Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation.

Author:

Abou-Alfa Ghassan K.1,Macarulla Teresa2,Javle Milind M.3,Kelley Robin Kate4,Lubner Sam Joseph5,Adeva Jorge6,Cleary James M.7,Catenacci Daniel V.T.8,Borad Mitesh J.9,Bridgewater John A.10,Harris William Proctor11,Murphy Adrian Gerard12,Oh Do-Youn13,Whisenant Jonathan R.14,Chamberlain Christina X.15,Jiang Liewen15,Gliser Camelia15,Pandya Shuchi Sumant15,Valle Juan W.16,Zhu Andrew X.17

Affiliation:

1. Memorial Sloan Kettering Cancer Center & Weill Medical College at Cornell University, New York, NY;

2. Hospital Universitario Vall d'Hebron, Barcelona, Spain;

3. MD Anderson Cancer Center, Houston, TX;

4. University of California San Francisco, San Francisco, CA;

5. University of Wisconsin Carbone Cancer Center, Madison, WI;

6. Hospital Universitario 12 de Octubre, Madrid, Spain;

7. Dana Farber Cancer Institute, Boston, MA;

8. University of Chicago Medical Center, Chicago, IL;

9. Mayo Clinic, Scottsdale, AZ;

10. UCL Cancer Institute, London, United Kingdom;

11. University of Washington, Seattle, WA;

12. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD;

13. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea;

14. Utah Cancer Specialists, Murray, UT;

15. Agios Pharmaceuticals, Inc., Cambridge, MA;

16. University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom;

17. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA;

Abstract

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Funder

Agios Pharmaceuticals, Inc

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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