuCana; has participated in speaker bureaus for Ipsen, Novartis, and Pfizer. AXZ is on advisory boards for Bayer, Eisai, Exelixis, Lilly, Merck, Roche–Genentech, and Sanofi. JA and JW declare no competing interests.
Funding Information:
This study was supported by Agios Pharmaceuticals. Medical writing assistance was provided by Vanessa Ducas, of Excel Medical Affairs, supported by Agios Pharmaceuticals.
PY - 2020/6
Y1 - 2020/6
N2 - Background: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Findings: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Interpretation: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Funding: Agios Pharmaceuticals.
AB - Background: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Findings: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Interpretation: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Funding: Agios Pharmaceuticals.
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UR - http://www.scopus.com/inward/citedby.url?scp=85085329434&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(20)30157-1
DO - 10.1016/S1470-2045(20)30157-1
M3 - Article
C2 - 32416072
AN - SCOPUS:85085329434
VL - 21
SP - 796
EP - 807
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 6
ER -