Rapid Readouts: Final Results from Phase 3 ClarIDHy Trial

Ghassan K. Abou-Alfa, MD, discusses data from the following presentation: “Final results from ClarIDHy [NCT02989857], a global, phase 3, randomized, double-blind study of ivosidenib versus placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 mutation.” (Abou-Alfa, ASCO 2021, Abstract 4069)

• The objective of this presentation was to provide the final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib vs placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 mutation (NCT02989857).
• Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), safety, and health-related quality of life (HRQOL) were among the outcomes discussed.
• Cholangiocarcinoma is a rare cancer that affects the bile duct and for which there are a limited number of effective therapeutic options.
• Isocitrate dehydrogenase 1 mutations produce an oncogenic metabolite known as D-2-hydroxyglutarate. The mutations occur in approximately 20% of patients with an intrahepatic cholangiocarcinoma diagnosis.
• Ivosidenib is an oral, noncytotoxic small molecule inhibitor of mutant isocitrate dehydrogenase 1.
• ClarIDHy compared ivosidenib with placebo in patients with unresectable or metastatic cholangiocarcinoma who had an isocitrate dehydrogenase 1 mutation.
• Initial safety and efficacy data from ClarIDHy have been published previously (Abou-Alfa, Lancet, 2020). Dr. Abou-Alfa reviewed these results, then reported updated OS, safety, and HRQOL data.
  • Investigators randomized patients 2:1 to ivosidenib 500 mg or placebo, each given orally once daily in continuous 28-day cycles. Those who received placebo and had evidence of disease progression were permitted to cross over and receive open-label ivosidenib. Investigators used the rank-preserving structural failure time (RPSFT) method to adjust for confounding inherent to crossover.
  • The primary end point of ClarIDHy was PFS as assessed by an independent radiology center (IRC). Secondary end points included OS, ORR, PFS as assessed by the study investigator, pharmacokinetics, pharmacodynamics, HRQOL, and safety and tolerability.
  • The trial included 123 patients in the ivosidenib arm and 59 patients in the placebo arm. By study end, 43 patients who had initially received placebo crossed over to receive ivosidenib based on radiographic disease progression. A total of 25 patients, including 6 who crossed over from placebo, remained on ivosidenib for 1 year or more. Dr. Abou-Alfa highlighted the fact that 8 patients were still receiving ivosidenib by study end compared with 0 in the placebo group.
  • Median PFS as assessed by IRC was significantly longer in the ivosidenib arm vs the placebo arm (2.7 months vs 1.4 months, respectively; HR 0.37; P < .0001).
  • Median OS was 10.3 months in the ivosidenib arm and 5.1 months in the RPSFT-adjusted placebo arm (HR, 0.49; P < .0001).
  • By study end, a total of 166 patients had received ivosidenib (123 initially assigned plus 43 who crossed over). A numerically lower percentage of patients who received ivosidenib discontinued the drug due to treatment-emergent adverse events compared with those who received placebo (6.6% vs 8.5%, respectively).
  • HRQOL questionnaire results significantly favored ivosidenib in the areas of physical functioning, cognitive functioning, emotional functioning, pain, dyspnea, anxiety, and tiredness. Patients who received ivosidenib also scored better with appetite loss and eating, although the difference compared with those who received placebo did not reach statistical significance.
  • These efficacy data, coupled with the tolerable safety and HRQOL data, have helped to demonstrate the clinical benefit of ivosidenib in patients with cholangiocarcinoma who have an isocitrate dehydrogenase 1 mutation. A supplemental drug application was filed with the FDA for ivosidenib in early 2021.
• Dr. Abou-Alfa closed with some final thoughts on how these data will impact treatment.
  • Ivosidenib is a first-in-class, noncytotoxic, nonchemotherapeutic agent that offers survival benefit to the 20% of patients with cholangiocarcinoma who have the isocitrate dehydrogenase 1 mutation. Its approval by the FDA is greatly anticipated.