1867 - ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation

Background

CC is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in up to ∼15% of CC, resulting in production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein.

Methods

Patients (pts) with mIDH1 CC were randomized 2:1 to IVO (500 mg once daily) or matched PBO and stratified by number of prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic mIDH1 CC based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic PD. Primary endpoint: progression-free survival (PFS) by central review. Secondary endpoints included safety, ORR, PFS (local investigator review), and overall survival (OS; by ITT). Crossover-adjusted OS was derived using rank preserved structural failure time (RPSFT).

Results

As of 31Jan2019, 185 pts were randomized to IVO (n = 124) or PBO (n = 61). Median age 62 y, M/F 68/117, 91% intrahepatic CC, 92% metastatic disease, 43% had 2 prior therapies. Primary endpoint (PFS by central review) was met: HR = 0.37 (95% CI 0.25, 0.54; p < 0.001); median PFS was 2.7 (IVO) vs. 1.4 (PBO) mo. PFS rates at 6 and 12 mo were 32.0% and 21.9% in IVO arm; no PBO pts were progression-free for ≥6 mo at data cutoff. ORR for IVO was 2.4% (3 PRs), with 50.8% SD (n = 63) vs. 0% ORR in PBO and 27.9% SD (n = 17). By ITT analysis, median OS was 10.8 mo for IVO and 9.7 mo for PBO (HR = 0.69; one-sided p = 0.06) with 57% of PBO pts crossed over to IVO. The RPSFT-adjusted median OS was 6 mo for PBO (HR = 0.46; p = 0.0008). PFS by local review HR = 0.47 (p < 0.001). Common TEAEs (>15%) in IVO arm: nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), vomiting (16.0%). Grade ≥3 adverse events reported in 46% IVO vs. 36% PBO. There were no treatment-related deaths.

Conclusions

IVO resulted in significant improvement in PFS and favorable OS trend vs. PBO. This is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in pts with advanced mIDH1 CC.

Clinical trial identification

NCT02989857.

Editorial acknowledgement

Yvonna Fisher-Jeffes of Agios Pharmaceuticals, Inc and Helen Varley of Envision Pharma Group.

Legal entity responsible for the study

Agios Pharmaceuticals, Inc.

Funding

Agios Pharmaceuticals, Inc.

Disclosure

G.K. Abou-Alfa: Advisory / Consultancy, Research grant / Funding (institution): 3DMedcare; Advisory / Consultancy: ActaBiologica; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Research grant / Funding (institution): Array; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientifc; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genentech; Advisory / Consultancy: Genoscience; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Advisory / Consultancy: Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Janssen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Research grant / Funding (institution): Mabvax; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Novella; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Advisory / Consultancy: Redhill; Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxar; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva. T. Macarulla Mercade: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Sanofi; Honoraria (self): Tesaro; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy: QDE; Advisory / Consultancy, Travel / Accommodation / Expenses: H3B; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi/Aventis; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Baxalta; Honoraria (self): Genzyme; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Genentech; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Hallozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merrimarck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. M. Javle: Research grant / Funding (self): QED; Research grant / Funding (self): Novartis; Honoraria (self): Taiho; Research grant / Funding (self): Meclun; Honoraria (self): Seattle Genetics; Research grant / Funding (institution): Arqule; Honoraria (self): Merck; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Origimed; Advisory / Consultancy: More Health; Advisory / Consultancy: EDO. R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy: Target Pharma Solutions; Advisory / Consultancy: Genentech/Roche. J.M. Cleary: Honoraria (self), Travel / Accommodation / Expenses: Agios; Honoraria (self), Travel / Accommodation / Expenses: BMS; Research grant / Funding (self): Merck; Research grant / Funding (self): Tesaro; Travel / Accommodation / Expenses: Roche. D.V. Catenacci: Honoraria (self): Astellas; Honoraria (self): Five Prime; Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): Lilly; Honoraria (self): Taiho; Honoraria (self): Daichii Sankyo; Honoraria (self): Genentech/Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Tempus; Honoraria (self): Guardant Health. M.J. Borad: Research grant / Funding (institution): Senhwa Pharmaceuticals; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Agios Pharmaceuticals; Research grant / Funding (institution): Halozyme Pharmaceuticals; Research grant / Funding (institution): Celgene Pharmaceuticals; Research grant / Funding (institution): EMD Merck Serono; Research grant / Funding (institution): Toray; Research grant / Funding (institution): Dicerna; Research grant / Funding (institution): Taiho Pharmaceuticals; Research grant / Funding (institution): Sun Biopharma; Research grant / Funding (institution): Isis Pharmaceuticals; Research grant / Funding (institution): Redhill Pharmaceuticals; Research grant / Funding (institution): Boston Biomed; Research grant / Funding (institution): Basilea; Research grant / Funding (institution): Incyte Pharmaceuticals; Research grant / Funding (institution): Mirna Pharmaceuticals; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bioline; Research grant / Funding (institution): Sillajen; Research grant / Funding (institution): ARIAD; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Novartis Pharmaceuticals; Research grant / Funding (institution): QED Pharmaceuticals; Research grant / Funding (institution): Pieris; Honoraria (self): Exelixis; Honoraria (self): G1 Therapeutics; Honoraria (self): Immunovative Therapies; Shareholder / Stockholder / Stock options: OncBioMune Pharmaceuticals; Honoraria (self): Western Oncolytics; Honoraria (self): Lynx Group; Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Inspyr Therapeutics; Honoraria (self): ADC Therapeuctics; Shareholder / Stockholder / Stock options: Intercept; Shareholder / Stockholder / Stock options: AVEO. J.A. Bridgewater: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Incyte; Advisory / Consultancy: Basilea; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Travel / Accommodation / Expenses: MDS Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb/Medarex; Travel / Accommodation / Expenses: Bristol-Myers Squibb. W.P. Harris: Advisory / Consultancy: NeoTherma; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Bristo-Myers Squibb; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): BTG; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Merck. A.G. Murphy: Research grant / Funding (self): Bristol-Myers Squibb. D. Oh: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. B. Wu: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Agios. L. Jiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. C. Gliser: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. S.S. Pandya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. J.W. Valle: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: NuCana; Advisory / Consultancy, Speaker Bureau / Expert testimony: Abbott; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sirtex; Advisory / Consultancy: Agios; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Baxalta; Advisory / Consultancy: Bioven; Advisory / Consultancy: Delcath; Advisory / Consultancy: Genoscience Pharma; Advisory / Consultancy: Incyte; Advisory / Consultancy: Keocyt; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Midatech; Advisory / Consultancy: Mundipharma; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: QED Pharmaceuticals. A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.